Background Obesity is associated with chronic inflammation, liver steatosis and increased liver enzymes such as gamma- glutamyltransferase (GGT) and alanine aminotransferase (ALT), markers for non-alcoholic fatty liver disease (NAFLD) and liver fat content. Increased platelet counts (PCs) are a biomarker reflecting inflammation and the degree of fibrosis in NAFLD. We investigated alterations in PCs, GGT, ALT, C-reactive protein (CRP) and ferritin after Roux-en-Y gastric bypass (RYGBP). Methods One hundred twenty-four morbidly obese non-diabetic patients were evaluated before (baseline) and 12 months after (follow-up) RYGBP. 2 2 Results Body mass index (BMI) was reduced from 43.5 kg/m (baseline) to 31.1 kg/m (follow-up), and p < 0.001 and weight 9 9 declined from 126.2 to 89.0 kg. PCs decreased from 303 × 10 to 260 × 10 /l, p < 0.001. GGT was reduced from 0.63 to 0.38 μkat/l, p < 0.001. ALT decreased from 0.69 to 0.59 μkat/l, p = 0.006. CRP was lowered from 7.3 to 5.4 mg/l p <0.001 and ferritin from 106 to 84 μg/l p < 0.001. The alterations in PCs correlated with the changes in CRP (r =0.38, p = 0.001), BMI (r =0.25, p = 0.012), weight (r =0.24, p = 0.015) and inversely correlated with ferritin (r =21, p =0.036). Conclusions PCs, GGT and ALT (markers for NAFLD), and CRP and ferritin (markers for inflammation) decreased in morbidly obese after RYGBP. The decrease in PCs correlated with alterations in CRP, BMI, weight and ferritin. The lowering of liver enzymes may reflect a lowered liver fat content and decreased general inflammation. . . . . . Keywords Morbid obesity Gastric bypass Platelet counts Gamma-glutamyltransferase Alanine aminotransferase C-reactive protein Ferritin Introduction alanine aminotransferase (ALT) are validated surrogate markers for NAFLD and liver fat content [9, 10] as well as Roux-en-Y gastric bypass (RYGBP) has become a frequent- markers for metabolic syndrome and predictors for death . ly used procedure for obesity treatment, reducing the onset Increased platelet counts (PCs) and high concentrations of and inducing remission of type 2 diabetes mellitus (T2DM) circulating C-reactive protein (CRP) have been observed in [1, 2]. Furthermore, bariatric surgery has also been shown to conditions with chronic inflammation such as the metabolic reduce cardiovascular mortality and mortality in general syndrome, as well as obesity, possibly due to secondary [3, 4]. Obesity is an inflammatory condition [5, 6]and is thrombocytosis [12, 13]. However, biopsies of liver tissue associated with non-alcoholic fatty liver disease (NAFLD) have shown that increased fibrosis is linearly associated with [7, 8]. Plasma gamma-glutamyltransferase (GGT) and decreased PC . Platelet count has been shown to be a valuable surrogate marker predicting the severity of fibrosis in NAFLD patients  and could be used to predict the activity of the disease . Furthermore, high PCs are also * Hans-Erik Johansson firstname.lastname@example.org related to cardiovascular death and all-cause mortality . 1 The impact of bariatric surgery on PCs and mechanisms of Department of Public Health and Caring Sciences/Geriatrics, action are mostly unknown. Raoux et al. have recently sug- Uppsala University, Uppsala Science Park, 75185 Uppsala, Sweden gested, due to their results, that bariatric surgery has a positive Östervåla Primary Health Care Centre, Åbygränd 2, impact on platelet metabolism, possibly mediated by weight 74046 Östervåla, Sweden loss . Dallel et al. have shown a significant decrease in Department of Surgery, Falu Lasarett and Uppsala University, PCs in patients treated with RYGBP . Previously, we re- Uppsala, Sweden 4 ported in a small pilot study decreased PCs after RYGBP and Faculty of Medicine, Uppsala University, Uppsala, Sweden OBES SURG (2018) 28:1526–1531 1527 biliopancreatic diversion with duodenal switch . The aim Statistics of this study was to evaluate changes in liver enzymes, (GGT, ALT), CRP, ferritin and PCs in non-smoking, non-diabetic All analyses were defined a priori. Results are presented as obese patients treated with RYGBP with follow-up 1 year arithmetic means, with standard deviations. Changes between after surgery. different time points were analysed using paired t tests. Tests were two-tailed and a p value < 0.05 was considered signifi- cant. Statistical software JMP 5.0 for PC (SAS Corporation, Cary, TX, USA) was used. Material and Methods Patients Results One hundred twenty-four morbidly obese patients 18 years or older, all consecutive, undergoing RYGBP surgery (90 wom- Baseline Data en, 34 men), all Caucasians, non-smoking and free from established diabetes at a single outpatient obesity centre were Patient clinical characteristics at baseline, i.e. before RYGBP, recruited. They were investigated preoperatively (baseline) and at 1 year (follow-up) are shown in Table 1.At baseline,a and 1 year (follow-up) after RYGBP. The study was approved correlation was observed between PCs and CRP (r = 0.28, by the regional ethics review board at Uppsala University. p <0.003). RYGBP Surgery Procedure Follow-up Data at 1 Year After RYGBP It is considered by many to be the gold standard because of its high level of effectiveness and durability. A small gastric Over the 12-month period, there were significant mean chang- pouch was created (2 cm × 3 cm) and the remaining stomach es at baseline to follow-up regarding weight, BMI, sagittal is excluded. The proximal jejunum was divided 30 cm distal diameter, PCs, plasma concentrations of GGT, ALT and to the ligament of Treitz, to perform a gastrojejunal anastomo- CRP, fasting blood glucose, HbA1 , haemoglobin (Hb), mean sis which excluded the stomach and duodenum from passage corpuscular volume (MCV) and ferritin (Table 1). of food. The jejunal limb (Roux limb) was made 100 cm long Weight was lowered by 29%, from 126.2 kg at baseline to and the small intestinal continuity was maintained by an 89.0 kg at follow-up (p < 0.001) and sagittal diameter was enteroenterostomy between the Roux limb and the proximal reducedby29%,from31.9cmatbaselineto22.8cmat jejunum creating Y-shaped junction where the ingested food follow-up (p < 0.001). BMI decreased by 28%, from and the gastric acid and bile are mixed . All participants 2 2 43.5 kg/m at baseline to 31.1 kg/m at follow-up were given the same kind of dietary advice after surgery and (p < 0.001), as shown in Fig. 1a. were recommended to take a daily oral supplement containing PCs were reduced by 14%, from 303 × 10 /l at baseline vitamins and minerals (Mitt Val Kvinna®) and an intramus- to 260 × 10 /l at follow-up (p < 0.001) as presented in cular injection of 1 mg cobalamin (vitamin B ) every third Fig. 1b. month. GGT was markedly lowered by 40%, from 0.63 μkat/l at baseline to 0.38 μkat/l at follow-up (p =0.011) as shown in Test Procedures Fig. 1c. ALT was reduced by 18%, from 0.69 μkat/l at base- line to 0.59 μkat/l at follow-up (p =0.006). All participants underwent physical examination and blood CRP decreased by 25%, from 7.3 mg/l at baseline to tests for PCs, GGT, ALT, CRP, ferritin and glucose preopera- 5.5 mg/l at follow-up (p < 0.001) as presented in Fig. 1d. tively (baseline) and at follow-up at 1 year. Blood samples Ferritin was lowered by 25%, from 106 μg/l at baseline to were collected from each patient (following an overnight fast) 84 μg/l at follow-up (p <0.001). and were analysed using Equalis, quality-assured routine tests The plasma fasting glucose concentration was reduced by at the Department of Clinical Chemistry at Falun Hospital, 8%, from 5.9 mmol/l at baseline to 5.4 mmol/l at follow-up County of Dalarna, Sweden. (p <0.001), and HbA1 was lowered by 11%, from 37.9 mmol/mol at baseline to 33.9 mmol/mol at follow-up Clinical Measurements (p <0.001). Haemoglobin was lowered over the period by 4% from 142 Weight (kg) and height (m) were measured on standardised to 137 g/l, and MCV was increased by 3% from 86.7 to calibrated scales and BMI (kg/m ) was calculated. 89.2 fL (both p <0.001). 1528 OBES SURG (2018) 28:1526–1531 Table 1 Baseline characteristics RYGBP baseline RYGBP 1 year p for difference and 1 year follow-up data of 124 morbidly obese patients who Gender (women/men) 90/34 –– underwent Roux-en-Y gastric bypass surgery Age (years) 43.2 (11.6) –– Height (cm) 170.0 (8.5) 169.3(8.4) – Weight (kg) 126.2 (19.4) 89.0 (13.8) < 0.001 BMI (kg/m ) 43.5 (6.0) 31.1 (5.4) < 0.001 Sagittal diameter (cm) 31.9 (3.7) 22.8 (3.7) < 0.001 Platelet counts (×10 /l) 303 (66) 260 (58) < 0.001 P-GGT (μkat/l) 0.63 (0.41) 0.38 (0.39) < 0.001 P-ALT (μkat/l) 0.69 (0.32) 0.59 (0.21) 0.006 P-CRP (mg/l) 7.3 (3.9) 5.4 (1.8) < 0.001 P-Ferritin (μg/l) 106 (91) 84 (65) < 0.001 P-Glucose (mmol/l) 5.9 (0.6) 5.4 (0.4) < 0.001 HbA1 (mmol/mol) 37.9 (4.3) 33.9 (3.7) < 0.001 Haemoglobin (g/l) 142 (12.4) 137 (10.6) < 0.001 MCV (fL) 86.7 (5.1) 89.2 (5.1) < 0.001 Data shown are arithmetic means (± SD). Normal range: platelets 165–390 × 10 /l, ALT < 0.8 μkat/l, GGT < 0.8 μkat/l, ferritin 10–175 μg/l BMI body mass index, GGT gamma-glutamyltransferase, ALT alanine aminotransferase, P plasma, CRP C- reactive protein, MCV mean corpuscular volume Fig. 1 a–d The changes in body mass index (BMI) (a), platelet counts at follow-up (1 year). Mean values are shown. Statistical significance is (b), concentrations of gamma-glutamyltransferase (GGT) (c) and C- indicated by p values reactive protein (CRP) (d) are shown at baseline, i.e. before surgery and OBES SURG (2018) 28:1526–1531 1529 Pearson’s Product-Moment Correlation Coefficients of circulating acute-phase proteins and proinflammatory cyto- kines frequently observed in inflammatory conditions are ex- The alterations in PCs during the 1-year follow-up (delta- plained by their increased production by hepatocytes . The value) after RYGBP correlated with the changes in CRP hepatocyte production of acute-phase proteins is in turn influ- (r =0.38, p =0.001), BMI (r =0.25, p = 0.012), weight (r = enced by the degree of liver steatosis [30, 31]. NAFLD includ- 0.24, p = 0.015) and inversely correlated with ferritin (r =21, ing steatosis, commonly observed in obese patients, is associ- p = 0.036) but did not correlate with the changes in sagittal ated with elevated acute-phase proteins and liver enzymes [30, diameter (p = 0.289) or glucose concentration (p =0.94). 32, 33]. Lowered concentrations of liver enzymes (GGT, ALT) indicate decreased inflammation and decreased fibrosis in NAFLD hepatocytes. The circulating GGT concentration is Discussion suggested to be a major predictor for alterations in inflamma- tion and fibrosis in NAFLD hepatocytes, the two major prog- The main findings in this study were that the circulating con- nostic features in liver steatosis . Another acute-phase centrations of CRP and liver enzymes, GGT and ALT, de- protein ferritin, also a marker for inflammation, iron deficien- creased after RYGBP surgery along with a decrease in PCs, cy and iron stores, was evaluated in this study. Iron deficiency, which may indicate a decline in the general inflammatory low ferritin, increases PCs  and there is an inverse rela- status and decreased liver steatosis. The impact of bariatric tionship between ferritin and PCs . Unexpectedly, we ob- surgery on PCs is still unclear. A 12-month follow-up study served a lowering of both PCs and ferritin suggesting that the by Raoux et al. has shown positive effects of bariatric surgery latter is due to decreased degree of inflammation rather than by lowered PCs still within normal range and on platelet me- iron deficiency . Over the period, mean corpuscular vol- tabolism, possible mediated by weight loss by altered platelet ume was not lowered further indicating iron deficiency as less volume which is associated with platelet hyperactivity and evident. Unfortunately, we do not have data on iron and total cardiovascular risk . Regarding gastric banding, a previ- iron binding capacity. ous study showed a non-significant trend to lower PCs over Conditions with a low-grade inflammation, such as obesity, 1year . Dallal et al. have shown a significant reduction in are characterised by increased PCs, although the PCs may be PCs after RYGBP with a follow-up period of 1 year . within normal ranges . However, in more severe stages of From a previous, small pilot study, we reported a significant NAFLD with fibrosis, after initially increasing PCs, a con- reduction in PCs for both RYGBP and biliopancreatic diver- sumption of thrombocytes are observed resulting in decreased sion with duodenal switch (BPD-ds) during the first year after PCs . Thus, the initial increase in PCs observed in liver surgery. However, the reduction was sustained only in the steatosis and NAFLD may be exchanged for decreased PCs in BPD-ds group 3 years after surgery . The different re- liver fibrosis, seen in more advanced stages of NAFLD, pos- sponses on PCs might be explained by different procedure- sibly with portal hypertension and splenomegaly. Yoneda related effects on general inflammation and liver steatosis. et al. have used liver biopsies to evaluate the clinical useful- Both CRP and PCs are not only biomarkers for inflamma- ness of measuring PCs for predicting the severity of liver tion, but also risk factors associated with prothrombotic states, fibrosis in 1048 patients with NAFLD . They suggest hypercoagulability and intravascular clotting . Obesity is platelet count to be a major biomarker for this purpose, as also associated with increased concentrations of acute-phase there is a linear association between decreased PCs and in- reactants such as CRP and fibrinogen which might further creased fibrosis in the histopathology of liver. Furthermore, explain the increased risk of thromboembolism in patients Garjani A et al. have evaluated 1305 patients by abdominal treated with bariatric surgery . Furthermore, higher PCs ultrasonography and they conclude that platelet count in within normal range are associated with a more severe state of NAFLD patients can serve as an indicator of the severity of atherosclerosis and worse outcome in patients with myocardi- the disease and they also observed a correlation between ab- al infarction and stroke [23, 24] which implies that platelet normal ALT and higher PCs . count represents a useful marker of CVD risk. Overweight RYGBP surgery improves or reverses NAFLD but there is and obese individuals have significantly elevated PCs as com- still scant data on PC changes after bariatric surgery. Our data pared to normal-weight individuals [23, 24]. PCs depend on a show a sustained reduction in PCs and lowered concentrations variety of factors such as physical activity, ethnicity, age and of GGT, ALT and CRP at follow-up 1 year after RYGBP gender. However, longitudinal studies show considerable sta- surgery possibly due to a decrease of liver inflammation and bility of steady-state PCs and the repeatability has been shown liver fat content along with alterations in cytokine state, acti- to be very high . vation of acute-phase proteins, prothrombotic and proinflam- Obesity is an inflammatory condition [26, 27]and amajor matory states. The reduction in PCs observed in this study is in risk factor for the development of NAFLD, frequently ob- accordance with 1 year data from Dallal et al.  but needs to served in obese patients . The increased concentrations be confirmed in further studies. 1530 OBES SURG (2018) 28:1526–1531 6. Lemieux I, Pascot A, Prud'homme D, et al. Elevated C-reactive There are several limitations in the present study such as protein: another component of the atherothrombotic profile of ab- the small number of patients and the lack of morbidly obese dominal obesity. 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Published: Dec 8, 2017