Metabolic Surgery: Not Just a “Little Intestinal Operation”
The diagrams may be simple and the operations do involve less than 10 % of the entire gut, but the effects on metabolism are highly complex.
Reducing the mechanisms of these operations to mere contact between food and the gut is, however, most misleading. The RYGB, for example, has multiple complex and interwoven outcomes [6]:
1.
Reduction in food volume by the small gastric pouch (about 30 cc)
2.
Delayed gastric emptying due to the small gastroenterostomy (about 10 mm)
3.
Early “dumping” of undigested food into the upper jejunum
4.
Partial injury to the vagus nerve supply to the stomach
5.
Exclusion of food from the fundus, antrum, duodenum, and proximal jejunum
6.
Rapid transit of food through the small bowel
7.
Alterations in the microbiome (i.e., the microorganisms of the gut)
8.
Changes in dietary intake
In addition, there are:
9.
Secondary effects such as weight loss with a reduction and change in adipokines
10.
Changes in signaling between the gut, liver, muscle, adipocytes, and each organ system
11.
Multiple other, still-to-be-discovered pathways.
The clear conclusion is that the gut plays a critical role in metabolism and the more we know about that role, the more likely we are to find new and far more effective therapies for the various expressions of the metabolic syndrome.
The Broad Effects of Metabolic Surgery on Just One Disease: Type 2 Diabetes Mellitus
The next section of this chapter can be summarized in one phrase: “metabolic bariatric surgery affects every organ system and every tissue in the body.”
The best example of the broad effects of metabolic surgery is the effect of the gastric bypass on type 2 diabetes (T2DM). In 1982, surgeons at East Carolina University (ECU) [7] first reported that their “Greenville Version of the Gastric Bypass” was not only more effective in producing weight loss than any other previous therapy, but it also induced remission of T2DM [8]. In later publications, the group reported that the remissions were full, durable, and safe with a reduction in mortality by 78 % when compared to a matched control group [9]. Further, the remission occurred in a number of days before there was significant weight loss—an observation that demonstrated the important role of the foregut in the regulation of energy metabolism. Further studies at ECU documented that T2DM patients are not unable to produce insulin; in fact, fasting insulin levels continue to increase with the progression of T2DM to the point where some diabetic patients have insulin levels nine times the normal, levels that prevent the normal post-meal insulin response. Their further observation that the insulin levels return to normal simultaneously with the remission of T2DM, while insulin resistance improved but had not returned to normal within 3 months, led to the conclusion that T2DM is not due to peripheral insulin resistance, the commonly accepted concept, but that the insulin resistance in T2DM is due to excessively high levels of insulin [10]. Since the hyperinsulinemia resolved following surgery of the gut, the intestine must play a major role in the etiology of T2DM, most likely through a “diabetogenic factor” (DGF), stimulated by contact with food in vulnerable individuals [11].
That reasoning led to an examination of insulin levels in the various other diseases associated with T2DM, a grouping known collectively as the “metabolic syndrome,” including obesity, hypertension, sleep apnea, nonalcoholic steatohepatosis (NASH), and polycystic ovary syndrome. Although the study is still underway, it appears that each of these entities is also characterized by hyperinsulinemia.
Skepticism of the concept that an excess of insulin could produce such a variety of disease states is justified, but such broad effects are certainly seen in other endocrine diseases. Abnormalities of the thyroid gland are excellent examples: excess levels of thyroxine produce goiters, increased appetite, cardiac arrhythmias, thyroid storm, menstrual changes, exophthalmos, sweating, and weight loss; while low levels can lead to depression, weight gain, cretinism, weakness, fatigue, thickening of the skin and hair, etc. Hormones have wide-ranging effects.
Given these findings, it is appropriate to ask whether the current gluco-centric approaches to T2DM (fasting blood glucose, Hb1Ac, oral glucose tolerance test) still make sense and whether, instead, insulin levels might be a better gauge of disease severity and response to bariatric surgery.
Other Effects of Bariatric Metabolic Surgery
The effects of the bariatric operations are far broader than the remission of T2DM. Blackstone R (2003, personal communication) also reported resolution of hypertension (63.3 %), obstructive sleep apnea (68.9 %), gastroesophageal reflux disease (GERD) (87.6 %), venous insufficiency (71.0 %), asthma (66 %), stress incontinence (84 %), depression (31.4 %), degenerative joint disease (67.1 %), and hyperlipidemia (61.4 %). In addition, Christou [12] and his colleagues reported in an observational two-cohort study that the group who underwent bariatric surgery (n = 1,035) versus those who did not (n = 5,746) had a “significant reduction” in mean percent excess weight loss (67.1 %, P < 0.001), as well as significant risk reductions for developing cardiovascular, cancer, endocrine, infectious, psychiatric, and mental disorders compared with controls, with the exception of hematologic (no difference) and digestive diseases (increased rates in the bariatric cohort). The mortality rate in the bariatric surgery cohort was 0.68 % compared with 6.17 % in controls (relative risk 0.11, 95 % confidence interval 0.04–0.27), which translates to a reduction in the relative risk of death by 89 %.
The major complex effects of bariatric metabolic surgery will be summarized as follows in alphabetical order. We do not yet have enough information to list these changes in order of occurrence or importance. For more detailed information, please see the noted references and the Index Medicus for references later than July 2012.
Adipose Tissues and Circulating Lipids
Bariatric surgery is, by far, the most effective therapy to produce durable and striking control of severe obesity. Each of the operations produces dramatic and durable weight loss ranging from 40 % to 60 % of excess weight (%EWt). Most of the weight loss is due to a reduction in adipose tissue, but the process is far more complex than just a diminution of stored lipids. First, there are several, still not-well-understood types of fat ranging from subcutaneous, visceral (omental and mesenteric), retroperitoneal (as in perirenal fat), and brown fat, each of which differs markedly in their release of adipokines and metabolic behavior. These tissues not only differ in color and appearance; they also vary in their venous drainage with visceral and mesenteric adipose tissue outflow to the portal system, while the subcutaneous, retroperitoneal, and brown fat drain into the systemic circulation.
The various bariatric operations differ in their effects on the lipid profile. In a comparison of the DS, SG, and RYGB, Nelson and his colleagues [13] found that cholesterol and low-density lipoprotein showed significantly greater improvement at all time points with DS compared with SG and GB (P < .01). Further, baseline C-reactive protein (CRP) levels among DS patients were double that of SG and RYGB, but rapidly declined to equivalent levels by 3 months and normalized in 79 %. They concluded that the DS procedure resulted in a superior reduction in cardiovascular and proinflammatory risk markers compared with GB and SG.
In addition to marked improvements in the lipid profiles, bariatric surgery affects the proportion of lipids in the circulation. Heneghan et al. [14] reported that within 6 months after bariatric surgery with a decrease in mean body mass to 35.7 ± 5.0 kg/m2, corresponding to 51.3 % ± 10.0 % excess weight loss, the fasting total cholesterol, triglycerides, low-density lipoprotein, free fatty acids, ApoB100, ApoB100/ApoA1 ratio, and insulin resistance estimated from the homeostasis model of assessment of insulin resistance were significantly reduced compared with the preoperative values. The ApoB100/ApoA1 ratio correlated with a reduction in ceramide subspecies (C18:0, C18:1, C20:0, C24:0, and C24:1; P < .05). ApoB100 and the ApoB100/ApoA1 ratio also correlated positively with the reduction in triglycerides, low-density lipoprotein, and homeostasis model of assessment of insulin resistance (P < .05). Brachial artery reactivity testing correlated inversely with ApoB100 and total ceramide (P = .05).
These changes may be affected by gender and age. Pohle-Krauza et al. [15] also reported that bariatric surgery imparts a pronounced improvement in the blood lipid profile of recipients, however, stressing that these effects might be moderated by other factors, such as age and gender, independently of the baseline weight status of the patients.
Studies of the effects of bariatric surgery on lipid metabolism appear to be one of the most promising areas of cardiovascular research.
Bone
Metabolic surgery is followed by significant bone loss, probably due to the significant loss of weight; malnutrition, especially in patients who do not comply with dietary instructions and micronutrient supplementation; endocrine signaling to and from the bone; as well as changes in bone metabolism. A review by Scibora et al. [16] revealed “Hip and lumbar spine areal bone mineral density (aBMD) reductions primarily in women despite calcium and vitamin D supplementation. Femoral neck aBMD declines of 9–11 % and lumbar spine aBMD reductions up to 8 % were observed at the first postoperative year following malabsorptive procedures. Mean T- and Z-scores up to 25 years following surgery remained within normal and healthy ranges. Of those studies reporting development of osteoporosis following gastric bypass, one woman became osteoporotic after 1 year. Despite observed bone loss in the hip region post-surgery, the data do not conclusively support increased incidence of osteoporosis or increased fracture risk in post-bariatric patients.” Similarly, in a systematic review, Viégas et al. [17] found that based on still early data, “bariatric surgery is associated with alterations in bone metabolism, loss of bone mass and an increased risk of fracture.” They were not able to find evidence for increased rates of fracture, but maximum follow-up in these series was only 2 years.
It seems reasonable to conclude, given that bariatric surgery has been practiced in millions of patients around the world for about three decades; that while bone loss occurs following the metabolic operations, at least so far, there is little evidence that this change is harmful; and that long-term studies are essential.
Cardiovascular System
In their report from the Swedish Obesity Study, the longest and most thorough follow-up of bariatric surgery for more than two decades, Romeo et al. [18] found that “bariatric surgery was associated with a reduced myocardial infarction incidence” with 38/345 (11.0 %) in the surgery versus 43/262 (16.4 %) (p = 0.017) in the control group. The effect was stronger in individuals with higher serum cholesterol and triglycerides at baseline.
The salutary effects of bariatric surgery on cardiovascular risk are probably due to the improvements in lipid metabolism as noted previously, but there may be other operative factors as well. While the reasons are not yet clear, the evidence is solid. Johnson and his group [19], for example, in a retrospective cohort study compared cardiovascular outcomes in bariatric surgical patients (n = 349) to morbidly obese other surgical controls (n = 903).
Among the bariatric patients, 19 deaths occurred in 986 person-years of follow-up versus 150 deaths among controls in 3,138 person-years of follow-up. Unadjusted all-cause mortality was estimated at 7 ± 2 per cent at 5 years in bariatric patients compared with 19 ± 2 per cent (P < 0.001) in controls. Adjusting for age, comorbidities, and event history, the relative risk of mortality was reduced by 40 percent in bariatric patients compared with controls [hazard ratios (95 % confidence interval): 0.60 (0.36, 0.99).
Endocrine System
In addition to being severely obese, bariatric surgery patients have a high preoperative prevalence of hormonal abnormalities. Fierbracci et al. [20] reported that in 783 consecutive obese subjects (174 males and 609 females), “the overall prevalence of endocrine diseases, not including type 2 diabetes mellitus, was 47.4 %. The prevalence of primary hypothyroidism was 18.1 %; pituitary disease was observed in 1.9 %, Cushing syndrome in 0.8 %, while other diseases were found in less than 1 % of subjects with a prevalence of newly diagnosed endocrine disorders was 16.3 %.” Jankovic et al. [21] in a group of 433 consecutive morbidly obese patients found that before surgery, thyroid-stimulating hormone (TSH) was elevated compared to an age- and sex-matched normal weight control group (2.4 ± 1.2 vs. 1.5 ± 0.7 μ[mu]U/ml; p < 0.001). Criteria for the metabolic syndrome (MetS) were fulfilled by 39.5 % of the patients. Impaired glucose tolerance and diabetes mellitus were observed in 23.5 and 22.6 %, respectively. Seventy-two percent were insulin resistant. During follow-up, weight (BMI 47 ± 6.9 vs. 36 ± 6.4 vs. 32 ± 6.6 kg/m2; p < 0.001) and TSH decreased significantly (2.4 ± 1.2 vs. 1.8 ± 1.0 vs. 1.8 ± 1.0 μ[mu]U/ml; p < 0.001). Serum cortisol was higher in the MetS(+) group compared to the MetS(−) group (15.0 ± 6.3 vs. 13.5 ± 6.3 μ[mu]g/dl; p = 0.003).
Given the correction of the polycystic ovary syndrome, the correction of menses, the return of fertility, as well as the rare cases of secondary hypoparathyroidism, it is likely that the effects of bariatric metabolic surgery are reflected widely throughout the endocrine system.
Female Reproductive System
Metabolic surgery has multiple effects on the reproductive system of women including the reversal of the polycystic ovary syndrome (PCOS), a component of the metabolic syndrome associated with obesity, as well as an insulin resistance and hyperinsulinemia. Garruti et al. [22] provide an excellent review that documents the endocrine role of adipocytes that “play an endocrine/paracrine role, such as adiponectin, atrial natriuretic peptide, leptin, resistin, tumour necrosis factor alpha (TNF-alpha).” They argue that the metabolic syndrome is a chronic low-grade inflammatory condition in which adipokines play a major role. Isolated adipocytes from women with PCOS express higher mRNA concentrations of some adipokines involved in cardiovascular risk and insulin resistance. However, environmental factors and lifestyle play a major role in determining the appearance of the phenotypes of PCOS. In morbidly obese women with PCOS, bariatric surgery decreases bodyweight and fat excess and reverses hyperandrogenism and sterility. The relationships of hyperinsulinemia to PCOS are not clear nor is it evident how bariatric surgery produces remission of the syndrome.
Two other points deserve emphasis: First, contraception during the first postoperative year is essential because the patients, usually unable to become pregnant for years before the procedures, often become highly fertile following bariatric surgery. Second, in addition to the consequences of unwanted pregnancies, there are concerns about the nutrition of the fetus following an operation designed to induce malnutrition, especially in mothers who do not comply with the recommendations to take nutritional supplements.
Gastrointestinal Tract
The broad physiologic and metabolic effects of bariatric surgery force us to broaden our understanding of the function of the gut and the importance of its signaling systems. It should have been evident earlier. The intestine is a remarkably efficient mechanism for the sensing and evaluation, digestion, and absorption of a wide variety of foods in concert with a microbiome that weighs about 1.5 kg and includes more microorganisms than the cells in the body has. Complex signals are required to manage such a system with hormonal signals between adjacent cells (paracrine) and distant cells (endocrine) in addition to the sympathetic, parasympathetic, and systemic neurological networks. Further, the signals are multidirectional—to and from the gut to every organ system and tissue throughout the body.
A large number of the signals, including cholecystokinin (CCK), peptide YY3–36 (PYY), glucagon-like peptide-1 (GLP-1), gastric inhibitory polypeptide (GIP), pancreatic glucagons, ghrelin, and gastrin, among others, have been identified, but it is likely that we are just beginning to understand the complexity of this network. Good examples include the role of the gut in lipid homeostasis [23], in the control of the immune response [24], and the regulation of caloric intake [25].
VIPomas such as the Zollinger-Ellison syndrome [26] and pancreatic neuroendocrine tumors [27] probably represent neoplastic variations of this gut signaling system. If it is true that hyperinsulinemia due to overstimulation of the islets by the gut is the common denominator in the metabolic syndrome, it follows that T2DM might actually be also due to a still unidentified VIPoma.
Genomic Effects
The wide extent of the metabolic effects of bariatric surgery is illustrated by what are best explained as epigenetic effects. Marceau’s group in Quebec [28] compared the cardiometabolic risk factors in 111 children born to 49 mothers after maternal biliopancreatic diversion bariatric surgery (AMS) with those children born before maternal surgery (BMS). AMS children had lower birth weight (2.9 ± 0.1 AMS vs. 3.3 ± 0.1 kg BMS, P = 0.003), associated with a reduced prevalence of macrosomia (1.8 AMS vs. 14.8 % BMS, P = 0.03), with no difference in underweight. At the time of follow-up, AMS children exhibited threefold lower prevalence of severe obesity (11 vs. 35 %, P = 0.004), greater insulin sensitivity (homeostasis model assessment of insulin resistance index 3.4 ± 0.3 vs. 4.8 ± 0.5, P = 0.02), improved lipid profile (cholesterol/high-density lipoprotein cholesterol 2.96 ± 0.11 vs. 3.40 ± 0.18, P = 0.03; high-density lipoprotein cholesterol 1.50 ± 0.05 vs. 1.35 ± 0.05 mmol/l, P = 0.04), lower C-reactive protein (0.88 ± 0.17 vs. 2.00 ± 0.34 μg/ml, P = 0.004), and leptin (11.5 ± 1.5 vs. 19.7 ± 2.5 ng/ml, P = 0.005) and increased ghrelin (1.28 ± 0.06 vs. 1.03 ± 0.06 ng/ml, P = 0.005) than BMS offspring (AMS vs. BMS, respectively, for all). In addition, the post-bariatric surgery children performed better in school than their siblings.
Kral et al. [29] in another report of the same study concluded “among children of both genders who were aged 6–18 years of age and born after maternal surgery, the prevalence of overweight was reduced to population levels.”
Inflammation and the Immune Response
Obesity is associated with chronic low-grade inflammation, a response that is blamed, in part, for the high prevalence of cancer, asthma, and degenerative joint disease. Although many studies have been published, Rao’s meta-analysis [30] of this important subject revealed how little hard information is available. He was able to retrieve only observational studies that were not very helpful; i.e., he found that “bariatric surgery produces about 66 and 27 % reduction in CRP and interleukin-6 (IL-6) levels, respectively. The change in TNFα(alpha) after bariatric surgery did not approach statistical significance.” Viardot’s study [31] with the effects of the gastric band (i.e., an operation designed to reduce intake rather than changing the arrangements of the bowel) found significant decreases in expression of proinflammatory activation markers: granulocyte CD11b, monocyte CD66b, and T-cell CD69 and CD25. Proinflammatory Th1 cell numbers fell by greater than 80 %, as did the Th1-to-Th2 ratio. The fall in the Th1-to-Th2 ratio related to weight (P < 0.05) and waist loss (P < 0.05). Reduction in immune cell activation was more pronounced in subjects with prediabetes. Weight and abdominal fat loss were predicted by lower activation of adipose tissue macrophage in the sc and visceral adipose tissue (P < 0.05).
Fenske et al. [32] in a prospective study of RYGB, AGB, and GS noted that “all three treatment arms showed a significant decrease in the mean body mass index, mean arterial pressure, and urinary and serum inflammatory markers (all P < .001). The reduction in urinary and serum cytokine levels correlated directly with body weight loss (P
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