\r\n\tMain emphasis should be on its applications. In every field MOFs can be used due to its greater stability and high surface area, but the focus should be on applications.
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Introduction
Cancer has a major impact on society across the world. Estimated number of new cases of cancer, current cases of cancer, deaths, survival rate, mortality and in depth information, symptoms of cancer, its early detection, prevention and treatment all are provided by American Cancer Society. Nearly 13% of cancer diagnosed in 2017 was in the young at age of 20. The new review statistics shows 28 types of rare cancer which talks about mortality rate, survival, diagnosis and also provides an idea about symptoms and risk factors related to different types of cancer [1].
Therapeutic approaches such as development of nanoemulsions, liposomes, microspheres and nanoparticles have facilitated in fighting cancer. Among these, the simplest platforms are the nanoemulsion having size range of 100 to 500 nm which are kinetically stabilized having high content of oil and low amount of surfactant [2]. Solubility of poorly soluble drugs [3, 4] and its bioavailability can be increased by converting the drug into forms like capsule and gels [5] or can be used in their original form. The method used for the fabrication of nanoemulsion are high energy methods (microfluidization and sonication) and low energy emulsification method [6, 7, 8].
Theranostics is a term originally coined to define an approach that combine’s diagnostics with therapeutics [9]. It embraces multiple techniques to arrive at comprehensive diagnosis, molecular images and an individualized treatment regimen [10, 11]. Recently, there is an effort to tangle the emerging approach with nanotechnologies, in an attempt to develop theranostic nanoplatforms and methodologies [12]. Given that cancer is a highly heterogeneous and adaptable disease, diverse types of treatment options need to be chosen depending on patient’s characteristics and disease progression.
2. Theranostics
Drugs or methods that are used for accompanying diagnosis and cure [13] are referred to as Theranostics. One of the achievements of nanotechnology is the fabrication of theranostic nanomedicine for the preparation of these types of drugs. The term defines “a nanotherapeutic system which can deliver targeted therapy and diagnose”. This aspect provides help when fabricating nano based image contrasting agent and also in image guided therapeutics [14].
Rapid drug development, advanced disease management, reduced associated risk and cost are assumed to be the result of mutual techniques. Such type of investigation which involves quick diagnosis and treatment are very helpful in disease which are a major cause of morbidity and/or mortality and cancer is one of the disease and coincidently the initial research in theranostic is dedicated to oncology. Sound knowledge, core understanding of detection and therapy mechanism are required for the formation of theranostic agents. In order to fabricate theranostic agents one should have understanding of diagnostic strategies, molecular mechanism adverse effect and toxicity of material and techniques for nanoparticles preparation for therapy and diagnostic purpose.
Research in theranostics has rapidly improved in the past decade resulting into preparation of different contrast media and active ingredient with different method of preparation. Preparation of dual purpose nanoparticle system is the main aim of theranostics. Therefore it is important to put attention on all factors that influences the process, right from the preparation of nanoemulsion/nanoparticle till the removal of metabolites of the active molecules and other materials used. The factors can be the compatibility between chemicals, the condition in which the formulation is prepared, modification in formulations because of selected route of administration, the toxicity, metabolites of active ingredient, its biocompatibility and biodegradability and evaluation of pharmacodynamic and pharmacokinetic parameter and eventually the disadvantage and benefits of the process.
The basis of diagnosis in theranostics depends upon using different contrast agent during imaging. MRI is the most studied and used technique among all different imaging mechanism and a lot has been spent on research related to magnetic particles used as contrasting agent. Metals like gold, silver, iron oxide have been studied with the object of finding suitable particle for imaging with least toxicological effect. Diseased tissue and healthy tissue are differentiated in MRI by the use of these particles.
As stated one of the brutal disease is cancer and hence theranostic research has put an eye on this area. Day by day the research is going on in positive direction and much useful research has already been carried out. In order to understand the concept of diagnosis of cancer and therapy related to it the use of nanoparticle agents is in progression [27, 28]. One such example of theranostic agent is manganese oxide nanoparticle carrying drugs and contrast agents [29] and silica nanoparticle with magnetic and fluorescent tags [30]. In the past few years, combination of metal nanoparticle or shells [31, 32, 33] with magnetic components has yielded different theranostic agents for biomedical applications which are widely used. Some examples of theranostic agents are given in Table 1.
Contrast agent | Drug used | Applications | Size | Zeta potential | References |
---|
Manganese oxide | siRNA | MRI plus RNA delivery | — | — | [15] |
Gold | DOX Diagnosis | tumor targeting and PTT | 45.97 nm and 6.3 nm | −3.54 mV | [16, 17, 18] |
Iron oxide | siRNA, DOX, docetaxel | Targeting, MRI and therapy | 30 nm | −5 mV | [19, 20, 21] |
Silica | Pyropheophorbide (HPPH), DOX | Drug carrier, X-ray/CT imaging, Photodynamic therapy | 30 nm and 126 nm | −39 mV | [22, 23] |
CNTs | DNA plasmid, DOX, PTX | Diagnosis, DNA and drug delivery | 20 nm and 120.6 nm | — | [24, 25] |
QDs | DOX, MTX | Imaging, therapy and sensing | — | — | [26] |
Table 1.
Different theranostic agents used for biomedical applications.
Abbreviations: siRNA: short interfering ribonucleic acid, CNTs: carbon nanotubes, QDs: quantum dots, DOX: Doxorubicin, HPPH: 2-[1-hexyloxyethyl]-2-devinyl pyropheophorbide-alpha, MTX: Methotrexate, PTX: Paclitaxel, MRI: Magnetic resonance imaging, CT: Computed topography.
3. Nano theranostics
Theranostic nanosystems comprise of platforms/nanocarriers that are used as imaging as well as therapeutic agents via a single entity. Nanotheranostic devices can be made by many types of inorganic and organic nanomaterials. Preclinical implementations make use of nanotheranostic system because they might provide a way or method of understanding many crucial aspects of drug delivery and how these systems can assist in knowing the power of personalized medicines.
4. Therapeutic agents
At present radiotherapy, surgery and chemotherapy are possible treatments for cancer patients. The purpose of the theranostic is to use these therapeutic strategies and reduce the risk associated with chemotherapy and radiotherapy and in addition to it avoid complications related to surgery and trauma. In addition, with the help of nanotechnology, theranostics may support the diversification of therapeutic approaches like PTT, PDT and immunotherapy. Here we report some of these therapeutic strategies often used in theranostics, like radiotherapy, chemotherapy, PDT, PTT and immunotherapy.
5. Chemotherapy for management of cancer
Anticancer drugs have proven beneficial in improving survival rate of cancer patients [34]. There are huge numbers of clinical anti-cancer drugs which are broadly applied to theranostics. On the basis of structure and resource of chemotherapy drugs, cancer therapeutic agents can be classified into six types: alkylating agent, antitumor antibiotic, phytogenic anticarcinogen, antimetabolites, hormone and miscellaneous anti-cancer drugs. Thermo DOX for liver cancer, Doxil for ovarian cancer therapy and Myocet for metastatic breast cancer are few cancer nanomedicines that have been approved by the FDA. Theranostic systems also make use of prodrugs like platinum (IV) prodrug to reduce the toxicity of drug and by increasing the active hits to the cells of tumors site. Due to their broad availability these prodrugs are very popular option. The UV light is transformed from NIR light by UCNP which activates the prodrugs to highly toxic platinum (II) complexes that enters the cell by endocytosis after grafted onto up converting nanoparticles (UCNP) [35]. In order to attain best therapeutic efficacy of drug delivery systems a high payload is essential. In theranostics, in order to maintain the original size and solubility in aqueous media a carrier with large pore volume and surface area are given preferences so that more therapeutic agent can be carried [36]. For example, Sorafenib with a loading ration of 28.2% can be loaded on porous silica nanoparticles and may release the therapeutic agent in sustained fashion [37]. GO, Ws2 and MoS2 are some of the popular 2-D nanomaterials that have a very high drug payload as they can bear chemotherapeutics on both sides of sheet. Some of the example of high drug payload include 118% for 7-ethyl-10-hydroxycamptothecin (SN38) and approx 239% for DOX were observed on MoS2 [38], DOX (approximately 400%) on GO [39] was also significant. Cancer cells show multidrug resistance (MDR) often when they are treated by single drug which can be overcome by employing efficient strategies of theranostics. By combining P-glycoprotein (P-gp) reversing agent with anticancer drug the hurdle of MDR can be resolved [40]. The function of P-gp reversing agent is to avoid the pumping of chemotherapeutic drugs out of cancer cells due to over expression of P-gp. One way to overcome MDR is by covering the positive change that is present on anticancer drugs. DOX alone cannot produce significant cancer effect but when it is adsorbed on the surface of polymeric nanoparticle more chance are there that cancer cell may readily uptake it and accumulate within cancer cell and produce more cytotoxicity to cancer cell. Nanocarriers loaded with combination of anticancer drugs provide synergistic effect thereby improving overall management of cancer [41, 42].
6. Photothermal therapy for management of cancer
Microwave, light irradiation or magnetic field can potentiate the effect of thermal therapy which in turn employs hyperthermia to kill cancer cells. Among all the above mentioned therapies photothermal therapy has the maximum capacity to destroy cancer cell while causing least damage to nearby healthy cells. Localized hyperthermia under light irradiation at tumor site is generated by using NIR absorbing agent in photothermal therapy [43]. In MR region an ideal PTT agent should show strong absorbance and must exhibit less fluorescence quantum yield thereby promoting efficient conversion of absorbed light energy into heat via non-radiative transition rather than fluorescence emission.
Inorganic nanoparticles and organic dyes are extensively employed as PTT agents. Examples of organic dyes include Prussian blue, IR780, ICG, IR820, Cypate, IR825. These organic dyes have an added advantage of ease of loading on nanoplatforms and ideal NIR absorbance [44]. In order to improve the photostability and targeting ability of organic dyes they are being encapsulated into nanocarriers [45]. Carbocyanine dyes namely cypate and ICG were loaded into the polymeric micelle with loading rate of 50% and 20% for cypate and ICG respectively. Upon comparing loaded theranostic polymeric micelle with carbocyanine dye alone showed marked cellular uptake and longer retention time at the site of tumor. Remarkable PTT results were observed along with increased photothermal effect and photostability of organic dyes when nanomaterials like graphene derivatives absorbing strongly in the NIR regions were employed [46]. In NIR and PTT imaging techniques both cypate and ICG can be used as theranostic agents.
Photothermal conversion efficiency will decrease in presence of high fluorescence quantum yield and fluorescence imaging is disturbed in case of low quantum yield hence there is not much surety in theranostic application of organic dyes. Apart from the organic dyes, a wide range of inorganic nanoparticles have been fabricated for theranostic applications. Inorganic nanoparticles exhibit strong photothermal conversion efficiency and NIR absorption for PTT. It encompasses customized gold nanostructure like nanoshell, nanocages, nanorods and nanotubes. On comparing the gold nanorods alone against gold nanorods coated with Pt nanodots, the latter showed significant better photothermal effect than the former [47]. And the better results were due to the presence of Pt shell in the endosomes which not only prevented the original sharp LSPR band of gold nanorods from shifting and dampening but also prevented the aggregation of gold nanorods. Carbon nanotubes [48], carbon dots [49], GO are some of the other nanomaterials that can used for PTT. GO for in-vivo PTT was used for the first time by Liu group. Further they reduced the GO to rGO which had 7 times more NIR absorption than GO hence increasing the PTT effect [50]. PTT for now might only be used for treating skin cancer and not for internal cancer because of limiting light penetration depth but its noteworthy therapeutics capacities with minimum possible side effect cannot be ignored. Further study is required to get deeper insight about how phototoxicity is caused by PTT.
Apart from PTT, hyperthermia induced magnetically is also one of the non-invasive procedures to treat cancer [51]. Dielectric constant and microwave frequency between malignant tissue and normal tissue in breast can be employed for the detection and treatment of breast cancer. Dielectric contrast is used for scattering of an illuminating microwave signal and the incident microwave produces hyperthermia thereby treating malignant tissues [52].
7. Photodynamic therapy for management of cancer
Photosensitizers (PSs) used in PDT plays a vital role in the treatment of cancer and possess enormous potential. Cytotoxic reactive oxygen species or free radicals are generated when the molecular oxygen surrounding the diseased cell reacts with the absorbed light that is being transferred by PSs under laser irradiation which finally causes cell apoptosis and damage to cancerous cells [53]. No side effects are observed from photosensitizes and generate ROS only when laser light is irradiated upon them.
PDT requires low light density to cause damage to cancer cell unlike the PTT which requires high density laser light to generate hyperthermia that can cause damage to cancer cells [54]. PDT encompasses noteworthy advantages like very less invasiveness, on repeating the therapy is show no cumulative toxicity, very less damage to immune and hemopoietic system thereby improving the overall health and contributing to quality life for the patient. An ideal PS must have following properties like triplet state formation of high quantum yield and a good amount of triplet lifetime so that interaction with ground state oxygen is possible thereby generating sufficient ROS. However many PSs does not have good tumor selectivity, good amount of photosensitivity and absorption maxima above 700 nm [55]. A distinctive NIR absorption at 700 nm was observed by the help of extra axial mob linkers in monosubstituted phthalocyanine [56] that produced 20 nm red shift of characteristic Q band. PEG functionalized iron oxide nanocluster surface when loaded with Ce6 the absorption peak of chlorine e6 (Ce6) showed red shift from 650 nm to 704 nm [57]. The energy transferred from UCNPs to PSs are able to excite the combination of PSs and UCNP’s, therefore inhibiting the growth of tumor by generation of cytotoxic singlet oxygen [58].
8. Radiation therapy for management of cancer
Radiation therapy has become an integral part to treat many sarcomas. The mechanism of action of radiation therapy is that the radiation damages strings of DNA in the nucleus of cells which stops the cell multiplication. Apart from aforementioned functions of radiation therapy, it also produces reactive oxygen therapy (ROS) which indirectly damages the tumor cell and also damages the DNA of mitochondria and other organelle of cell. In case of surgical resection, the survival could be prolonged by employing radiation therapy. However due to frequent and repeated high dose of X-ray irradiation that causes systemic side effects and resistance to radiation had been noticed in cancerous cells.
Metal nanoparticles in strong association with strong capacities of photoelectric absorbance are used as radiation dose enhancing agents. For example research shows that radio sensitization is being mediated by Gold NP due to greater energy deposition and absorption in surrounding tissue from photoelectrons. Radiotherapy with prolonged circulation time in blood has been demonstrated by Auger electrons and characteristic X-rays [59] and polyethylene glycosylation modified gold nanoparticle (N GNPs). Radiotherapy can relieve the symptoms and prolong the lives of terminal cancer patients. However radiotherapy is not an easy task and may cause loss of organ functions also as it may also induce many complications. Moreover, it cannot completely remove cancer cells. In coming future we may see highly accurate and precise exposure of tumor site to high radiation by the application of radiation wave knife for much better clinical results.
9. Immunotherapy for management of cancer
After radiotherapy, surgery or chemotherapy it has been observed that a small number of cancer cells may still remain alive and in addition to it the overall treatment quality is also decreased due to drug resistance. Immunotherapy has great potential to treat cancer as it acts on the immune system rather than on the tumor itself. Immunotherapy is considered as a unique and promising strategy for cancer therapy [60] and the main advantages include its specific promotion on immune cells only aiming on target cells or target tissues. So far, the related investigations have been gradually transformed from laboratory research to clinical practice. For clinical treatment the use of immunotherapeutic drugs such as immune checkpoint inhibitors and T cells have been approved by FDA and have great potential for cancer treatment. Improved immunotherapeutic nanomaterials loaded with antigens, immune adjuvants and nucleic acids have been demonstrated to be helpful. The nanoplatforms may affect and alter immune cell actions and response non-specifically. They may easily damage the cancer cells and achieve tumor targeting with pathogens factors. For e.g. repetitive and homogenous antigens conjugated with gold nanoparticles are able to trigger immune response in an in-vitro setting even without the use of adjuvant. Recently a combination of IR phthalocyanine dye IR700 with monoclonal antibodies had been fabricated and this novel technique is known as Photoimmunotherapy [61]. Least side effect and significantly fast cell necrosis rate is observed when antibodies bind to target tumor cells during the PIT and is activated by NIR light irradiation. Hence for monitoring and treating cancer in a highly selective manner PIT is a good theranostic approach.
10. Multimodal therapy for management of cancer
Conventional cancer therapies often do not succeed to eradicate tumor completely. In order to recover anticancer efficacy, the arrangement of two or more therapeutic modalities such as chemo photodynamic, photothermal photodynamic, chemo photo thermal synergistic formulations have been explored. Thermomotherapeutic characteristics in association with theranostic methods result in development of anticancer drug that possess synergistic therapeutic effect [62]. Chemotherapy could be improved by the use of photothermal effect which aids the intracellular translocation of anti-cancer drugs [63]. Risk of overtreatment could be minimized along with the reduction in dose of therapeutic agent with less laser exposure time. All these can be attained by combination of PDT/PTT. Synergistic effect of PTT/PDT have been seen when GO was loaded with methylene blue [64]. In this system, lesser dose of nano GO was applied, as compared to the particular PTT treatment of nano GO. In addition, the PTT and PDT combinational treatment could be spoil both superficial and deep regions of the tumor, and thus overcome the drawbacks of single treatments [65]. To further progress cancer therapy efficacy, numerous types of theranostic platforms were developed to combine chemotherapy, PTT and PDT simultaneously [66]. Treating cancer with combinational therapy has become an essential trend in cancer therapeutics. Compared to single modality therapy, the combined therapy can reduce the dosage of the drugs and thus decrease the side effects in treatment. More prominently, the combined therapy has the potential to decrease multidrug resistance of tumor cells, thus improving the therapeutic efficacy. The combined therapy may bring a novel opportunity to the next invention of cancer treatment [67].
11. Imaging-guided therapy for management of cancer
The theranostic nanoparticles have an ever increasing consideration for image guided therapy in current years because these nanoparticles can follow the pharmacokinetic process, guide the treatment and monitor therapeutic process and outcome. They could be employed to imagine and quantify the performance of drug delivery systems for numerous special purposes such as biodistribution and pharmacokinetics of nanocarriers, metabolic response and drug release process of the nanocarriers. Koukourakis group and Harrington group engaged Technetium and Indium labeled PEGylated liposomes respectively to monitor drug targeting to the sarcomas and breast cancer sites [69]. In the clinical practice, surgical resection is a regular and inevitable procedure for cancer therapy. Theranostics gives a possibility in intraoperative imaging to guide the operation process. During the surgery, physicians could congregate the diagnostic information for precise imaging as well as visualized therapy. In theranostic platform, DOTA-Gd act as a MRI contrast agent for preoperative finding and surgical planning; the Raman molecules visualized the excellent margin of tumor, allowing precise resection for the duration of operation process. The multimodal NP could recognize tumor edge for precise resection of tumor. This approach could be planned for simple intraoperative navigation and real-time imaging [70]. Theranostic technologies commonly utilized for cancer treatment are given in Table 2.
Imaging method | Imaging agent | Therapeutic agent | Function |
---|
Optical Imaging | Cy5.5 | Paclitaxel | Real time tracking of NP location |
FITC-coumarin pair | Doxorubicin | Drug release monitoring |
Dicyanomethylene-4H-pyran | Camptothecin | Drug release monitoring |
Cy7, 111In | Cyclophosphamide, etoposide | Real time imaging of apoptosis |
Cy5.5-BHQ pair | Doxorubicin | Real time imaging of apoptosis |
Ce6 | Ce6 | Real time tracking of NP location & PDT |
Ce6-BHQ pair | Ce6 | Drug release monitoring & PDT |
UCNP (β-NaYF4:Yb3+,Er3+) | Cisplatin prodrug | Imaging of NP location |
UCNP (NaYF4:Er) | TPGSd | Dual imaging (optical, CT) & reducing multidrug resistance |
UCNP (NaYF4:Yb/Er) | Ce6, doxorubicin | Imaging of particle location & chemotherapy/PDT |
MR imaging | Gd | Doxorubicin | Real time monitoring of drug delivery |
SPION | SPION | Detection & hyperthermia treatment of tumor |
SPION | Doxorubicin | Tumor detection & chemotherapy |
SPION/FITC | siRNA | MR imaging & gene therapy |
CT imaging | GNP | Doxorubicin | CT imaging of cancer & chemotherapy |
GNR | GNR | Dual imaging (X-ray/CT) & PTT/radio sensitization |
PET Imaging | 64Cu | Doxorubicin | Quantitative biodistribution analysis & Chemotherapy |
64Cu | siRNA | Quantitative determination of biodistribution & efficacy of siRNA NPs |
US imaging | Perfluoropentane | Docetaxel | Triggered drug release & chemotherapy |
CaCO3 | Doxorubicin | Tumor imaging & triggered drug release |
Perfluorooctyl bromide | Camptothecin | Chemotherapy & ablation therapy |
Perfluorohexane | CPT11m | Tumor imaging & chemotherapy/ablation Therapy |
Table 2.
Theranostic technologies for cancer treatment [68].
12. Conclusion
Theranostic approach to management of cancer offers numerous advantages. They are designed to monitor cancer treatment in real time. A wide variety of theranostic nanoplatforms that are based on diverse nanostructures like magnetic nanoparticles, carbon nanotubes, gold nanomaterials, polymeric nanoparticles, or silica nanoparticles showed great potential as cancer theranostics. Nano therapeutic platforms have been successful in integrating image guidance with targeted approach to treat cancer.
Conflict of interest
Authors declare no conflict of interest related to this manuscript.
Abbreviations
PTT | Photothermal therapy |
PDT | Photodynamic therapy |
DOX | Doxorubicin |
NIR | Near infrared |
MRI | Magnetic resonance imaging |
PET | Positron emission tomography |
CT | Computed topography |
UNCPs | Up converting nanoparticles |
GO | Grapheme oxide |
MDR | Multidrug resistance |
MoS2 | Molybdenum disulfide |
ICG | Indocyanine green |
WS2 | Tungsten disulfide |
Ce6 | Chlorine e6 |
\n',keywords:"nanomedicine, theranostics, targeted delivery, cancer, functionalized nanomedicine",chapterPDFUrl:"https://cdn.intechopen.com/pdfs/73727.pdf",chapterXML:"https://mts.intechopen.com/source/xml/73727.xml",downloadPdfUrl:"/chapter/pdf-download/73727",previewPdfUrl:"/chapter/pdf-preview/73727",totalDownloads:128,totalViews:0,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:1,dateSubmitted:"August 19th 2020",dateReviewed:"October 8th 2020",datePrePublished:"October 27th 2020",datePublished:"December 16th 2020",dateFinished:"October 27th 2020",readingETA:"0",abstract:"Cancer is a leading cause of mortality worldwide, accounting for 8.8 million deaths in 2015. The landscape of cancer therapeutics is rapidly advancing with development of new and sophisticated approaches to diagnostic testing. Treatment plan for early diagnosed patients include radiation therapy, tumor ablation, surgery, immunotherapy and chemotherapy. However the treatment can only be initiated when the cancer has been diagnosed thoroughly. Theranostics is a term that combines diagnostics with therapeutics. It embraces multiple techniques to arrive at comprehensive diagnosis, molecular images and an individualized treatment regimen. Recently, there is an effort to tangle the emerging approach with nanotechnologies, in an attempt to develop theranostic nanoplatforms and methodologies. Theranostic approach to management of cancer offers numerous advantages. They are designed to monitor cancer treatment in real time. A wide variety of theranostic nanoplatforms that are based on diverse nanostructures like magnetic nanoparticles, carbon nanotubes, gold nanomaterials, polymeric nanoparticles and silica nanoparticles showed great potential as cancer theranostics. Nano therapeutic platforms have been successful in integrating image guidance with targeted approach to treat cancer.",reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/73727",risUrl:"/chapter/ris/73727",book:{slug:"molecular-pharmacology"},signatures:"Asad Ali, Zeeshan Ahmad, Usama Ahmad, Mohd Muazzam Khan, Md. Faheem Haider and Juber Akhtar",authors:[{id:"252107",title:"Dr.",name:"Juber",middleName:null,surname:"Akhtar",fullName:"Juber Akhtar",slug:"juber-akhtar",email:"juberakhtar@gmail.com",position:null,institution:null},{id:"255360",title:"Dr.",name:"Usama",middleName:null,surname:"Ahmad",fullName:"Usama Ahmad",slug:"usama-ahmad",email:"usamaahmad.10@outlook.com",position:null,institution:{name:"Integral University",institutionURL:null,country:{name:"India"}}},{id:"329245",title:"Dr.",name:"Asad",middleName:null,surname:"Ali",fullName:"Asad Ali",slug:"asad-ali",email:"16asadali1991@gmail.com",position:null,institution:null},{id:"329246",title:"Dr.",name:"Zeeshan",middleName:null,surname:"Ahmad",fullName:"Zeeshan Ahmad",slug:"zeeshan-ahmad",email:"zeeshanahmad2086@gmail.com",position:null,institution:null},{id:"329247",title:"Dr.",name:"Mohd",middleName:null,surname:"Muazzam Khan",fullName:"Mohd Muazzam Khan",slug:"mohd-muazzam-khan",email:"khanmuazzam936@gmail.com",position:null,institution:null},{id:"329248",title:"Dr.",name:"Md. Faheem",middleName:null,surname:"Haider",fullName:"Md. Faheem Haider",slug:"md.-faheem-haider",email:"fhaider89@gmail.com",position:null,institution:null}],sections:[{id:"sec_1",title:"1. Introduction",level:"1"},{id:"sec_2",title:"2. Theranostics",level:"1"},{id:"sec_3",title:"3. Nano theranostics",level:"1"},{id:"sec_4",title:"4. Therapeutic agents",level:"1"},{id:"sec_5",title:"5. Chemotherapy for management of cancer",level:"1"},{id:"sec_6",title:"6. Photothermal therapy for management of cancer",level:"1"},{id:"sec_7",title:"7. Photodynamic therapy for management of cancer",level:"1"},{id:"sec_8",title:"8. Radiation therapy for management of cancer",level:"1"},{id:"sec_9",title:"9. Immunotherapy for management of cancer",level:"1"},{id:"sec_10",title:"10. Multimodal therapy for management of cancer",level:"1"},{id:"sec_11",title:"11. Imaging-guided therapy for management of cancer",level:"1"},{id:"sec_12",title:"12. Conclusion",level:"1"},{id:"sec_16",title:"Conflict of interest",level:"1"},{id:"sec_15",title:"Abbreviations",level:"1"}],chapterReferences:[{id:"B1",body:'[https://www.cancer.org/research/cancer-facts-statistics/all-cancer-facts-figures/cancer-facts-figures-2017.html (last accessed on 01/08/2020)]'},{id:"B2",body:'[McClements DJ. Nanoemulsions versus microemulsions: Terminology, differences, and similarities. Soft Matter. 2012;8(6):1719-1729]'},{id:"B3",body:'[Ahmad, U., Akhtar, J., Singh, S.P., Badruddeen, Ahmad, F.J., Siddiqui, S. and Wahajuddin, 2017. Silymarin nanoemulsion against human hepatocellular carcinoma: development and optimization. Artificial cells, nanomedicine, and biotechnology, 46(2), pp.231-241]'},{id:"B4",body:'[Shakeel F, Shafiq S, Haq N, Alanazi FK, Alsarra IA. Nanoemulsions as potential vehicles for transdermal and dermal delivery of hydrophobic compounds: An overview. Expert Opinion on Drug Delivery. 2012;9(8):953-974]'},{id:"B5",body:'[Sarker DK. 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Theranostics. 2016;6(9):1362]'},{id:"B69",body:'[Koukourakis Sofia Koukouraki, Alexandra Giatromanolaki, SteliosKakolyris, VassilisGeorgoulias, AntigoniVelidaki, SpyridonArchimandritis and Nikolaos N. Karkavitsas, M.I., 2000. High intratumoral accumulation of stealth liposomal doxorubicin in sarcomas: rationale for combination with radiotherapy. Actaoncologica, 39(2), pp.207-211]'},{id:"B70",body:'[Kircher MF, De La Zerda A, Jokerst JV, Zavaleta CL, Kempen PJ, Mittra E, et al. A brain tumor molecular imaging strategy using a new triple-modality MRI-photoacoustic-Raman nanoparticle. Nature Medicine. 2012;18(5):829]'}],footnotes:[],contributors:[{corresp:null,contributorFullName:"Asad Ali",address:null,affiliation:'- Faculty of Pharmacy Integral University, India
'},{corresp:null,contributorFullName:"Zeeshan Ahmad",address:null,affiliation:'- Makams Industries Private Limited, India
'},{corresp:"yes",contributorFullName:"Usama Ahmad",address:"usamaahmad.10@outlook.com",affiliation:'- Faculty of Pharmacy Integral University, India
'},{corresp:null,contributorFullName:"Mohd Muazzam Khan",address:null,affiliation:'- Faculty of Pharmacy Integral University, India
'},{corresp:null,contributorFullName:"Md. Faheem Haider",address:null,affiliation:'- Faculty of Pharmacy Integral University, India
'},{corresp:null,contributorFullName:"Juber Akhtar",address:null,affiliation:'- Faculty of Pharmacy Integral University, India
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Kiang, Risaku Fukumoto and Nikolai V. 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Konieczko",authors:[{id:"141806",title:"Dr.",name:"Mary",middleName:null,surname:"Vagula",fullName:"Mary Vagula",slug:"mary-vagula"},{id:"150947",title:"Prof.",name:"Elisa",middleName:null,surname:"Konieczko",fullName:"Elisa Konieczko",slug:"elisa-konieczko"}]}]}]},onlineFirst:{chapter:{type:"chapter",id:"74693",title:"Nutritional Deficiencies Post Bariatric Surgery: A Forgotten Area Impacting Long-Term Success and Quality of Life",doi:"10.5772/intechopen.95123",slug:"nutritional-deficiencies-post-bariatric-surgery-a-forgotten-area-impacting-long-term-success-and-qua",body:'1. Introduction
Bariatric surgery (BS) has proven to be an effective treatment for weight loss, reducing obesity associated comorbidities, improving quality of life, and reducing mortality rates [1, 2]. The increasing amount of evidence on the benefits of BS has contributed to its increased popularity over the last decade [1]. Despite the proven benefits of BS, it also carries the risk of short- and long-term complications. An important complication is the nutritional and micronutrient deficiencies. Nutritional deficiencies can present with a wide range of clinical manifestations, depending on the specific nutrients/micronutrients that are involved, the severity, and the duration of the deficiency states. Additionally, these deficiencies can worsen over time, leading to severe consequences, such as anemia (iron, folate, B12), peripheral neuropathy (folate, B6, B12, copper), Wernicke encephalopathy (B1) and metabolic bone disease (vitamin D, calcium). Therefore, lifelong screening of individuals who had undergone bariatric surgery is critical to identify these complications and treat them effectively to ensure long-term success. This chapter will provide a comprehensive review of these nutritional complications. The chapter will also furnish information about the recommended micronutrient supplementations and nutritional follow-up.
2. Micronutrient deficiencies prior to bariatric surgery
Nutritional deficiencies often exist prior to BS [3, 4, 5]. Subjects with obesity typically adopt an unhealthy high calorie, low quality diet with unbalanced nutritional composition [6]. For instance, one study showed that in female BS candidates, despite consumption of high-caloric diet (2801 ± 970 kcal/day), 66% of them had at least a single micronutrient deficiency [7]. Prior to BS, low iron, ferritin, vitamin B12 and hemoglobin were observed among 12.6%, 8.7%, 10.6% and 7.7%, of patients respectively [7]; and the incidence of folate deficiency before BS was 26.8% [8]. Vitamin D deficiency is the most common deficiency in patients undergoing BS with a prevalence as high as 78.8% [7, 8].
Research found that low preoperative levels of hemoglobin, vitamin B12, and ferritin were independently associated with reduction in the levels of micronutrients postoperatively [8]. Moreover, vitamins D and B1 and albumin deficiencies before BS predicted deficiencies one year after surgery [8].
Such findings highlight the need for complete nutritional assessments and adequate correction of pre-existing deficits before BS. Therefore, all BS candidates must undergo appropriate nutritional evaluation, including micronutrient measurements at least once preoperatively. Screening should include iron studies, and vitamins D and B12 and folic acid levels. The repetition of the tests until surgery should be individualized as clinically indicated [9, 10]. In comparison with purely restrictive procedures, more extensive nutritional evaluations are required for malabsorptive procedures. For instance, thiamine and vitamins A and E levels may be assessed in patients prior to Roux en Y gastric bypass (RYGB) and biliopancreatic diversion with duodenal switch (BPD/DS) [10].
Deficiencies found on screening prior to BS should be treated accordingly to avoid worsening of the symptoms post-surgery [9]. For vitamin D, there is a lack of solid evidence regarding the cutoff value where treatment should be started. A group of experts advocated supplementation in all patients with values below 20 ng/mL, and in an individualized manner for values between 21 and 30 ng/mL [9].
3. Micronutrient deficiencies post bariatric surgery
3.1 Causes of micronutrient deficiencies post bariatric surgery
Several factors and mechanisms contribute to the development of nutritional deficiencies post BS. Below are some examples:
3.1.1 Non-compliance with nutritional supplementation
Nonadherence to the recommended nutritional supplementation is recognized as a critical factor that leads to nutritional deficiency after BS. Compliance with multivitamins tends to be good in the early post-surgery period and decreases on the long term. For instance, a study of 16,620 patients post BS showed that the pharmacy dispensing of micronutrient supplements by patients significantly decreased between the first and fifth years for iron (from 27.7 to 24.5%), calcium (from 14·4 to 7·7%), but increased for vitamin D (from 33·1 to 34·7%) [11]. Barriers to vitamin adherence post BS include forgetting to take the supplementation and difficulty in swallowing the pills [12].
3.1.2 Lack of follow up
Despite clear international guidelines, long-term follow-up after BS is poor. A study assessed the follow up with the bariatric surgeon after RYGB and demonstrated a significant increase in the time between follow ups (13.3 ± 7.8 vs. 86.9 ± 39.9 months) in the long-term [13]. The same study demonstrated that a shorter time since last surgeon visit was independently predictive of multivitamin use (p = 0.001) [13]. Research also reported that male sex, younger age, absence of type 2 diabetes and poor 1-year follow-up were predictors of poor 5-year follow-up [11].
3.1.3 Other causes
Other contributing factors include pre-operative deficiencies, post-surgery food intolerance, poor eating habits, vomiting, changes in taste and eating patterns [14].
3.2 Mechanisms of micronutrient deficiency after bariatric surgery
The underling mechanisms that contribute to micronutrient deficiency following BS include reduced food intake due to restrictive effect of surgery, rerouting of nutrient flow which affect absorption, and changes in gastrointestinal anatomy/physiology post-surgery. It is important to note that the anatomical changes and the mechanisms of action of the various procedures dictate the frequency and severity of nutritional deficiencies after BS. For instance, micronutrient deficiencies are less common in restrictive procedures such as gastric banding (LAGB) and laparoscopic sleeve gastrectomy (LSG), where there are no alterations of the intestinal continuity and normal digestive processes. However, micronutrient deficiencies are more common after surgical procedures that cause malabsorption such as RYGB, one-anastomosis gastric bypass (OAGB), single anastomosis duodeno–ileal bypass with sleeve gastrectomy (SADI-S) and BPD/DS [10, 15].
3.3 Water soluble vitamin deficiency post bariatric surgery
3.3.1 Vitamin B1 (thiamin)
Vitamin B1 is absorbed in the jejunum and therefore may be excluded from absorption after RYGB and BPD/DS [16]. Additionally, the storage of thiamine is low in the human body and can become rapidly devoid without regular and adequate intake [8]. These characteristics might explain why thiamin deficiency is observed subsequent to a short period of persistent vomiting after surgical complications such as band slippage post LAGB [17], stomach oedema after LSG [18], or stoma stenosis after RYGB [19]. Cases of thiamine deficiencies have also been reported after BPD/DS [20].
The manifestations of thiamine deficiency include peripheral neuropathy, Wernicke’s encephalopathy (WE), Korsakoff’s psychoses and cardiomyopathy [14, 10] (Table 1). These clinical conditions could be severe or even fatal if they are not recognized and treated promptly. Borderline deficiency may cause less severe symptoms that could be missed. Therefore, oral or parenteral thiamine supplementation should be initiated in any bariatric patient presenting with persistent vomiting severe enough to interfere with adequate nutrition, even before obtaining confirmatory laboratory data [10, 14]. In symptomatic patients, oral supplementation may be used only after 1–2 weeks of parenteral administration and continued until symptom resolution [10].
Mico/micro deficiency | Clinical features and complications | Management |
---|
Vitamin B1 Thiamin | Wernicke encephalopathy (confabulations, ophthalmoplegia, ataxia) Korsakoff syndrome Dry Beriberi (polyneuropathy, paresthesia) Wet Beriberi (cardiomegaly, tachycardia, CHF) | Oral: 100 mg 2–3 times daily until symptoms resolve IV: 200–500 mg once or twice daily for 3–5 d, followed by 250 mg/d for 3–5 d or until symptoms resolve, then 100 mg/d orally, indefinitely, or until risk factors resolve IM: 250 mg once daily for 3–5 d or 100–250 mg monthly |
Vitamin B12 Cobalamin | Macrocytic anemia, peripheral and central neuropathy, myelopathy, memory disturbance, dementia, depression, delusions | 1000 μg/d to achieve normal levels and then resume dosages recommended to maintain normal levels |
Folate | Macrocytic anemia, leukopenia peripheral neuropathy, myelopathy, glossitis, fetal neural defects. May aggravate B12 deficiency | Oral dose of 1 mg of folate daily to reach normal levels and then resume recommended dosage to maintain normal levels |
Vitamin A | Ocular xerosis, night blindness, decreased immunity, scaling skin | Vitamin A deficiency without corneal changes: 10,000–25,000 IU/d of vitamin orally until clinical improvement Vitamin A deficiency with corneal changes: 50,000–100,000 IU of vitamin A IM for 3 d, followed by 50,000 IU/d IM for 2 weeks |
Vitamin D | Osteomalacia, bone demineralization, increased risk of fractures | Vitamin D3 at least 3000 IU/d and as high as 6000 IU/d, or 50,000 IU vitamin D2 1–3 times weekly |
Vitamin E | Hemolytic anemia, peripheral neuropathy, loss of deep tendon reflexes, ataxia, diminished perception of vibration and position ophthalmoplegia, myopathy, rash | Optimal therapeutic dose of Vitamin E for bariatric patients is not defined Potential antioxidant benefits can be achieved with supplements of 100–400 IU/d Additional dose may be required for replacement |
Vitamin K | Coagulopathy, excessive bleeding or bruising | Parenteral dose (10 mg) for symptomatic patient acute malabsorption A dose of either 1–2 mg/d orally or 1–2 mg/week parenterally recommended for patients with chronic malabsorption |
Iron | Microcytic anemia, fatigue glossitis, nail dystrophy | Oral: 150–200 mg of elemental iron daily to amounts as high as 300 mg 2–3 times daily (ferrous sulfate, fumarate, gluconate) Vitamin C supplementation may be added to increase iron absorption IV iron infusion (ferric gluconate or sucrose forms) for patients with severe intolerance to oral iron or refractory deficiency Blood transfusion for severe iron deficiency anemia |
Calcium | Fatigue, arrhythmia, myopathy, bone demineralization | Repletion of calcium deficiency varies by surgical procedure BPD/DS: 1800–2400 mg/d; LAGB, LSG, RYGB: 1200–1500 mg/d |
Zinc | Hair loss, pica, dermatitis, chronic diarrhea, dysgeusia, hypogonadism or erectile dysfunction (in males) | Optimal therapeutic dose is unknown. Treatment should target normal biochemical levels. For every 8–15 mg/day elemental zinc provided, 1 mg/day copper should be supplemented to avoid inducing a copper deficiency |
Copper | Anemia, neutropenia, myeloneuropathy sensory ataxia, impaired wound healing | Treatment varies with severity of deficiency Mild–moderate: 3–8 mg/d oral copper gluconate or sulfate until indices return to normal Severe: 2–4 mg/d intravenous copper can be initiated for 6 d or until serum levels return to normal and neurologic symptoms resolve Copper gluconate or sulfate is recommended |
Selenium | Anemia, persistent diarrhea, cardiomyopathy, metabolic bone disease | Optimal therapeutic dose of selenium for bariatric patients is not defined RDA for selenium is 55 micrograms per day |
Table 1.
Summary of common micro and micro nutritional deficiencies.
IV intravenous; IM intramuscular; D: day, CHF: congestive heart failure, LAGB laparoscopic gastric band, LSG laparoscopic sleeve gastrectomy, RYGB Roux en Y gastric bypass, BPD/D biliopancreatic diversion.
In severely malnourished patients receiving nutrition support, empiric thiamine supplementation along with fluid and electrolyte monitoring and replacement are indicated to avoid exacerbation of thiamin deficiency and refeeding syndrome [10]. Refeeding syndrome is a condition that results from fluid and electrolyte imbalances, particulalry hypophosphatemia, causing serious complications such as cardiac arrhythmias [21]. Empiric thiamine supplementation is also indicated for high-risk bariatric patients and patients with risk factors for thiamine deficiency such as females, African Americans, patients not attending the dietitian clinic, patients with gastrointestinal symptoms, heart failure, persistent vomiting, or on parenteral nutrition and those with excessive alcohol use [10]. The recommended dose for prevention and treatment of thiamin deficiency is summarized in Table 1.
Wernicke Encephalopathy: is a serious complication of thiamin deficiency. It is an acute neuropsychiatric syndrome characterized by ataxia, ophthalmoparesis, nystagmus, and confusion. WE most commonly occurs during the first weeks to months following BS [17]. Among patients who were diagnosed with WE, 52% had RYGB and 21% had LSG [15]. Symptoms of WE are typically preceded by malnutrition, which results from persistent prolonged vomiting, although vitamin noncompliance or increased alcoholism are also risk factors [15]. Radiologic imaging of the brain especially magnetic resonance imaging can be used to support the diagnosis of WE, but is not always sensitive to WE symptoms. Findings include hyperintensities in the thalamic region, the mammillary bodies, and the region around the third and fourth ventricle [22]. The recommended treatment is 500 mg of parenteral thiamine three times daily until symptoms of acute WE resolute [10]. The treatment is lifesaving and has the potential to reverse this acute neuropsychiatric syndrome. Recovery typically occurs within 3–6 months of initiation of therapy if the symptoms are recognized early [23]. Studies have shown that patients who received suboptimal thiamin dose or had more than one acute symptom were more likely to progress later into a permanent neurologic deficits (Korsakoff’s syndrome) [17]. Korsakoff’s syndrome is neuropsychiatric disorder characterized by severe amnesia, executive problems, and confabulations, leading to lifelong impairment [17].
3.3.2 Vitamin B12 (cobalamin)
Vitamin B12 (cobalamin) binds to the intrinsic factor, a protein secreted by the stomach. The complex formed is then absorbed by the small intestine [16]. Vitamin B12 deficiency post BS can result from inadequate secretion of intrinsic factor, limited gastric acidity, and most importantly from the bypassing of the duodenum, which is the main site of vitamin B12 absorption [6, 24]. Cobalamin stores in the liver are usually high and therefore vitamin B12 deficiency is rare in the first year after BS; however the incidence tends to increase on the long term [25]. The prevalence vitamin B12 deficiency is 14.3% after LSG and 16% post RYGB [26]. In addition to anemia, vitamin B12 deficiency can cause neurological and psychiatric symptoms [6] (Table 1). Therefore, regular screening is required (e.g., every 3 months) in the first year after BS and at least annually after that or as clinically indicated. This is particularly important with chronic use of medications that worsen B12 deficiency such as metformin, proton-pump inhibitors, and seizure medications [10]. In some instances, serum B12 may not be adequate to identify B12 deficiency; in such cases measuring serum methylmalonic acid, with or without homocysteine, should be considered to identify metabolic deficiency of B12, especially in symptomatic or in patients with history of B12 deficiency [10]. Intramuscular or intranasal regimens is preferred over oral supplementation as only 1% of oral vitamin B12 is passively absorbed without intrinsic factor [14].
3.3.3 Folic acid
Complex dietary folates are absorbed throughout the small intestine but mainly at the brush border of the duodenum and upper jejunum [16]. Since folate is absorbed throughout the small intestine, the deficiency is primarily induced by the decrease in dietary intake and to a lesser extent due to malabsorption specially after procedures that bypass the first part small intestine (RYGB, BPD/DS) [6]. Furthermore, folate deficiency can be aggravated by vitamin B12 deficiency since the latter is necessary for the conversion of inactive methyltetrahydrofolic acid to the active tetrahydrofolic acid [6]. The reported prevalence of folate deficiency after LSG and RYGB is 3.6% and 4.2% respectively [26]. Folate deficiency has been associated with a variety of symptoms (Table 1) [6, 23]. Maternal folate deficiency in pregnancy can cause fetal neurological abnormalities such as growth retardation, and congenital defects (neural tube) [16, 27]. Therefore, adequate folate supplementation is particularly important after malabsorptive procedures and in women of the childbearing age [10].
3.4 Fat soluble vitamin deficiency post bariatric surgery
3.4.1 Vitamin A
The absorption of vitamin A is reduced after bariatric procedures. The incidence of vitamin A deficiency is 11.1% at one year post LSG [26]. A higher prevalence is reported after malabsorptive procedures where deficiency was found in up to 70% of patients 4 years after RYGB and BPD/DS [28]. This is due to fat malabsorption and steatorrhoea. Therefore, routine fat-soluble vitamin supplementation is recommended in all patients post BPD/DS [10]. The clinical manifestations of vitamin A deficits are night blindness, xerophthalmia and dry hair [6].
3.4.2 Vitamin D
Vitamin D is a fat-soluble vitamin absorbed preferentially in the jejunum and ileum. Hence, a high incidence of vitamin D deficiency in seen after malabsorptive procedures despite routine supplementation [16]. The reported deficiency after LSG and RYGB is 66.7% and 65.4% respectively [26]. The prevalence of post BPD/DS vitamin D deficiency ranged from 37.1% at one year to 50.8% at 6 years [29]. The most important consequence of vitamin D deficiency is bone demineralization. Therefore, despite the absence of conclusive evidence regarding the long-term risk of fractures after BS, calcium and vitamin D routine supplementation is strongly recommended, especially after RYGB and malabsorptive procedures [10, 30]. The standard supplementation is frequently insufficient to maintain adequate vitamin D levels in patients with malabsorption, and much higher oral or parenteral doses may be required [8, 28]. For treatment, vitamin D3 is recommended as it is a more potent than vitamin D2; however, both can be utilized [10].
3.4.3 Vitamin K
Low levels of vitamin K have been observed in 1.8% post RYGB and 7.4% post SADI patients one year after surgery [31]. However, clinical symptoms such as easy bruising, and increased bleeding are rare [6]. Some cases of fetal and newborn intracranial hemorrhage related to maternal vitamin K deficiency have been described after BPD/DS [27], and have been also reported after LAGB in a pregnant woman with prolonged vomiting due to slippage of the gastric band resulting in gastric outlet obstruction [32].
3.4.4 Vitamin E
Vitamin E deficiency after BS is rare. The reported incidence is 4.8% and 0.9% after RYGB and SADI respectively [31, 33]. The most common symptoms associated with vitamin E deficiency include neuropathy, myopathy and anemia [21] (Table 1). Vitamin E neuropathy and myopathy can be treated with a dose of vitamin E 400 IU daily.
3.5 Minerals
3.5.1 Iron
Iron deficiency with or without anemia is frequently observed after BS [10]. The incidence after LAGB and LSG ranges between 14 to 18% [10]. The prevalence after RYGB and BPB/DS is 51.3% and 15% respectively [34, 35]. Several mechanisms lead to iron deficiency post BS. First, iron malabsorption can occur as a result of the bypassing of the duodenum and proximal jejunum post BS where most of iron absorption occurs. Second, decreased gastric acidity and accelerated gastric emptying impair the reduction of iron from the ferric (Fe 3+) to the absorbable ferrous state (Fe 2+). Third is the decreased intake of iron-rich foods (meats, vegetables) post BS. Finally, the absorption of iron may be affected by the interaction with other nutritional supplements (e.g., calcium) [10, 14]. Menstruating women are at higher risk for iron deficiency and anemia, specially patients with polymenorrhagia [25]. Other risk factors for iron deficiency include malabsorptive procedures, young age, preoperative anemia and low baseline ferritin level [36]. The clinical features of iron deficiency are summarized in Table 1. The measurement of serum ferritin is the best diagnostic test for detecting iron deficiency and a better indicator of iron body capacity as it becomes abnormal prior to the decrease in serum iron concentration [6]. Prophylactic iron supplementation is recommended after all types of BS to minimize the risk of deficiency [10]. Iron is usually included in oral multivitamin and mineral preparations with the inclusion of vitamin C, which will increase iron absorption [10]. They should not be taken along together with calcium supplements as such supplements may affect the absorption of iron. Severe cases of iron deficiency anemia require intravenous iron or blood transfusion [36].
3.5.2 Calcium
Calcium absorption occurs mainly in the duodenum and proximal jejunum and is facilitated by vitamin D in an acid environment. Thus, any BS that bypass the first part of the intestine, reduces gastric acid production and lowers vitamin D levels is often associated with reduced calcium absorption [15]. The prevalence of calcium deficiency post LGG and RYGB is 3.9% and 4.3 respectively [37]. Low calcium level may affect bone mineralization, therefore, should be supplemented routinely post BS [8].
3.6 Trace elements
Although most of the literature focuses on calcium and iron, deficiencies of other essential minerals such, zinc, copper, and selenium have been reported in bariatric patients [10]. These essential minerals act as enzymatic cofactors in several biochemical pathways, and therefore, their deficiency could cause variable clinical manifestations that involve neurological, cardiac and gastrointestinal systems. Mineral deficiencies are more common after BPD and RYGB [6].
3.6.1 Zinc
Zinc is absorbed by the small intestine and hence BS such RYGB or BPD/DS which partially exclude nutrient from the small bowel, can cause zinc malabsorption [16]. The prevalence of zinc deficiency is 23.9% after LSG [38]. Moderate zinc deficiency presents with hypogeusia, hyposmia, anorexia, eczema, somnolence, and reduced dark adaptation, whereas severe forms are associated with acrodermatitis enteropathica, bullous or pustular dermatitis, diarrhea, balding, mental abnormalities including depression, and recurrent infections due to impaired immune function [16].
3.6.2 Copper
Copper functions as a cofactor in many enzymatic reactions that are vital for the hematologic, vascular, skeletal, antioxidant, and neurologic systems [39]. It is absorbed mainly in the stomach and proximal duodenum. Copper deficiency is rare and underrecognized. More recently, it has been reported after malabsorptive procedures [39]. Symptoms of copper deficiency are often similar to symptoms of vitamin B12 deficiency (hematological and neurological problems). Peripheral neuropathy, myeloneuropathy with spastic ataxic gait have been reported after BS [40]. Recently, a case of severe pancytopenia with refractory anemia secondary to copper deficiency has been observed after BS [39]. In this case, administration of intravenous copper resulted in dramatic clinical improvement [39].
3.6.3 Selenium
Selenium is absorbed in the duodenum and proximal jejunum and it is an essential element that provides an important part of the multifunctional selenoproteins that are important for health [41]. Selenium deficiency has been associated with cardiomyopathy, immune system dysfunction and infertility in men. Since RYGB results in the bypass of the duodenum and upper jejunum, micronutrient deficiencies such as selenium are common after this procedure. The prevalence of selenium deficiency post LSG is 7.1% and post RYGB is 3.8% [26]. A case report described a 40 year-old woman that presented with symptoms of heart failure nine months after RYGB which was confirmed by echocardiography and cardiac markers [42]. The patient was diagnosed with selenium-deficient cardiomyopathy, and she had complete resolution of her symptoms after 3 months of oral selenium [42].
4. Protein malnutrition post bariatric surgery
Protein malnutrition remains the most serious macronutrient complication associated with malabsorptive surgical procedures. It can occur in up to 15% of patients after BPD/DS [43]. Studies reported that 3·0–18·5% of BPD/DS patients required reversal of their procedure because of protein malnutrition or excessive weight loss, or both [44]. Protein malnutrition can also occur after RYGB specially when the Roux limb exceeds 150 cm, where the reported prevalence is 9% at 2 years after surgery [43]; however protein malnutrition rarely necessitates reversal or conversion of a RYGB. It is also less common after LSG and LAGB, and in such cases it is likely due to maladaptive eating behaviors after surgery, especially in patients who avoid protein food sources or have protracted vomiting [6]. The clinical presentation of protein malnutrition includes edema, fatigue, skin, hair, and nail problems [6]. Because protein level often remains in the normal range until late, monitoring the serum albumin concentration is more useful for the assessment of the protein nutritional status. Patients with severe protein malnutrition should be treated with protein supplements that are rich in branch-chain amino acids and, in severe cases enteral feeding is recommended [6]. For prevention of protein malnutrition, an average daily protein intake of 60–120 g (1.1 g/kg of ideal body weight) is required and should be increased by 30% for patients post BPD/BD [16].
5. Complications of micro nutritional deficiencies post bariatric surgery
5.1 Anemia
Anemia is common after BS. The prevalence of macrocytic and microcytic anemia is 52% post LSG, 64% post RYGB and 39% after biliopancreatic diversion [45]. Patients with mild anemia post BS are likely to be asymptomatic; however, when the anemia worsens, patients could present with symptoms, such as fatigue, pallor, and dyspnea on exertion [6]. Post-bariatric anemia is in most cases due to iron deficiency, along with vitamin B12 deficiency as a secondary cause. Other causes of nutritional anemias after malabsorptive BS includes folate, protein, copper, selenium, and zinc deficiencies. Therefore, these factors should be evaluated if routine screening for iron-deficiency anemia is negative [10].
5.2 Neurological complications
Neurological complications may occur after BS. They have attracted attention because of their diversity, complexity and potentially devastating effects [46]. Different patterns of complications can be observed according to the time of presentation. For instance, at an early stage, immediate peripherical nerve injury, Wernicke’s encephalopathy, and polyradiculoneuropathy are the most frequent. Late complications may appear after years, and include optic neuropathy, myelopathy, and peripherical neuropathy [47]. The prevalence of neurological events after BS is difficult to determine. A cross-sectional study reported a rate of 3% among 451 patients who underwent BS [48]. Axonal polyneuropathy was the most frequent neurological complication, but cases of Wernicke syndrome, vitamin B12 deficiency, Guillain-Barre syndrome and copper deficiency were also identified [44]. The majority of patients (93.3%) had full recovery from the neurological signs and symptoms [49]. In another retrospective study involving 592 post LSG patients, only 1.18% were found to have neurological complications [50]. In this cohort, all the patients had decrease in oral intake and rapid weight loss, with a mean weight loss of 35 kg three months after LSG suggesting that this could be the predisposing cause [50]. All patients were treated for neuropathy secondary to vitamin B1 deficiency and had significant improvement and/or resolution of their symptoms. [50]. A recent study showed that among 61 patients post RYGB and LAGB, 11.4% developed some signs of polyneuropathy, that eventually disappeared at 24 months. The most common manifestations were paresthesia and muscle weakness [51]. The majority of neurological complications post BS is attributed to vitamin and micronutrient deficiencies such as vitamins B12, B6, E, thiamine, folate and copper [23, 47, 46]. It is imperative to note that failure of diagnosis and the delay in the management of these complications can lead to irreversible neurological deficits. However, many of these complications can be prevented with regular follow-ups, routine screening of micronutrients, and nutritional supplementation where a deficiency is identified.
5.3 Metabolic bone disease
The bone mineral density rapidly decreases initially after BS, which reflects a skeletal adaptation to a lower body weight. Bone loss however, continues even after weight loss has stopped [52]. This is likely due to the lower calcium absorption and vitamin D deficiency causing secondary hyperparathyroidism [53]. The prevalence of secondary hyperparathyroidism has been shown to increase progressively with time from 35.4% at 1 year after BS to 63.3% at 5 years after surgery [54]. Patients who underwent a single anastomosis gastric bypass had the highest prevalence of secondary hyperparathyroidism (73.6%) followed by RYGB (56.6%), gastric banding (38.5%), and sleeve gastrectomy (41.7%) at 5 years after surgery [54]. The decrease in bone density may predispose patients to the risk of fractures especially with malabsorptive procedures. However, data on the incidence of fractures post BS remain controversial, with some studies suggesting an increased risk of fractures (non-vertebral fractures, especially in the upper limbs) and others showing no increased risk [55, 56, 57]. For instance, one study reported a significantly increased number of fractures only after biliopancreatic diversion (adjusted relative risk 1·60, 95% CI 1·25–2·03; p < 0·001, 56]. Others found that 60% of LAGB and 29% of RYGB patients had increased risk of fractures 3–4 years after surgery [55]. Future long-term studies are required to assess the effect of BS on bone health.
Evaluation of patients for metabolic bone disease after BS may include serum parathyroid hormone, total calcium, phosphorus, 25-hydroxyvitamin D, and 24-hour urine calcium levels [10]. In post-bariatric patients with established osteoporosis, pharmacologic treatment with bisphosphonates may be considered. Before starting bisphosphonate treatment, vitamin D deficiency needs to be fully corrected in order to avoid severe hypocalcaemia, hypophosphatemia, and osteomalacia. In these cases, intravenous form of bisphosphonates should be used (zoledronic acid, 5 mg once a year, or ibandronate, 3 mg every 3 months) for better absorption and to avoid potential anastomotic ulceration with orally administered bisphosphonates [10]. More research is needed to examine the effectiveness of both intravenous and oral bisphosphonates in improving bone mineralization [15].
6. Guidelines for nutritional management post bariatric surgery
Recently, updated guidelines for post-operative nutritional and metabolic support of patients post bariatric surgery were published by the American Association of Clinical Endocrinologists in collaboration with multiple societies [10].
The follow-up should be scheduled depending on the bariatric procedure performed.
For LAGB, it should monthly for the first year and then annually
For LSG, it is recommended at 1, 3, 6, 12 months and then annually
For RYGB, the recommended follow up is at 1, 3, 6, 12 months and biannually or annually thereafter
For BPD/DS and other malabsorptive procedure, the recommended follow up is at 1, 3, 6 months and biannual thereafter.
Routine metabolic and nutritional monitoring is recommended after all bariatric procedures. This includes:
Complete metabolic panel, complete blood count with each visit
Iron studies at baseline and after BS as needed
B12 annually then every 3–6 months for all type of BS (measurement of methylmalonic acid and homocysteine level are optional)
Folic acid level (measurement of red blood cell folic acid level is optional), 25-vitamin D and intact parathyroid hormone (PTH) post RYGB and BPD/DS
Vitamin A (initially and every 6–12 months thereafter) for BPD/DS and it is optional for RYGB
Copper/ceruloplasmin, zinc, selenium evaluation after malabsorptive bariatric surgical procedures (RYGB and BPD/DS) at least annually, or with symptoms of deficiency
Thiamine evaluation in symptomatic patients
Dual-energy X-ray absorptiometry for bone density at 2 years: for RYGB and BPD/DS.
The recommended micronutrients supplementations post bariatric surgery to prevent nutritional deficiencies include [10]:
Two adult multivitamins plus minerals (each containing iron, folic acid, thiamine, zinc, copper; chewable form initially then tablets).
Vitamin B12 (Cobalamin): 350–1000 μg dose can be administrated orally (disintegrating tablet, sublingual, or liquid), nasal spray or parenteral (1000 μg monthly intramuscular or subcutaneous).
Iron: 18–60 mg of elemental iron daily included in the multivitamins and additional supplements can be added if required.
Vitamin D: at least 2000–3000 international units of vitamin D (titrated to therapeutic 25-hydroxyvitamin D levels >30 ng/mL)
Elemental calcium: appropriate dose of daily calcium varies by bariatric procedure. About 200–1500 mg daily for LAGB, LSG and RYGB, and 1800–2400 mg daily for or BPD/DS. Calcium citrate is preferred than calcium carbonate because it is better absorbed in the absence of gastric acid.
Commercial products that are used for micronutrient supplementation after BS need to be discussed with a healthcare professional familiar with dietary supplements, since many products are adulterated and/or mislabeled [10].
7. Preventive strategies of nutritional deficiencies
Since increased adherence with follow-up is associated with improved outcomes, various strategies should be implemented to minimize attrition. Addressing the problem of non-adherence in BS will require the support of qualified healthcare professionals [10, 15]. Multidisciplinary teams with strong communication skills and the involvement of behavioral health experts assist in identifying and addressing compliance barriers. The following strategies may help to improve adherence in the bariatric patients and prevent nutritional deficiencies:
Increase patient engagement in after care appointments. The bariatric team can utilize strategies such as frequent calls, reminders letters, flexible scheduling/variety of appointment times, laboratory results, newsletters to provide reinforcement for follow up [58]
Develop innovative strategies to address barriers to follow-up, such as remotely delivered interventions, smart-phone apps, and follow up video appointments [59]
The long-term follow-up visits should include screening for micronutrient deficiencies, bone health, and monitoring of nutrition-related diseases. Reinforcing healthy eating habits is also recommended, such as eating slowly, portion control, and meeting protein requirements
Focus on adherence in the areas that are most critical for patient well-being. For instance, vitamin deficiency can cause serious health problems, including, in rare cases, encephalopathy
Address barriers and causes of non-compliance with multivitamins supplementation. For example, the most frequent reasons for non-adherence to vitamins, i.e., forgetting, difficulty swallowing or not liking to take pills. These issues can be solved by using pill organizers and electronic reminders which can assist with memory issues. Offering chewable or liquid form of vitamins to will also aid bariatric patients with swallowing difficulty [59]
The role of the family physician in bariatric post-surgery care is important to consider. However, the nature of their involvement post-surgery care is currently unclear [60]. Greater role clarity and enhanced collaboration between surgeons, general practitioners and patients following surgery is likely to enhance the experience and outcomes for patients and encourage and support the maintenance of postsurgical care [60].
Patient education before and after surgery plays a key role in the adherence to micronutrient supplementation and improvement of BS outcomes. Patients should be encouraged to become involved in their own care. Lectures and discussions provided by healthcare experts from multiple disciplines in small groups, or individual sessions utilizing both written or web-based delivery should be done to support learning needs of the bariatric patients. Moreover, patient education methods should focus on high-quality, cost-effective, and patient-centered educational programs for bariatric surgery [61].
8. Conclusions
BS is the most effective strategy for the treatment of severe obesity and for the resolution of comorbid medical conditions. Post-surgery, patients are at increased risk for nutritional deficiencies which may result in serious complications if they are not recognized and treated promptly. Adherence to multivitamins supplementations is important to prevent such deficiencies. Multidisciplinary approach with close monitoring is the key for the long-term success after bariatric surgery.
Conflict of interest
The authors declare no conflict of interest.
Acronyms and abbreviations
BS | bariatric surgery |
LAGB | gastric banding |
LSG | laparoscopic sleeve gastrectomy |
RYGB | Roux en Y gastric bypass |
OAGB | one-anastomosis gastric bypass |
SADI-S | single anastomosis duodeno–ileal bypass with sleeve gastrectomy |
BPD/DS | biliopancreatic diversion with duodenal switch |
\n',keywords:"obesity, bariatric surgery, micronutrients, deficiencies, water soluble vitamins, fat soluble vitamins, minerals, trace elements, protein malnutrition",chapterPDFUrl:"https://cdn.intechopen.com/pdfs/74693.pdf",chapterXML:"https://mts.intechopen.com/source/xml/74693.xml",downloadPdfUrl:"/chapter/pdf-download/74693",previewPdfUrl:"/chapter/pdf-preview/74693",totalDownloads:74,totalViews:0,totalCrossrefCites:0,dateSubmitted:"July 21st 2020",dateReviewed:"November 24th 2020",datePrePublished:"January 5th 2021",datePublished:null,dateFinished:"January 5th 2021",readingETA:"0",abstract:"Bariatric surgery (BS) results in significant weight loss and improvement of obesity associated comorbidities. Despite the benefits achieved with these operations, deficiencies of vitamins and other micronutrients are common. Such deficiencies may become clinically significant if not discovered and treated early. Therefore, it is imperative to undertake thorough screening, and have sound preventive strategies in place in order to make BS a safer procedure. This chapter will provide the multidisciplinary bariatric team with a comprehensive review of micronutrient deficiencies before and after bariatric surgery. The focus will be on the most common micronutrient deficiencies that are encountered in various types of BS procedures, including water soluble vitamins, fat-soluble vitamins, minerals and trace elements deficiencies, as well as protein malnutrition. The chapter starts with an overview of the causes of micronutrient deficiencies in patients with obesity and before undergoing BS. It reviews the screening of patients for preexisting micronutrient deficiencies prior to their BS. Then the chapter addresses the potential causes and mechanisms leading to such deficiencies after BS. It then conducts an in depth discourse of the prevalence of deficiencies by the type of BS, the presenting symptoms, and the investigations required for the diagnoses. The chapter will also discuss the management of each deficiency according to the severity of the symptoms. The chapter also reviews the recent updated guidelines for standard nutritional care post BS. We will finally conclude with a framework of the preventive strategies for optimal care to ensure long term success post-surgery.",reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/74693",risUrl:"/chapter/ris/74693",signatures:"Wahiba Elhag and Walid El Ansari",book:{id:"9818",title:"Bariatric Surgery - From the Non-surgical Approach to the Post-surgery Individual Care",subtitle:null,fullTitle:"Bariatric Surgery - From the Non-surgical Approach to the Post-surgery Individual Care",slug:null,publishedDate:null,bookSignature:"Dr. Nieves Saiz-Sapena and Dr. Juan Miguel Oviedo",coverURL:"https://cdn.intechopen.com/books/images_new/9818.jpg",licenceType:"CC BY 3.0",editedByType:null,editors:[{id:"204651",title:"Dr.",name:"Nieves",middleName:null,surname:"Saiz-Sapena",slug:"nieves-saiz-sapena",fullName:"Nieves Saiz-Sapena"}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"}},authors:null,sections:[{id:"sec_1",title:"1. 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Factors associated with complete and partial remission, improvement, or unchanged diabetes status of obese adults 1 year after sleeve gastrectomy. Surg Obes Relat Dis Off J Am Soc Bariatr Surg. 2020]'},{id:"B3",body:'[Gregory DM, Twells LK, Lester KK, et al. Preoperative and postoperative assessments of biochemical parameters in patients with severe obesity undergoing laparoscopic sleeve gastrectomy. Obesity Surgery. 2018;28:2261-2271]'},{id:"B4",body:'[van Rutte PWJ, Aarts EO, Smulders JF, Nienhuijs SW. Nutrient deficiencies before and after sleeve gastrectomy. Obesity Surgery. 2014;24:1639-1646]'},{id:"B5",body:'[Wolf E, Utech M, Stehle P, Büsing M, Stoffel-Wagner B, Ellinger S. Preoperative micronutrient status in morbidly obese patients before undergoing bariatric surgery: Results of a cross-sectional study. Surg Obes Relat Dis Off J Am Soc Bariatr Surg. 2015;11:1157-1163]'},{id:"B6",body:'[Lupoli R, Lembo E, Saldalamacchia G, Avola CK, Angrisani L, Capaldo B. Bariatric surgery and long-term nutritional issues. World Journal of Diabetes. 2017;8:464-474]'},{id:"B7",body:'[Sánchez A, Rojas P, Basfi-fer K, et al. Micronutrient deficiencies in morbidly obese women prior to bariatric surgery. Obesity Surgery. 2016;26:361-368]'},{id:"B8",body:'[Guan B, Yang J, Chen Y, Yang W, Wang C. Nutritional deficiencies in Chinese patients undergoing gastric bypass and sleeve gastrectomy: Prevalence and predictors. Obesity Surgery. 2018;28:2727-2736]'},{id:"B9",body:'[Martínez-Ortega AJ, Olveira G, Pereira-Cunill JL, et al. Recommendations Based on Evidence by the Andalusian Group for Nutrition Reflection and Investigation (GARIN) for the Pre- and Postoperative Management of Patients Undergoing Obesity Surgery. Nutrients. 2020;12. Jul 6. doi: 10.3390/nu12072002]'},{id:"B10",body:'[Mechanick JI, Apovian C, Brethauer S, et al. Clinical practice guidelines for the perioperative nutrition, metabolic, and nonsurgical support of patients undergoing bariatric procedures - 2019 update: cosponsored by American Association of Clinical Endocrinologists/American College of Endocrinology, The Obesity Society, American Society for Metabolic & Bariatric Surgery, Obesity Medicine Association, and American Society of Anesthesiologists. Surg Obes Relat Dis Off J Am Soc Bariatr Surg. 2020;16:175-247]'},{id:"B11",body:'[Thereaux J, Lesuffleur T, Païta M, et al. Long-term follow-up after bariatric surgery in a national cohort. The British Journal of Surgery. 2017;104:1362-1371]'},{id:"B12",body:'[Modi AC, Zeller MH, Xanthakos SA, Jenkins TM, Inge TH. Adherence to vitamin supplementation following adolescent bariatric surgery. Obes Silver Spring Md. 2013;21:E190-E195]'},{id:"B13",body:'[Mehaffey JH, Mehaffey RL, Mullen MG, et al. Nutrient deficiency 10 years following Roux-en-Y gastric bypass: Who’s responsible? Obesity Surgery. 2017;27:1131-1136]'},{id:"B14",body:'[Allied Health Sciences Section Ad Hoc Nutrition Committee, Aills L, Blankenship J, Buffington C, Furtado M, Parrott J. ASMBS Allied Health Nutritional Guidelines for the Surgical Weight Loss Patient. Surg Obes Relat Dis Off J Am Soc Bariatr Surg. 2008;4:S73-108]'},{id:"B15",body:'[Busetto L, Dicker D, Azran C, et al. Obesity Management Task Force of the European Association for the Study of Obesity Released “Practical Recommendations for the Post-Bariatric Surgery Medical Management.” Obesity Surgery 2018;28:2117-2121]'},{id:"B16",body:'[Mingrone G, Bornstein S, Le Roux CW. Optimisation of follow-up after metabolic surgery. The Lancet Diabetes and Endocrinology. 2018;6:487-499]'},{id:"B17",body:'[Oudman E, Wijnia JW, van Dam M, Biter LU, Postma A. Preventing Wernicke encephalopathy after bariatric surgery. Obesity Surgery. 2018;28:2060-2068]'},{id:"B18",body:'[Hamilton LA, Darby SH, Hamilton AJ, Wilkerson MH, Morgan KA. Case report of Wernicke’s encephalopathy after sleeve gastrectomy. Nutr Clin Pract Off Publ Am Soc Parenter Enter Nutr. 2018;33:510-514]'},{id:"B19",body:'[Loh Y, Watson WD, Verma A, Chang ST, Stocker DJ, Labutta RJ. Acute Wernicke’s encephalopathy following bariatric surgery: Clinical course and MRI correlation. Obesity Surgery. 2004;14:129-132]'},{id:"B20",body:'[Negri M, Macerola N, Mancarella FA, et al. A late onset of Wernicke-Korsakoff encephalopathy after biliopancreatic diversion: A case report. Obesity Surgery. 2019;29:2309-2311]'},{id:"B21",body:'[Boateng AA, Sriram K, Meguid MM, Crook M. Refeeding syndrome: Treatment considerations based on collective analysis of literature case reports. Nutr Burbank Los Angel Cty Calif. 2010;26:156-167]'},{id:"B22",body:'[Sechi G, Serra A. Wernicke’s encephalopathy: New clinical settings and recent advances in diagnosis and management. Lancet Neurology. 2007;6:442-455]'},{id:"B23",body:'[Becker DA, Ingala EE, Martinez-Lage M, Price RS, Galetta SL. Dry beriberi and Wernicke’s encephalopathy following gastric lap band surgery. J Clin Neurosci Off J Neurosurg Soc Australas. 2012;19:1050-1052]'},{id:"B24",body:'[Damms-Machado A, Friedrich A, Kramer KM, et al. Pre- and postoperative nutritional deficiencies in obese patients undergoing laparoscopic sleeve gastrectomy. Obesity Surgery. 2012;22:881-889]'},{id:"B25",body:'[Mechanick JI, Kushner RF, Sugerman HJ, et al. American Association of Clinical Endocrinologists, The Obesity Society, and American Society for Metabolic & Bariatric Surgery medical guidelines for clinical practice for the perioperative nutritional, metabolic, and nonsurgical support of the bariatric surgery patient. Obes Silver Spring Md. 2009;17 Suppl 1:S1-70, v]'},{id:"B26",body:'[Vinolas H, Barnetche T, Ferrandi G, et al. Oral hydration, food intake, and nutritional status before and after bariatric surgery. Obesity Surgery. 2019;29:2896-2903]'},{id:"B27",body:'[Jans G, Matthys C, Bogaerts A, et al. Maternal micronutrient deficiencies and related adverse neonatal outcomes after bariatric surgery: A systematic review. Adv Nutr Bethesda Md. 2015;6:420-429]'},{id:"B28",body:'[Cruz S, Machado S, Cruz S, Pereira S, Saboya C, Ramalho A. Comparative study of the nutritional status of vitamin a in pregnant women and in women who became pregnant or did not after Roux-en-Y gastric bypass. Nutrición Hospitalaria. 2018;35:421-427]'},{id:"B29",body:'[Alejo Ramos M, Cano Rodríguez IM, Urioste Fondo AM, et al. Secondary hyperparathyroidism in patients with biliopancreatic diversion after 10 years of follow-up, and relationship with vitamin D and serum calcium. Obesity Surgery. 2019;29:999-1006]'},{id:"B30",body:'[Parrott J, Frank L, Rabena R, Craggs-Dino L, Isom KA, Greiman L. American Society for Metabolic and Bariatric Surgery Integrated Health Nutritional Guidelines for the surgical weight loss patient 2016 update: Micronutrients. Surg Obes Relat Dis Off J Am Soc Bariatr Surg. 2017;13:727-741]'},{id:"B31",body:'[Enochs P, Bull J, Surve A, et al. Comparative analysis of the single-anastomosis duodenal-ileal bypass with sleeve gastrectomy (SADI-S) to established bariatric procedures: An assessment of 2-year postoperative data illustrating weight loss, type 2 diabetes, and nutritional status in a single US center. Surg Obes Relat Dis. Elsevier. 2020;16:24-33]'},{id:"B32",body:'[Van Mieghem T, Van Schoubroeck D, Depiere M, Debeer A, Hanssens M. Fetal cerebral hemorrhage caused by vitamin K deficiency after complicated bariatric surgery. Obstetrics and Gynecology. 2008;112:434-436]'},{id:"B33",body:'[Cuesta M, Pelaz L, Pérez C, et al. Fat-soluble vitamin deficiencies after bariatric surgery could be misleading if they are not appropriately adjusted. Nutrición Hospitalaria. 2014;30:118-123]'},{id:"B34",body:'[Obinwanne KM, Fredrickson KA, Mathiason MA, Kallies KJ, Farnen JP, Kothari SN. Incidence, treatment, and outcomes of iron deficiency after laparoscopic Roux-en-Y gastric bypass: A 10-year analysis. Journal of the American College of Surgeons. 2014;218:246-252]'},{id:"B35",body:'[Gloy VL, Briel M, Bhatt DL, Kashyap SR, et al. Bariatric surgery versus non-surgical treatment for obesity: A systematic review and meta-analysis of randomised controlled trials. BMJ. 2013;347:f5934]'},{id:"B36",body:'[Gowanlock Z, Lezhanska A, Conroy M, et al. Iron deficiency following bariatric surgery: A retrospective cohort study. Blood Advances. 2020;4:3639-3647]'},{id:"B37",body:'[Antoniewicz A, Kalinowski P, Kotulecka KJ, et al. Nutritional deficiencies in patients after Roux-en-Y gastric bypass and sleeve gastrectomy during 12-month follow-up. Obesity Surgery. 2019;29:3277-3284]'},{id:"B38",body:'[Belfiore A, Cataldi M, Minichini L, et al. Short-term changes in body composition and response to micronutrient supplementation after laparoscopic sleeve gastrectomy. Obesity Surgery. 2015;25:2344-2351]'},{id:"B39",body:'[Abusabeib A, El Ansari W, Elhag W. First case report of acquired copper deficiency following Revisional single anastomosis Duodeno-ileal bypass with sleeve gastrectomy (SADI-S) leading to severe pancytopenia with refractory anemia. Obesity Surgery. 2020:1-4. DOI: 10.1007/s11695-020-04916-3]'},{id:"B40",body:'[Robinson SD, Cooper B, Leday TV. Copper deficiency (hypocupremia) and pancytopenia late after gastric bypass surgery. Proc Bayl Univ Med Cent. 2013;26:382-386]'},{id:"B41",body:'[Hassan Zadeh M, Mohammadi Farsani G, Zamaninour N. Selenium status after Roux-en-Y gastric bypass: Interventions and recommendations. Obesity Surgery. 2019;29:3743-3748]'},{id:"B42",body:'[Massoure P-L, Camus O, Fourcade L, Simon F. Bilateral leg oedema after bariatric surgery: A selenium-deficient cardiomyopathy. Obesity Research & Clinical Practice. 2017;11:622-626]'},{id:"B43",body:'[Suárez Llanos JP, Fuentes Ferrer M, Alvarez-Sala-Walther L, et al. PROTEIN MALNUTRITION INCIDENCE COMPARISON AFTER GASTRIC BYPASS VERSUS BILIOPANCREATIC DIVERSION. Nutrición Hospitalaria. 2015;32:80-86]'},{id:"B44",body:'[Bolckmans R, Himpens J. Long-term (>10 Yrs) outcome of the laparoscopic biliopancreatic diversion with duodenal switch. Annals of Surgery. 2016;264:1029-1037]'},{id:"B45",body:'[Mingrone G, Bornstein S, Le Roux CW. Optimisation of follow-up after metabolic surgery. The Lancet Diabetes and Endocrinology. 2018;6:487-499]'},{id:"B46",body:'[Zafar A, Khatri IA. An overview of complications affecting the central nervous system following bariatric surgery. Neurosci Riyadh Saudi Arab. 2018;23:4-12]'},{id:"B47",body:'[Landais A. Neurological complications of bariatric surgery. Obesity Surgery. 2014;24:1800-1807]'},{id:"B48",body:'[Algahtani HA, Khan AS, Khan MA, Aldarmahi AA, Lodhi Y. Neurological complications of bariatric surgery. Neurosci Riyadh Saudi Arab. 2016;21:241-245]'},{id:"B49",body:'[Alqahtani A, Elahmedi M, Qahtani ARA. Laparoscopic sleeve gastrectomy in children younger than 14 years: Refuting the concerns. Annals of Surgery. 2016;263:312-319]'},{id:"B50",body:'[Tabbara M, Carandina S, Bossi M, Polliand C, Genser L, Barrat C. Rare neurological complications after sleeve gastrectomy. Obesity Surgery. 2016;26:2843-2848]'},{id:"B51",body:'[Riccò M, Rapacchi C, Romboli A, et al. Peripheral neuropathies after bariatric surgery. Preliminary results from a single-Centre prospective study in northern Italy. Acta Bio-Medica Atenei Parm. 2019;90:259-265]'},{id:"B52",body:'[Shanbhogue VV, Støving RK, Frederiksen KH, et al. Bone structural changes after gastric bypass surgery evaluated by HR-pQCT: A two-year longitudinal study. European Journal of Endocrinology. 2017;176:685-693]'},{id:"B53",body:'[Costa TL, Paganotto M, Radominski RB, Kulak CM, Borba VC. Calcium metabolism, vitamin D and bone mineral density after bariatric surgery. Osteoporosis International. 2015;26:757-764]'},{id:"B54",body:'[Wei J-H, Lee W-J, Chong K, et al. High incidence of secondary hyperparathyroidism in bariatric patients: Comparing different procedures. Obesity Surgery. 2018;28:798-804]'},{id:"B55",body:'[Lalmohamed A, de Vries F, Bazelier MT, Cooper A, van Staa T-P, Cooper C, et al. Risk of fracture after bariatric surgery in the United Kingdom: Population based, retrospective cohort study. BMJ. 2012;345:e5085]'},{id:"B56",body:'[Rousseau C, Jean S, Gamache P, et al. Change in fracture risk and fracture pattern after bariatric surgery: Nested case-control study. BMJ. 2016;354:i3794]'},{id:"B57",body:'[Zhang Q, Chen Y, Li J, et al. A meta-analysis of the effects of bariatric surgery on fracture risk. Obes Rev Off J Int Assoc Study Obes. 2018;19:728-736]'},{id:"B58",body:'[Gourash WF, Ebel F, Lancaster K, et al. Longitudinal assessment of bariatric surgery (LABS): Retention strategy and results at 24 months. Surg Obes Relat Dis Off J Am Soc Bariatr Surg. 2013;9:514-519]'},{id:"B59",body:'[Hood MM, Corsica J, Bradley L, Wilson R, Chirinos DA, Vivo A. Managing severe obesity: Understanding and improving treatment adherence in bariatric surgery. Journal of Behavioral Medicine. 2016;39:1092-1103]'},{id:"B60",body:'[Jose K, Venn A, Nelson M, Howes F, Wilkinson S, Ezzy D. A qualitative study of the role of Australian general practitioners in the surgical management of obesity. Clin Obes. 2017;7:231-238]'},{id:"B61",body:'[Groller KD. Systematic review of patient education practices in weight loss surgery. Surg Obes Relat Dis Off J Am Soc Bariatr Surg. 2017;13:1072-1085]'}],footnotes:[],contributors:[{corresp:"yes",contributorFullName:"Wahiba Elhag",address:"welansari9@gmail.com",affiliation:'- Department of Bariatric Surgery/Bariatric Medicine, Hamad General Hospital, 3050, Qatar
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- College of Medicine, Qatar University, Qatar
- Schools of Health and Education, University of Skovde, Sweden
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