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1 Review Article J Clin Nutr 2017;9(2):48-55 pissn ㆍ eissn 비만대사수술후미세영양소결핍의발생과치료 박영석, 박기범, 민사홍, 이윤택, 안상훈, 박도중, 김형호 분당서울대학교병원외과 Incidence and Management of Micronutrient Deficiencies in Post-bariatric Surgery Patients Young Suk Park, Ki Bum Park, Sa-Hong Min, Yoontaek Lee, Sang-Hoon Ahn, Do Joong Park, Hyung-Ho Kim Department of Surgery, Seoul National University Bundang Hospital, Seongnam, Korea Bariatric surgery is considered one of the most effective methods of achieving long-term weight loss in morbidly obese patients. Nevertheless, bariatric procedures are associated with a number of complications, and nutrient deficiencies can lead to deleterious consequences. Furthermore, the diet of patients prior to bariatric surgery is often of poor nutrition quality that does not meet the recommended dietary guidelines for micronutrient intake. Therefore, optimization of the postoperative nutritional status should begin before surgery. This review covers the essential information about micronutrient management in patients before and after bariatric surgery. Key Words: Micronutrients, Deficiency, Bariatric surgery 서 론 비만대사수술은고도비만환자의장기적인체중감소및동반질환개선측면에서최선의치료법으로잘알려져있다. 1,2 전세계적으로가장많이시행되고있는비만대사수술은위소매절제술과루와이위우회술이고, 3 우리나라에서는조절형위밴드술이그동안많이시행되어왔으나현재는역시위소매절제술과루와이위우회술이큰비중을차지하고있다. 4 위소매절제술이란, 위를소매혹은바나나모양으로남기고나머지부분을절제 Received Dec 7, 2017; Revised Dec 12, 2017; Accepted Dec 12, 2017 Correspondence to Do Joong Park Department of Surgery, Seoul National University Bundang Hospital, 82 Gumi-ro 173beon-gil, Bundang-gu, Seongnam 13620, Korea Tel: , Fax: , djpark@snubh.org Conflict of interest: None. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. 하는섭취제한형수술이다. 위소매절제술후에는위바닥 (gastric fundus) 부위와대만곡 (greater curvature) 부위가절제되어위가자유롭게팽창하지못하기때문에, 환자는제한된용적의음식물만섭취할수있게된다. 또한수술후에도위내시경검사가가능하여위암등의진단에문제가없다. 이는위암의발생빈도가높은우리나라, 일본, 중국등에서큰장점으로작용할수있다. 루와이위우회술이란위를주머니처럼작게절제한후, 소장을끌어올려위주머니 (gastric pouch) 부분과연결시켜주는수술이다. 음식물이위의대부분과십이지장, 근위부소장을우회하여위주머니와연결된소장으로바로들어가기때문에섭취제한과흡수제한효과를동시에노릴수있다. 루와이위우회술은남은위의내시경검사가매우어렵다는단점은있으나, 체중감소효과와제2형당뇨병을개선시키는효과가위소매절제술보다더크다는연구결과들도있어초고도비만환자또는심한제2형당뇨병이있는환자에게서장점을발휘할수있다. 5,6 비만대사수술은다른어떤치료보다큰체중감량을유발하므 c 2017, The Korean Society for Parenteral and Enteral Nutrition. All Rights Reserved.
2 Incidence and Management of Micronutrient Deficiencies in Post-bariatric Surgery Patients 로, 급격히체중이빠지는시기에각종영양결핍이발생할수있다. 또한수술에의한합병증으로식이섭취가제한될때에도체중감량과동시에영양결핍이발생가능하다. 수술방법에따라서도영양결핍발생에차이를보일수있으며, 흡수제한효과가큰수술일수록영양결핍의발생률도올라간다. 본논문에서는비만대사수술인위소매절제술과루와이위우회술후발생가능한영양결핍, 특히미세영양소결핍의발생과치료에대하여고찰해보고자한다. 현재까지보고된진료지침과문헌의결과들을토대로작성하였으며, 미국비만대사외과학회 (American Society for Metabolic and Bariatric Surgery, ASMBS) 의 2008, 2017년영양진료지침과미국정맥경장영양학회 (American Society for Parenteral and Enteral Nutrition, ASPEN) 의 2015, 2017년영양진료지침을많은부분참고하였음을밝힌다 본론 1. 비만대사수술전미세영양소결핍비만대사수술의대상이되는고도비만환자들이주로고칼로리음식을섭취하는것은맞으나, 모든영양소를골고루포함하고있는건강한식품을섭취하는것은아니다. 실제로비만대사수술을준비하고있는환자를대상으로시행한연구에서환자들의평균하루섭취칼로리는약 2,700 2,800 kcal/d였고, 이중 50% 내외를탄수화물에서, 35% 내외를지방에서섭취하고있었다. 11,12 하지만철, 칼슘, 비타민 D와같은미세영양소의경구섭취는하루권장량보다낮았으며, 11 46%, 48%, 58% 의수술전환자에서철, 칼슘, 엽산결핍이있었고, 비타민 B12 및티아민 ( 비타민 B1) 의결핍도 14% 및 34% 나되었다. ASMBS의 2017년영양진료지침에따르면, 10 미세영양소결핍증발생률은비타민 D의경우 90%, 엽산 54%, 철 45%, 비타민 B12 2% 18% 까지높게보고되고있다 (Table 1) 비만대사수술후에는단기적으로문합부누출, 협착과같은합병증이발생할수있고, 장기적으로는구역, 구토, 덤핑증후군, 위산역류등의장기합병증이발생가능하다. 이렇게영양학적으로불안정한환자를수술한후위와같은합병증이발생하여경구섭취를원활히하지못한다면, 각종미세영양소결핍이심각한상태에서발견될수있다. 따라서수술전미세영양소상태의평가는필수적이며, 수술후여러가지합병증이발생하여금식시간이길어지는경우반드시미세영양소에관심을갖고주의를기울여야한다. 2. 비만대사수술후미세영양소결핍의발생과예방 ASMBS와 ASPEN의진료지침에서권장하는비만대사수술 후미세영양소의보충용량과스크리닝검사시기에대하여는각각 Table 2와 3에정리하였다 ) 철결핍 (iron deficiency) 철결핍은체내로의철흡수에비하여철의요구량이나소실이많아체내철의양이감소된것을말하며, 철결핍이계속진행되어적혈구생성이떨어져빈혈이생기는경우철결핍빈혈 (iron deficiency anemia) 이라한다. 13 철결핍시, 혈청철과혈청페리틴수치는감소하고, 총철결합능 (total iron binding capacity) 은증가하며트랜스페린포화도 (transferrin saturation) 는감소한다. 14 혈청페리틴수치는골수내저장철의양을대표하는지표로여겨지며철결핍의확진에사용될수있다. 13,14 루와이위우회술후에는매년철결핍의발생빈도가증가하여 2년후에는약 38% 40% 의환자에서발견되며, 3년후에는약 50% 이상의환자에서발견된다는보고도있다. 15,16 수술후음식물이십이지장과근위공장 ( 음식물로섭취한철은주로십이지장과상부공장에서흡수된다. 14 ) 을우회하도록해부학적구조가바뀌는것이하나의원인이고, 수술후환자가철의주공급원인붉은육류를잘먹지않고회피하는것등도다른원인으로여겨진다. 8 십이지장과소장의구조가바뀌지않는위소매절제술에서는철결핍의빈도가적을것으로예상할수있다. 실제로위소매절제술 1년후철결핍의빈도 ( 혈청페리틴기준 ) 가 7% 로많지않았음을보고한연구도있으나, 17 루와이위우회술과위소매절제술을비교한메타분석에서는철결핍의빈도가위소매절제술후에더낮지않음을보고하였다. 18 따라서철분보충은섭취제한형수술인위소매절제술후에도반드시필요하다고결론지을수있다. 빈혈은일반적으로수술전고도비만환자의약 12% 에서있다고조사된다. 19,20 수술후빈혈은루와이위우회술 2년째약 23% 46% 까지증가하고, 3년후에는약 60% 에서발견된다는보고가있다. 16,19,20 위소매절제술에서는수술후 1년째약 6.5%, 4 5년후에는약 10% 40% 에서빈혈이발생한다는보고가있다. 17,21-23 그러나빈혈의발생빈도에대한보고는문헌마다차이가크고, 비만과빈혈, 비만대사수술과빈혈의관계는단순히철, 비타민 B12, 엽산과같은영양소결핍에의하여설명될수없다는의견도있다. 19 체내염증반응과비만, 빈혈, 그리고비만대사수술의관계는향후심도있는논의가필요하다. 2) 칼슘및비타민 D 결핍 (calcium and vitamin D deficiency) 칼슘과비타민 D, 부갑상선호르몬, 그리고이와관련된뼈와미네랄대사는비만대사수술후의료진이항상관심을갖고주 Volume 9, Number 2, December
3 Young Suk Park, et al. Table 1. Preoperative micronutrient screening recommendations 7-10 Micronutrient Incidence of preoperative nutritional deficiency Screening recommendation Other considerations Iron 45% 1) Recommended for all patients. (Grade B) 2) A combination of tests (serum iron with serum transferrin saturation and total iron-binding capacity) is recommended for diagnosing iron deficiency. (Grade B) 3) Screening for iron deficiency should include assessment of clinical signs. (e.g., feeling tired and weak, decreased work performance, decreased immune function, and glossitis) Vitamin D and calcium Vitamin D: reported to be as high as 90% Recommended for all patients. (Grade A) Lab tests indicate iron deficiency if iron <50 g/dl, ferritin <20 g/dl, TIBC 4,450 g/dl. Use a combination of laboratory tests: vitamin D, 25-OH, serum alkaline phosphatase, PTH, and 24-hour urinary calcium in relationship to dietary intake. Thiamin 29% Recommended for all patients. (Grade C) Vitamin B12 2% 18% Recommended for all patients. (Grade B) Serum B12 levels alone may not be adequate to identify B12 deficiency. Elevated MMA levels (values 40.4 mmol/l) may be a more reliable indicator of B12 status. Folate 54% Recommended for all patients. (Grade B) RBC folate and serum homocysteine and normal MMA levels indicate folate deficiency. Fat-soluble Vitamin A: 14% Recommended for all patients. (Grade C) vitamins Vitamin E: 2.2% Zinc 24% 28% Recommended for all patients. (Grade D) Patients with obesity have lower serum zinc levels than leaner patients. Thus, repletion of zinc is indicated when signs and symptoms are evident and zinc assays are severely low. (Grade C) Copper Reported to be as high as 70% in pre-bpd women Recommended for all patients. (Grade D) Serum copper and ceruloplasmin are recommended for screening indices. Grade A = strong; Grade B = intermediate; Grade C = week; Grade D = no evidence; TIBC = total iron binding capacity; PTH = parathyroid hormone; MMA = methylmalonic acid; BPD = bilipancreatic diversion. 시해야할문제중하나이다. 비타민 D는장에서칼슘, 마그네슘, 인등의흡수를돕고기타다른생물학적효과를지닌지용성비타민그룹이며, 사람에게서는비타민 D3 (cholecalciferol) 와비타민 D2 (ergocalciferol) 가중요한성분이다. 이둘은달걀노른자, 생선, 시금치등을통하여음식으로섭취가능하지만, 사람에게더중요한비타민 D 획득방법은햇빛노출을통한피부에서의비타민 D3 합성이다. 음식으로섭취하거나피부에서합성된비타민 D는모두생물학적으로비활성화상태이고, 간과신장에서수산화 (hydroxylation) 과정을거쳐활성화상태로바뀌어야한다. Cholecalciferol과 ergocalciferol은모두간에서 calcifediol (25-hydroxycholecalciferol) 과 25-hydroxyergocalciferol로바뀌게되는데, 이것이소위 25-hydroxyvitamin D [25(OH)D] 라고불리는대사물이며, 혈중비타민 D 농도는이것을측정하여지칭하는것이일반적이다. Calcifediol은신장에서한번더수산화과정을거쳐 calcitriol (1,25-dihydroxycholecalciferol) 이되며이것이최종적인비타민 D의활성산물이다. 일반적으로비타민 D가감소하면혈청칼슘수치도떨어지고, 2차적으로부갑상선호르몬농도가증가하게된다. 그리고증가된부갑상선호르몬은간과신장에서의수산화과정을촉진시켜활성상태의비타민 D를증가시키고, 뼈에서의캄슘흡수를증가시키는피드백과정을거치게된다. 비만환자의경우, 건강하지못한식습관으로인해음식으로부터의섭취가부족하고야외활동이많지않아햇빛에노출되는시간또한부족하여비타민 D의흡수또는합성이저하되어 50 Journal of Clinical Nutrition
4 Incidence and Management of Micronutrient Deficiencies in Post-bariatric Surgery Patients Table 2. Supplement recommendations to prevent micronutient deficiency and repletion recommendations for micronutrient deficiency 7-10 Micronutrient Supplement recommendations to prevent postoperative deficiency Repletion recommendations for postoperative deficiency Iron Vitamin D and calcium Postoperative patients at low risk (males and patients without history of anemia) for post-wls iron deficiency should receive at least 18 mg of iron from their multivitamin. Menstruating females and patients who have undergone should take at least mg of elemental iron daily. Oral supplementation should be taken in divided doses separately from calcium supplements, acid-reducing medications, and foods high in phytates or polyphenols. Calcium: 1,200 1,500 mg Calcium should be given in divided doses. Calcium carbonate should be taken with meals. Recommended vitamin D3 dose is 3,000 IU daily, until blood levels of 25(OH)D are greater than sufficient (30 ng/ml). Oral supplementation should be increased to provide mg of elemental iron daily to amounts as high as 300 mg 2 3 times daily. If iron deficiency does not respond to oral therapy, intravenous iron infusion should be administered. Vitamin D3 at least 3,000 IU/d and as high as 6,000 IU/d, or 50,000 IU vitamin D2 1 3 times weekly Vitamin D3 is recommended as a more potent treatment than vitamin D2. Calcium: 1,200 1,500 mg Thiamin At least 12 mg daily Practitioners should treat post-wls patients with suspected thiamin deficiency before or in the absence of laboratory confirmation of deficiency. Oral therapy: 100 mg 2 3 times daily until symptoms resolve. IV therapy: 200 mg 3 times daily to 500 mg once or twice daily for 3 5 days, followed by 250 mg/days for 3 5 days or until symptoms resolve, then consider treatment with 100 mg/d orally, usually indefinitely or until risk factors have been resolved. IM therapy: 250 mg once daily for 3 5 days or mg monthly. Vitamin B12 Parenteral (IM or SQ): 1,000 mg monthly Orally by disintegrating tablet, sublingual, or liquid: mg daily Postoperative patients with B12 deficiency should take 1,000 mg/days to achieve normal levels. Folate g All post-wls patients with folate deficiency should take an oral dose of 1,000 mg of folate daily to achieve normal levels. Folate supplementation above 1 mg/d is not recommended in postoperative patients because of the potential masking of vitamin B12 deficiency. Fat-soluble vitamins Zinc Vitamin A: 5,000 10,000 IU Vitamin E: 15 mg Vitamin K: g RYGB: 8 22 mg Sleeve gastrectomy: 8 11 mg To minimize the risk of copper deficiency in postoperative patients, it is recommended that the supplementation protocol contain a ratio of 8 15 mg of supplemental zinc per 1 mg of copper. Vitamin A deficiency without corneal changes: a dose of vitamin A 10,000 25,000 IU/d should be administered orally until clinical improvement is evident (1 2 weeks). Vitamin A deficiency with corneal changes: a dose of vitamin A 50, ,000 IU should be administered IM for 3 days, followed by 50,000 IU/d IM for 2 weeks. For postoperative patients with acute malabsorption, a parenteral dose of 10 mg vitamin K is recommended. For postoperative patients with chronic malabsorption, the recommended dosage of vitamin K is either 1 2 mg/d orally or 1 2 mg/wk parenterally. Volume 9, Number 2, December
5 Young Suk Park, et al. Table 2. Continued Micronutrient Supplement recommendations to prevent postoperative deficiency Repletion recommendations for postoperative deficiency Copper RYGB: 2 mg Sleeve gastrectomy: 1 mg Mild to moderate deficiency (including low hematologic indices): Treat with 3 8 mg/d oral copper gluconate or sulfate until indices return to normal. Severe deficiency: 2 4 mg/d intravenous copper can be initiated for 6 d or until serum levels return to normal and neurologic symptoms resolve. RYGB = Roux-en Y gastric bypass. Table 3. Micronutrient screening recommendation 7-10 Preoperative screening Postoperative 3 months 6 months 12 months 18 months 24 months Iron Vitamin D and calcium Thiamin Vitamin B12 Folate Vitamin A Zinc Copper = screening recommendation. 있을뿐만아니라, 지용성비타민인비타민 D가과도한지방조직속에침착되어생체이용률이떨어진다. 24 때문에비타민 D 결핍은수술전환자에서약 70% 95% 까지보고되고있고, 체질량지수와비타민 D 수치는음의상관관계를지니고, 28 체질량지수와부갑상선호르몬의관계는양의상관관계를지닌다는보고도있다. 29 칼슘은비타민 D의도움을받아십이지장과근위공장에서주로흡수되는데, 루와이위우회술의경우비타민 D 의존적능동수송이일어나는십이지장과근위공장을우회하기때문에수술후칼슘흡수장애가발생할가능성이높다. 루와이위우회술후약산성환경또한칼슘카르보네이트 (calcium carbonate) 의흡수를저해할수있고, 이경우칼슘싸이트레이트 (calcium citrate) 를보충하는것이흡수에더용이할수있다. 저칼슘혈증은 2차적부갑상선호르몬증가를일으키기때문에칼슘의뼈흡수를촉진시켜골연화증및골다공증등의문제를일으킬수있고, 부갑상선호르몬증가는비타민 D의저하가없더라도수술에의한칼슘흡수장애를통하여발생할수있다. 30 실제로루와이위우회술후골무기질밀도 (bone marrow density, BMD) 를측정한연구에서수술후 1년 8% 11% 의둔부 BMD가감소하였음을보고하였고, 년후약 3% 의감소를 보고하였다 폐경후여성에서는골손실이더욱가속화된다는보고도있으나, 34 결과가일정하지는않다. 35 위소매절제술의경우, 이론적으로는루와이위우회술보다칼슘흡수가더용이하고골다공증과같은합병증도적어야하나, 루와이위우회술과비슷한정도의골손실률을보고하고있다. 36 3) 비타민 B1 결핍 (vitamin B1 deficiency) 티아민 (thiamine, 비타민 B1) 은수용성비타민으로근위공장에서능동수송을통하여흡수된다. 인간의신체중뇌, 심장, 근육, 간및신장등에는고농도의티아민이발견되며, 충분하고꾸준히섭취해주지않는다면티아민결핍은예상보다빠르게발생한다. 티아민의반감기는 9 18일밖에되지않으므로, 지속적으로구토를하거나티아민이부족한식사를하게되면단기간에티아민부족이나타나고심장, 위장관, 말초및중추신경계에증상 (beriberi symptoms) 이발현된다. 9 또한이를오진하거나발견하지못한다면, 환자에게불가역적인신경과근육병이남기때문에항상티아민결핍을배제하지말아야한다. 실제로루와이위우회술후구토가발생한지 2주밖에되지않은환자에서베르니케-코르사코프신드롬 (Wernicke-Korsakoff syndrome) 이발생하였다는보고가있다. 37 일단티아민결핍이 52 Journal of Clinical Nutrition
6 Incidence and Management of Micronutrient Deficiencies in Post-bariatric Surgery Patients 의심된다면 ( 근력약화, 말초또는다발성신경증상, 사지의통증, 운동실조, 심부전, 사지의부종, 호흡곤란, 구역, 구토, 소장팽창, 변비, 안근마비, 안구진탕등 ) 지체없이치료를시작해야하며, 경증의경우경구투여로도증상의호전을기대할수있으나, 신경병증이동반된중증환자의경우근육또는정맥주사를고려한다. 구토증상이동반된환자라면설하정을투여하거나경증이라도근육또는정맥주사제를사용한다. 9,10 강력한산화제로알려져있으며증가시동맥경화나신경손상을일으킨다. 44 엽산결핍은호모시스테인증가와관련이있으며, 진단시함께측정하는것이추천된다. 10 엽산결핍의증상으로는빈혈, 건망증, 불안, 적대감등이있으며심지어는편집증상까지일으키기도한다. 하지만철과비타민 B12와는달리일반적인종합비타민제에포함된엽산의양으로도대부분의비만대사수술환자에서결핍을예방하거나보정할수있다. 45 4) 비타민 B12 결핍 (vitamin B12 deficiency) 비타민 B12과엽산은모두적혈구의성숙에관여하여대구성빈혈 (macrocytic anemia) 을일으킬수있다. 펩시노겐 (pepsinogen) 은산성환경하에서펩신 (pepsin) 으로전환되고, 펩신은비타민 B12를단백질에서유리시키는데필요하다. 따라서루와이위우회술의경우이과정에서방해를받을수있고, 위산분비억제제를복용하는환자나위축성위염 (atrophic gastritis) 이있는환자에서도비타민 B12 결핍이잘일어날수있다. 위의벽세포 (parietal cell) 에서생성되는내인자 (intrinsic factor) 또한원위부회장에서비타민 B12 흡수에관여하기때문에내인자결핍을유발할만한병력은없는지, 회장말단부절제술을받은병력은없는지도수술전주의깊게살펴보아야한다. 수술후비타민 B12 결핍빈도는문헌에따라다르지만, 한전향적연구에서루와이위우회술 3년후발생빈도를우회한소장의길이에따라 33% 37% 로보고한바있다. 38 증상으로는빈혈, 신경병증 ( 무감각또는이상감각 ), 이명, 두통, 어지러움등이있을수있다. 고용량을경구로보충하여도효과적이라는연구가있으나, 39,40 ASPEN 진료지침에서는소장에서의빠른음식이동에따른흡수장애를이유로근주를더추천하고있고, 8 ASMBS 진료지침에서는특정투여방법을더선호하고있지는않다. 9,10 증상이없는낮은정상범위의비타민 B12 환자에서는메틸말로닉산 (methylmalonic acid, MMA) 검사가도움이된다. 9,10 비타민 B12는 MMA의한형태인 methylmalonyl CoA를 succinyl coenzyme으로전환시키기때문에비타민 B12 결핍시에는 MMA의농도가증가한다. 비타민 B12 수치만으로는 25% 30% 의결핍환자를놓칠수있으므로, MMA 검사를함께시행하는경우도움이될수있다. 41 6) 지용성비타민결핍 (fat-soluble vitamin deficiency) 비타민 A 결핍으로인한증상발현은드물지만, 안과적합병증 ( 야맹증, 안구건조증 ) 으로주로발현된다. 8 루와이위우회술후약 10% 의환자에서결핍증이발견되며수술후 6 12개월마다검사하는것이권유된다. 비타민 E 결핍은비만대사수술후드물고담췌전환술후약 4% 의환자에서발견되나, 유의한임상적증상이동반된경우는아직까지보고되진않았다. 8 7) 아연및구리결핍 (zinc and copper deficiency) 아연결핍의경우탈모, 설사, 식욕감퇴및상처회복지연등의증상으로발현될수있으며, 구리결핍은머리카락, 피부, 손톱의색소침착저하, 보행이상등의증상을나타낼수있다. 10 아연보충시, 장기간 50 mg 이상의아연이투여되면구리결핍이발생할수있으므로, 8 15 mg의아연보충시마다, 1 mg의구리를함께복용하도록한다. 9,10 결론 비만대사수술후영양결핍은매우흔한합병증이나증상이경미한경우가많아의료진이간과하기쉽다. 더구나미세영양소결핍은다량영양소 (macronutrient) 결핍에비해더놓치기쉬운부분이고복잡한경우가많다. 하지만적절한시기에적절한양을보충하지않는다면환자에게불가역적인후유증을남길수있으므로각별한주의가필요하다. 미세영양소결핍에대한치료는수술후가아니라수술전부터시행되어야함을다시한번강조하며, 수술합병증이발생하거나기저질환이있는환자, 알코올남용자에서는더욱주의를기울여야함을명심해야할것이다. 5) 엽산결핍 (folate deficiency) 엽산결핍은루와이위우회술후, 약 50% 60% 에서발생한다고알려져있다. 42,43 엽산, 비타민 B12, 비타민 B6 등은호모시스테인 (homocysteine) 이라는메티오닌대사산물을시스테인이나메티오닌으로환원시키는데관여한다. 호모시스테인은 REFERENCES 1. Schauer PR, Bhatt DL, Kirwan JP, Wolski K, Aminian A, Brethauer SA, et al. Bariatric surgery versus intensive medical therapy for diabetes-5-year outcomes. N Engl J Med 2017; 376(7): Volume 9, Number 2, December
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