Laparoscopic bariatric surgery - The normal course of liver values after surgery. A prospective cohort study

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Örebro University School of Medicine Degree project, 15 ECTS May 2017

Laparoscopic bariatric surgery – The normal course of liver

values after surgery. A prospective cohort study.

Author: Daniel Jamil

Supervisor: Erik Stenberg MD, PhD

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Abstract

Introduction

After laparoscopic bariatric surgery, elevated liver values have been reported. Aim

The primary aim of this pilot study was to take one step towards describing the normal course of liver values following laparoscopic bariatric surgery, in which Nathanson liver retractors were used.

Methods

Using data from the participants’ electronic medical record, 16 patients eligible for

laparoscopic bariatric surgery were included and underwent standardized laparoscopic Roux-en-Y gastric bypass or laparoscopic Sleeve Gastrectomy. Liver values, including alanine aminotransferase (ALAT), alkaline phosphatase (ALP), aspartate aminotransferase (ASAT), Lactate dehydrogenase (LD)(all presented as µkat/L), Total bilirubin (µmol/L) and C-reactive protein (CRP)(mg/L), were controlled pre-operatively, on post-operative day 1 (POD1) and on post-operative day 7 (POD7).

Results

ALAT was elevated at POD1 compared to pre-operative levels (mean ± SD) (1,48 ± 0,83 vs 0,98 ± 0,61; P = 0,003). ASAT showed a similar pattern (1,10 ± 0,62 vs 0,63 ± 0,28; P = 0,002) and was also elevated at POD7 compared to baseline (0,87 ± 0,37 vs 0,63 ± 0,28; P = 0,006). CRP was raised at POD1 compared to baseline (19,34 ± 13,26 vs 5,06 ± 4,20; P < 0,001), and at POD7 when compared to both POD1 (28,03 ± 13,60 vs 19,34 ± 13,26; P = 0,036) and pre-operative values (28,03 ± 13,60 vs 5,06 ± 4,20; P < 0,001). Bilirubin

decreased at POD1 (9,96 ± 2,15 vs 11,39 ± 3,41; P = 0,015) compared to baseline and raised at POD7 (12,30 ± 4,61 vs 9,96 ± 2,15; P = 0,037) compared to POD1. ALP was elevated at POD7 compared to both POD1 (1,33 ± 0,44 vs 1,17 ± 0,32; P = 0,015) and pre-operative values (1,33 ± 0,44 vs 1,20 ± 0,31; P = 0,019).

Conclusion

The findings suggest that, compared to pre-operative levels, ALAT and ASAT are elevated at POD1. ASAT also at POD7. CRP elevates from baseline to POD1 and is still elevated at POD7. Total Bilirubin may decrease at POD1 compared to baseline, and may then elevate to POD7 compared to POD1. Additional studies are needed to control and replicate our findings, and to assess the generalizability of the current results.

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Introduction

The world-prevalence of obesity is growing [1], reaching around 700 million people

nowadays [2]. Obesity, defined as a Body mass index (BMI) ≥ 30 kg/m2, is regarded as a risk factor for adverse medical illness (e.g. diabetes [3], heart failure [4], cancer [5], sleep-apnea syndrome, hypertension and dyslipidemia [6]). It is also associated with a reduced life expectancy [7] and a lower quality of life [8].

Bariatric surgery (surgery related to obesity) is among the most common procedures patients experience today [9]. During the last decade, the numbers of bariatric surgeries performed internationally has been increasing. However, the increase in annual rate is currently not as profound [10]. In Sweden, 6200 bariatric procedures were completed year 2015, which was a decrease with 500 operations compared to year 2014. 97 % of the bariatric operations were laparoscopic and the conversion-rate to open surgery was less than 1 %. In Sweden, during year 2015, laparoscopic gastric bypass was the most common bariatric procedure and laparoscopic Sleeve Gastrectomy accounted for almost 25 % of all the bariatric procedures [11].

Today, several studies support that surgical treatment is the most effective way to achieve a long-term weight loss. For morbidly obese patients, defined as a BMI ≥ 35 kg/m2_{, studies}

have described numerous benefits of surgery [10, 12]. In bariatric surgery, laparoscopic gastric bypass is considered as the gold standard [13].

As an essential part of laparoscopic Roux-en-Y gastric bypass (LRYGB) and laparoscopic Sleeve Gastrectomy (LSG), liver retraction is performed in order to ensure the availability of an appropriate working space and operative view. The retraction of the left liver lobe

facilitates the process of identifying anatomic landmarks, for instance the lesser and greater curvature of the stomach, the angle of His and the gastroesophageal junction, during the surgery [14].

To perform the liver retraction, one additional wound is required for insertion of the

traditional liver retractor, among one is named the Nathanson liver retractor. The traditional retractors are also described as bulky and may contribute to iatrogenic liver damage [15]. Additional wounds are risk factors for a local wound infection and may contribute to

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discomfort post-operatively [14]. The Nathanson liver retractor is a bent metal rod. It is supported by an external metal arm and by the diaphragm when retracting the liver. The retraction compresses the liver parenchyma between the diaphragm and the retractor. Previous studies have classified liver damage due to retraction, based on the frequency. The most common type is due to compression of the liver, leading to a reversible discoloration of the liver and a higher aspartate aminotransferase (ASAT) [16].

In morbidly obese patients, the retraction process is more challenging for the surgeons due to the hypertrophic fatty left liver lobe [17]. Therefore, the patients are recommended to reduce their weight, pre-operatively, by 10 % with the help of a low-calorie diet treatment. An

approximate decrease of liver volume by 18 % is observed during the commencing two weeks of treatment with a low-calorie diet. During four weeks of dieting, a gradual decline of

intrahepatic fat is observed [18]. Pre-operative weight loss is linked to a shorter duration of surgery [19] and a lower complication-rate [20].

Up to now, several studies have explored the relationships between laparoscopic gastric bypass and its risk factors. In one large prospective cohort register study, the risk of

postoperative complications was 3,4 % within 30 days after undergoing laparoscopic gastric bypass, and the strongest risk factors for complications were conversion to open surgery together with intraoperative adverse events [10].

Early complications may be detected by altered vital sign (for example fever or tachycardia) together with post-operative pain. These are important symptoms that surgeons consider when evaluating the patient [21]. This may lead to control of liver values, including CRP. However, the interpretation of these indicators could be difficult for the clinician because of the

probability that these values are effected by the surgical process.

A randomized controlled trial has linked the Nathanson liver retractor to increased liver dysfunction and increased post-operative pain compared to other liver retractors used during LRYGB [14]. Liver dysfunction is generally measured with alanine aminotransferase

(ALAT), aspartate aminotransferase (ASAT) and total bilirubin levels. ALAT- and ASAT-levels raised post-operatively compared to baseline ASAT-levels, reached their peak between 18 h to 24 h and the levels did not return to the normal range within one month [14, 22]. Total

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(POD1) and nearly returned to pre-operative levels after 1 month [14]. Importantly, this publication had several limitations, for example incomplete follow-up data and a small study cohort (n = 20) that underwent LRYGB using a Nathanson liver retractor [14].

Following a LRYGB, a short-term elevation of liver enzymes may be linked to multiple factors, e.g. local hepatic mechanical injury from the use of a liver retractor, the effects of anesthetic agents and CO2 pneumoperitoneum pressure [14, 22, 23]. The local hepatic injury

may be observed as visual signs that indicate liver ischemia [14]. Increased intraabdominal pressure, during the induced pneumoperitoneum (defined as existence of trapped air inside the peritoneal cavity) to secure an appropriate operative working area, may influence and

transiently decrease portal venous blood flow. A potential decrease of portal venous blood flow could contribute to the post-operative elevation of hepatic transaminases, which is a sign of hepatocyte injury [22].

The carbon dioxide pneumoperitoneum pressure of 10-15 mmHg is higher than the pressure of the portal venous blood flow of 7-10 mmHg. It also causes a temporary reduction of hepatic blood flow. At the end of the surgical procedure when the retraction is ended, the reperfusion may generate free radicals that damage endothelial cells of the hepatic sinusoids and the Kupffer cells [24, 25]. This mechanism may be responsible for a smaller part of the elevation of liver values. The local mechanical hepatocyte damage resulting from the

retraction may be responsible for a bigger part of the elevation [24]. The retraction may also reduce the hepatic blood flow temporarily, when the parenchyma becomes compressed [26]. When comparing the pneumoperitoneum pressure between different laparoscopic procedures, previous research suggest that the liver retraction is more important for the elevated liver values after LRYGB [24].

With varying reported specificity and sensitivity, the acute phase protein C-reactive protein (CRP), is valuable as a predictor of immediate post-operative complications. The reported optimal POD to control CRP-levels varies between POD1-POD5. There is no consensus regarding the ideal cutoff levels and it is an area of active research [27-30]. Patients with low risk of operative complications generally have a CRP-peak between 48-72 h

post-operatively [27, 31]. It is assumed that not declining CRP-levels after the post-operative peak indicates an active inflammatory process that is unrelated to the surgical-trauma, but may raise suspicion for complications, leading to supplementary radiological imaging [27].

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Baseline CRP-levels are elevated in obese patients due to the amount of adipose tissue and free fatty acids stimulating the release of pro-inflammatory cytokines as well as the hepatic production and release of CRP [27].

The normal course for alkaline phosphatase (ALP) and lactate dehydrogenase (LD) after minimally invasive bariatric surgery has, to our knowledge, not been described.

Research has, to a certain extent, described the effects of liver retractors being used during laparoscopic bariatric surgery. However, the natural course of liver values (e.g. ALAT, ASAT, ALP, Bilirubin, LD and CRP) following laparoscopic bariatric procedures has not yet been described to its full extent.

Aim

The primary aim of this study was to take one step towards describing the normal course of liver values following laparoscopic bariatric surgery, in which Nathanson liver retractors were used.

The secondary aim was to investigate if differences in the post-operative course of liver values could be observed on the basis of:

- The total operation time. - The livers visual appearance.

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Material and Methods

Study design and Setting

This study was performed as an observational pilot study at Lindesberg Hospital, in

collaboration with Örebro University. All patients underwent standardized LRYGB or LSG during a period of three months, from 2016-11-15 to 2017-02-01. Liver values, including CRP, were controlled prior to laparoscopic bariatric surgery (on the morning of the date of surgery), at post-operative day 1 (POD1) and at post-operative day 7 (POD7). The values of interest included ALAT, ASAT, ALP, Total Bilirubin, LD and CRP. These values were important for describing the normal course following laparoscopic bariatric surgery. The normal range for these liver values were; ALAT (women < 0,75 µkat/L; men < 1,10 µkat/L), ASAT (women < 0,60 µkat/L; men < 0,75 µkat/L), ALP (0,8-4,6 µkat/L), Total Bilirubin (< 25 µmol/L), LD (1,8-3,4 µkat/L) and CRP (< 3 mg/L).

Based on the median operation time, in our study cohort, patients were divided into one group with short duration of surgery and one group with longer duration of surgery. The aim was to observe if any of the two groups had a statistically significant difference in post-operative liver-parameters.

Furthermore, the livers visual appearance, at the end stage of surgery, was analyzed for statistically significant differences in post-operative liver values. At the end stage of

laparoscopic bariatric surgery, involving a liver retractor, the retractor has been effecting the liver during a major part of the surgery. If there was a liver discoloration, it would be clearly observed in the late phases. Therefore, based on the colour of the patient’s liver, the surgeon placed the patient in one of two groups;

- Visually discolored liver (indicating liver ischemia). - Visually normal liver.

The process of placing the patients in two groups was done immediately after each surgery. A picture of the liver was also taken before removing the Nathanson liver retractor via its port.

Description of liver values

ALAT is a cytoplasmic enzyme found primarily in hepatocytes and is used as an indicator of hepatocyte damage. ASAT is an enzyme found in mitochondrion and in the cytoplasm of

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different cell types, including hepatocytes. It is useful as a more unspecific marker of hepatocyte damage. ALP is a group of membrane-associated enzymes that are found in several cell types. In the liver, ALP is found in vessel endothelium and mainly in the bile ducts. Serum-ALP levels in adults predominantly stem from the bile ducts. The degree of bile stasis influences the ALP synthesis on the occasion of hepatocyte damage. Total bilirubin is used as a marker of liver function and its capability of conjugating bilirubin. LD is an enzyme found in the cytoplasm of all cell types and is useful as an unspecific marker of tissue

damage. Hepatocytes are an example of a cell type rich in LD. CRP is an acute phase protein that is synthetized in the liver as a response to an acute phase reaction, involving various cytokines, fibroblasts, macrophages and endothelial cells, following tissue damage. It has a role in phagocytosis in the classical pathway of the complement system. CRP can bind various substances from damaged cells and microorganisms in order to activate the

complement system. Serum CRP is useful for monitoring the post-operative period and for differentiating between bacterial and viral infections.

Data collection

The data containing the liver values, the total operation time, height, weight, age, gender, post-operative complications within 30 days, type of surgery, co-morbidity and length of hospital stay was obtained from all participants’ electronic medical record. BMI was calculated as weight (kg) divided by height2 (m2).

Study participants

All patients meeting the national and international criteria for bariatric surgery [32] and who were accepted for surgery, between 2016-11-15 to 2017-02-01, were potentially eligible for the study. Oral information and consent was retrieved prior to surgery. The study size was decided by the number of patients that gave blood test involving the values of interest, pre-operatively, at POD1 and at POD7 during the period of data-collection.

The general criteria for bariatric surgery included a BMI > 35 kg/m2, multiple previous serious weight reduction efforts, an abuse-free period of two years prior to surgery, a

capability to process and understand information regarding the surgery as well as an ability to understand the risks associated with the procedure [32].

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Operative procedure

Laparoscopic Roux-en-Y gastric bypass (LRYGB)

The participants underwent a standardized LRYGB with an ”antecolic and antegastric Roux-en-Y-loop” [33]. Antecolic is defined as in front of the colon and antegastric refers to in front of the stomach.

Six ports were used, including one for the Nathanson liver retractor placed in the Xiphoid region, two 12 mm working ports in the epigastric region, one 12 mm camera port in the upper midline and one 5 mm port in the left hypochondriac region. In order to achieve a safe access to the abdomen, a first optic was placed in the umbilical region with the Hasson open technique at the beginning of the operative procedure [34].

The Hasson open technique was used for creating the first port. At the base of the umbilicus, in the inferior umbilical fold, a longitudinal incision was completed [35, 36]. After elevating the skin edges, incisions following the lining of the umbilical ligament were made. The umbilical ligament and the fascial layer were passed before passing peritoneum and an access to the peritoneal cavity was established [35].

Liver retraction of the left liver lobe was performed using the Nathanson liver retractor. With the help of a cutting stapler, the stomach was partitioned between the lesser curvature and the angle of His, creating a 15-25 ml gastric pouch [33].

Furthermore, two anastomoses were created. One connecting the posterior wall of the gastric pouch with jejunum, using one linear stapler. This anastomosis is named the

gastro-jejunostomy (GE) and functions as a bypass. The second anastomosis connects a part of jejunum to a more distal part of the small intestine, in order to connect the road from the original stomach to the new road from the previously constructed gastric pouch [33]. This second anastomosis is known as the jejuno-jejunostomy (JJ). Both the mesenteric defect beneath the JJ and at Peterson’s space were closed in order to reduce the risk for internal hernia [13].

The part of the small intestine that links the gastric pouch, via GE, to the JJ is labelled the Roux limb [33]. The length of it was carefully decided to 100 cm.

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To complete the creation of the Roux-en-Y, a cutting stapler was used to divide the loop of the small intestine between the two described anastomoses [33]. The small intestine was now arranged into a Y-shape.

Laparoscopic Sleeve Gastrectomy (LSG)

Analogously, after creating the six ports, liver retraction of the left lobe was performed using the Nathanson liver retractor.

A bougie with a size of 35 French (Fr) (a surgical instrument for dilating passages), along the lesser curvature, was used to reach the correct sleeve size. Before transection of the stomach, the fundus was mobilized [37]. The transection of the stomach started from a distance of 5 cm proximally to the pylorus and was continued to the angle of His [12, 37]. A margin was kept from the gastroesophageal junction when performing the last firings [37] and absorbable running sutures were used to oversew the staple line manually [38]. The detached part of the stomach was retrieved through one of the ports [39].

Statistics

Microsoft Office Excel with Analysis ToolPak add-in, was used for paired test, unpaired T-test, descriptive statistics (for example n, median, mean and SD), diagrams and tables.

For the following description of the statistical methods used, the data was considered as normally distributed. Paired T-test was used to investigate if there was a statistically significant difference between the parameters of interest pre-operatively, at POD1 and at POD7. We had one nominal variable with two categories, as well as one ratio variable, and we were following the same cohort at three different occasions.

Unpaired T-test was used to investigate if there was a statistically significant difference in baseline characteristics and in the liver values of interest, between the group with longer operation time and the group with shorter duration of surgery. The data was also considered as normally distributed and we followed two groups at specific occasions, at a time. We had one nominal variable with two categories and one ratio variable to assess.

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To examine whether the group with liver-discoloration had a statistically significant

difference regarding the baseline characteristics and the post-operative liver values, multiple unpaired T-tests were used. The rationale for choosing unpaired T-test was similar to the description above.

Values were presented as mean ± SD, if not stated. To be considered statistically significant, a

P-value less than 0.05 was required.

Ethical considerations

This study involved data collection regarding the participants’ baseline characteristics and their liver values, from their electronic medical records. The data was handled with care and was presented on a group-level, in order to respect the confidentiality of the participants’ personal information. It should not be possible for the participants or their relatives to connect individual liver values with a specific patient. Generally, the ethical principles described in the declaration of Helsinki (6th rev) was followed.

Every patient was tested with one venous blood test at three specific occasions (pre-operatively, at POD1 and at POD7). This was a routine procedure for all patients going through bariatric surgery and did not contribute to additional test occasions for the participators.

All participants were orally informed about the study and were asked for their consent. They were also given the opportunity to withdraw at any stage from the study, without stating any reason.

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Results

During the period of 2016-11-15 to 2017-02-01, 48 patients were potentially eligible for this study and underwent laparoscopic bariatric surgery. However, only 16 patients, 4 men and 12 women, were included and analyzed for the aims of this study. The excluded 32 patients were lost to follow-up. The reason was that few surgeons followed the temporary guidelines for post-operative follow-up of patients, during the period of data collection, and included all the values of interest when blood-samples were taken.

At the time of surgery, the youngest patient was 23 year old and the oldest was 67 year old. The pre-operative data containing the baseline characteristics of the study population is summarized in Table 1. Pre-operative weight reduction was the reason behind the observed difference between pre-operative BMI and operative BMI.

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Throughout this report, the levels of ALAT, ALP, ASAT and LD were presented as µkat/L. Total Bilirubin levels were reported as µmol/L and CRP concentrations as mg/L.

The normal course of liver values

The ALAT- (1,48 ± 0,83 vs 0,98 ± 0,61; P = 0,003), ASAT- (1,10 ± 0,62 vs 0,63 ± 0,28; P = 0,002) and CRP-elevation (19,34 ± 13,26 vs 5,06 ± 4,20; P < 0,001) at POD1 compared to pre-operative levels was statistically significant. Bilirubin-values were lower at POD1 compared to pre-operative values and the difference was also statistically significant (9,96 ± 2,15 vs 11,39 ± 3,41; P = 0,015).

ALP- (1,33 ± 0,44 vs 1,17 ± 0,32; P = 0,015), Bilirubin- (12,30 ± 4,61 vs 9,96 ± 2,15; P = 0,037) and CRP-levels (28,03 ± 13,60 vs 19,34 ± 13,26; P = 0,036) were raised at POD7 compared to POD1. The difference was statistically significant.

ALP- (1,33 ± 0,44 vs 1,20 ± 0,31; P = 0,019), ASAT- (0,87 ± 0,37 vs 0,63 ± 0,28; P = 0,006) and CRP-values (28,03 ± 13,60 vs 5,06 ± 4,20; P < 0,001) were all significantly elevated at POD7 compared to pre-operative values.

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Duration of surgery and post-operative liver values

The subsequent comparison of liver values was performed between a group with long duration of surgery (≥72 min, n = 9) (79,6 ± 8,6 min) and a group with short duration of surgery (< 72 min, n = 7) (58,9 ± 6,4 min). The classification was based on the median operation time of 72 minutes, in our study population.

There was no difference in operative BMI between the group with short duration of surgery (37,73 ± 4,12 kg/m2) and the group with long operative time (37,70 ± 3,12 kg/m2; P = 0,494). However, we could observe a tendency of a higher age (48 ± 2,57 years compared to 39 ± 5,64 years; P = 0,092) in the group with longer duration of surgery, but there was no significant difference in co-morbidity between the groups.

A statistically significant elevation of ASAT at POD1 (1,33 ± 0,69; P = 0,032) was observed in the group with long duration of surgery compared to the group with short duration of surgery (0,79 ± 0,37). A tendency (P = 0,083) of higher ASAT-levels pre-operatively, in the

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group with longer duration of surgery (0,71 ± 0,32) compared to the group with short operation time (0,52 ± 0,20), was observed.

The group with long duration of surgery also had a tendency of ALAT-elevations at POD7 (1,36 ± 0,53 vs 1,02 ± 0,42; P = 0,084).

Furthermore, the group with long duration of surgery had a tendency of higher LD-levels at POD7 (3,27 ± 1,67 vs 2,39 ± 0,25; P = 0,078).

Liver colour-groups and post-operative liver values

The following comparison of the liver values of interest was made between the group with a visually normal liver (n = 11) and the group with visual liver discoloration (n = 5).

There was no significant difference in age between the group with liver discoloration (44,80 ± 11,30 years) and the group with a visually normal liver (43,73 ± 12,71 years; P = 0,435). Also, no significant difference in duration of surgery (P = 0,436) was observed. The group with liver discoloration had a mean operation time of 69,4 ± 20,3 min, compared to the group without discoloration with a mean operation time of 71 ± 9,35 min. A tendency of a higher operative BMI in the group with liver discoloration (39,54 ± 1,67 kg/m2 vs 36,88 ± 0,95 kg/m2; P = 0,105) was observed.

Pre-operatively, the group with a visually normal liver had statistically significant higher levels of ASAT (0,69 ± 0,32 vs 0,48 ± 0,10; P = 0,031) and ALAT (1,13 ± 0,69 vs 0,67 ± 0,13; P = 0,029).

At POD1 and at POD7 the ALP levels were higher in the group without liver discoloration (1,25 ± 0,34 vs 1,00 ± 0,20; P = 0,047 and 1,43 ± 0,51 vs 1,12 ± 0,13; P = 0,042,

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Discussion

Main results

The changes in the ALAT-, CRP-, ASAT- and the Bilirubin-course are sufficient for being considered as clinically important. The changes in ALP are not considered as clinically important due to small changes between the test occasions within the reference interval. The same can be said for LD, because of small differences over the time period, not statistically significant differences and because the majority of the patients were within the normal range. As a summary, compared to baseline levels, ALAT and ASAT may be elevated at POD1. ASAT may also be elevated at POD7 compared to levels at baseline. CRP may elevate from baseline to POD1 and is still elevated at POD7. Total Bilirubin may decrease at POD1 compared to baseline, and may then elevate to POD7 compared to POD1.

In the group with long duration of surgery, the ASAT-elevation at POD 1 is regarded as clinically important. A longer duration of surgery may be a risk factor for developing elevated serum ASAT at POD1.

In the group with a visually normal liver, the pre-operative serum ASAT and ALAT elevation may be regarded as clinically important. The elevation of ALP at POD1 and POD7 is not as important since the values are still within the reference interval. These results suggest that a liver discoloration, at the end of the operative procedure, does not increase the risk for additional elevations of post-operative liver values. However, these results must be interpreted with caution since only five patients had a liver discoloration.

The normal course of liver values

Partly in contrast to our findings, Goel et al. [14] described an initial post-operative drop in Bilirubin-levels before an increase at 18h. An increase at POD1, although lower levels compared to baseline, may be possible in our study population because of the schedule of our post-operative blood test monitoring. The minimum value could have been observed before the blood samples were taken at POD1, and we can therefore not determine whether an increase was observed between the minimum value and the POD1-value. The elevation of Bilirubin at POD7 match the results observed by Goel et al. [14].

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Compared to baseline, the ALAT and ASAT-elevations at POD1 are consistent with

previously reported results [14, 22]. The ASAT-elevation at POD7, compared to pre-operative levels, is in line with the results of a previous study [14].

The CRP-elevation at POD1 further supports the results in a recent publication [27]. At POD7, neither of ASAT nor CRP have returned to baseline levels. Instead, the CRP-values are rising from pre-operative levels to POD1 and is still elevated at POD7. A CRP-peak between POD1-POD7 is likely and the assumption is supported by earlier findings where CRP-levels peak between POD2 to POD4 [27, 40]. Williams et al. [27] hypothesized that their CRP-elevation observed at POD5 may relate to the small number of patients still at hospital at POD5 and that they probably had complications resulting in the second CRP-elevation at POD5. However, in our study cohort, every patient (except one leading to one missing CRP-value) was tested at POD7 after being discharged from hospital. In addition, only one patient had a post-operative complication within 30 days. These findings may suggest that it is possible that serum CRP elevates at POD1 and continues to be elevated to POD7. Our findings are partly supported by Csendes A et al. [41] who found continuously elevating serum CRP to POD5 in a study population without complications.

Duration of surgery and post-operative liver values

The group with long duration of surgery had an elevation of ASAT at POD1 compared to the group with short duration of surgery. Previous research on open RYGBP has shown that ASAT and ALAT have a smaller increase when the liver retraction period is shorter and effecting the liver less time [42]. It could be possible that operation time, as an indicator for the period of liver retraction, is important for ASAT and ALAT-elevation. A shorter duration of surgery also shortens the duration of the pneumoperitoneum pressure, which could have a smaller impact on post-operative liver values, but the previous reports are not completely consistent and not restricted to LRYGB or LSG [22, 24, 43, 44]. It is possible that a longer time of retraction and pneumoperitoneum pressure leads to more hepatocyte damage and thus ASAT and ALAT elevations.

The observed tendency of a higher age (48 ± 2,57 years compared to 39 ± 5,64 years; P = 0,092) in the group with longer duration of surgery, leads to the hypothesis that higher age could be a risk factor for longer duration of surgery and accordingly elevated ASAT. Previous

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publications have reported that age increases the risk for post-operative complications [10, 45]. Further research is required to evaluate the viability of these findings.

Liver colour-groups and post-operative liver values

Pre-operatively, the group with no liver discoloration had higher levels of ASAT and ALAT compared to the group with liver discoloration. This outcome is slightly contrary to that of Tamhankar et al. [16] who discussed that patients with liver discoloration often had raised post-operative levels of ASAT. These results may indicate that liver discoloration is not associated with additional post-operative elevations of liver values and possibly that the liver is relatively sustainable to a shorter period with ischemia. Interestingly, we could observe a tendency of a higher operative BMI in the group with liver discoloration (39,54 ± 1,67 kg/m2 vs 36,88 ± 0,95 kg/m2; P = 0,105). A higher operative BMI could increase the risk for developing a liver discoloration at the end of the surgery. A lower operative BMI could, on the other hand, be a risk factor for elevated ASAT and ALAT pre-operatively. These findings raise intriguing questions and should be interpreted with caution due to a small study cohort.

The generalizability of the findings in this study is subject to multiple limitations. The number of participants in our study cohort was small (n = 16). A larger study population would

probably contribute to achieving statistically significant results in the areas where a tendency is observed but the P-value does not reach < 0,05. A larger study population would also contribute to an increase of the statistical power of the study. On the other hand, this is considered as a pilot study that supplies a basis for estimating a study size in potential future studies. Although a small study cohort, generally, the post-operative course of each liver-value was relatively homogenous. Despite the variation within the standard deviation, the majority of the patients followed “their channel” during the post-operative period. As an example, a patient with higher CRP-levels at baseline was more likely to also have higher CRP-levels at POD1 and at POD7.

Another limitation is that two patients underwent laparoscopic Sleeve Gastrectomy (LSG). In this case, there is no difference in time during which the Nathanson liver retractor is used. The inclusion criteria for surgery is similar and the two patients did not differ greatly in baseline characteristics or in duration of surgery, when compared to the patients undergoing LRYGB. It is unlikely that the surgical method (when performing a LSG or a LRYGB), as such, effect the liver values differently, as we consider the Nathanson liver retractor (used in both

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methods) for being responsible for the major part of the effects. Previous research has reported varying effects on liver values depending on the type of retractor [14] and a lesser increase of ALAT and ASAT when the duration of retraction is reduced during the surgical process [26, 42]. This further supports the assumption regarding the importance of the liver retractor for the post-operative course of ALAT and ASAT.

This study is limited to the Nathanson liver retractor and its combined effects with the carbon dioxide pneumoperitoneum pressure and the anesthetic agents, on liver values. The

Nathansons liver retractor is widely used and the surgeons are familiar with the liver retraction technique. The CO2-pressure in the pneumoperitoneum may influence the

post-operative liver values and was therefore standardized to 16 mmHg in this study. Also, the anesthetic management was standardized.

A possible limitation could be the classification of livers depending on their visual appearance. Although the criterion is binary and implemented by highly competent and experienced bariatric surgeons, the evaluation is still subjective and to a certain extent operator dependent. In addition, our results suggest that there is no association between the livers visual appearance and the post-operative course of liver values.

Two key strengths of the present study are the prospective study design, and the almost complete follow up of all study participants (except one, leading to a missing CRP-value at POD7).

A deeper understanding of the normal course of liver values in the immediate post-operative period may contribute to a multifaceted approach when considering the liver values. We agree with Csendes et al. [41] that it is essential to describe the normal course of these parameters after surgery, particularly for patients having a post-operative course without complications. This would be useful for early detection of patients at risk for developing complications in the immediate post-operative period, when the post-operative course is regarded as “abnormal” [41].

Our findings should be replicated and controlled for other probable contributing factors. There is abundant room for further progress in describing the normal course of liver values after laparoscopic bariatric surgery. The progress would be facilitated by a bigger study

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cohort, after performing a power analysis, and by monitoring the values with a shorter time interval, in future publications.

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Conclusion

With this pilot study, we took one step towards describing the normal course of liver values after laparoscopic bariatric surgery. The findings suggest that, compared to pre-operative levels, ALAT and ASAT are elevated at POD1, and ASAT also at POD7. CRP elevates from baseline to POD1 and is still elevated at POD7. Total Bilirubin may decrease at POD1 compared to baseline, and may then elevate to POD7 compared to POD1. A longer duration of surgery may increase the risk for developing elevated serum ASAT at POD1.

Furthermore, our results suggest that there is no association between the livers visual appearance and the post-operative course of liver values. The findings may indicate that the liver is relatively sustainable to a shorter period with ischemia. These findings raise intriguing questions. Additional studies with a larger study cohort, based on a power analysis, are

needed to control and replicate our findings, and to assess the generalizability of the current results.

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References

[1] Yatsuya H, Li Y, Hilawe EH, Ota A, Wang C, Chiang C, et al. Global trend in overweight and obesity and its association with cardiovascular disease incidence. Circ J. 2014; 78:2807– 2818.

[2] Ng M, Fleming T, Robinson M, Thomson B, Graetz N, Margono C, et al. Global, regional, and national prevalence of overweight and obesity in children and adults during 1980–2013: a systematic analysis for the Global Burden of Disease Study 2013. The Lancet. 2014 Aug; 384(9945):766-781.

[3] Must A, Spadano J, Coakley EH, Field AE, Colditz G, Dietz WH. The disease burden associated with overweight and obesity. JAMA. 1999 Oct; 282(16):1523–1529.

[4] Kenchaiah S, Evans JC, Levy D, Wilson PW, Benjamin EJ, Larson MG et al. Obesity and the risk of heart failure. N Engl J Med. 2002 Aug; 347:305–313.

[5] Renehan AG, Tyson M, Egger M, Heller RF, Zwahlen M. Body-mass index and incidence of cancer: a systematic review and meta-analysis of prospective observational studies. Lancet. 2008 Feb; 371:569–578.

[6] Haslam DW, James WPT. Obesity. Lancet. 2005 Oct; 366(9492):1197-1209.

[7] Fontaine KR, Redden DT, Wang C, Westfall AO, Allison DB. Years of life lost due to obesity. JAMA. 2003 Jan; 289:187–193.

[8] Kolotkin RL, Crosby RD, Williams GR, Hartley GG, Nicol S. The relationship between health-related quality of life and weight loss. Obesity Res. 2001 Sep; 9:564–571.

[9] Buchwald H, Oien DM. Metabolic/bariatric surgery worldwide 2011. Obes Surg. 2013 Apr; 23(4):427–436.

(24)

[10] Stenberg E, Szabo E, Ågren G, Näslund E, Boman L, Bylund A, et al. Early

Complications After Laparoscopic Gastric Bypass Surgery: Results From the Scandinavian Obesity Surgery Registry. Ann Surg. 2014; 260:1040–1047.

[11] Scandinavian Obesity Surgery Registry. Annual Report 2015, part 1 – Statistics [Internet]. Örebro: Scandinavian Obesity Surgery Registry; 2016. [Cited 2017 Jan 6]. Available from: http://www.ucr.uu.se/soreg/.

[12] Alizai PH, Wendl J, Roeth AA, Klink CD, Luedde T, Steinhoff I, et al. Functional Liver Recovery After Bariatric Surgery - a Prospective Cohort Study with the LiMAx Test. Obes surg. 2015; 25:2047–2053.

[13] Stenberg E, Szabo E, Ågren G, Ottoson J, Marsk R, Lönroth H, et al. Closure of mesenteric defects in laparoscopic gastric bypass: a multicentre, randomised, parallel, open-label trial. Lancet. 2016; 387:1397–1404.

[14] Goel R, Shabbir A, Tai CM, Eng A, Lin HY, Lee SL, et al. Randomized controlled trial comparing three methods of liver retraction in laparoscopic Roux-en-Y gastric bypass. Surg Endosc. 2013; 27:679–684.

[15] Pasenau J, Mamazza J, Schlachta CM, Seshadri PA, Poulin EC. Liver hematoma after laparoscopic Nissen fundoplication: a case report and review of retraction injuries. Surg Laparosc Endosc Percutan Tech. 2000 Jun; 10(3):178–181.

[16] Tamhankar AP, Kelty CJ, Jacob G. Retraction-related liver lobe necrosis after laparoscopic gastric surgery. JSLS. 2011 Jan-Mar; 15(1):117-121.

[17] Nguyen NT, Longoria M, Gelfand DV, Sabio A, Wilson SE. Staged laparoscopic Roux-en-Y: a novel two-stage bariatric operation as an alternative in the super-obese with massively enlarged liver. Obes Surg. 2005 Aug; 15(7):1077–1081.

[18] Edholm D, Kullberg J, Karlsson FA, Haenni A, Ahlström H, Sundbom M. Changes in liver volume and body composition during 4 weeks of low calorie diet before laparoscopic gastric bypass. Surg Obes Relat Dis. 2015 May-Jun; 11(3):602-606.

(25)

[19] Alami RS, Morton JM, Schuster R, Lie J, Sanchez BR, Peters A, et al. Is there a benefit to preoperative weight loss in gastric bypass patients? A prospective randomized trial. Surg Obes Relat Dis. 2007 Mar-Apr; 3(2):141-145.

[20] Van Nieuwenhove Y, Dambrauskas Z, Campillo-Soto A, van Dielen F, Wiezer R, Janssen I et al. Preoperative very low-calorie diet and operative outcome after laparoscopic gastric bypass: a randomized multicenter study. Arch Surg. 2011 Nov; 146(11):1300-1305.

[21] Zeidan A, Al-Temyatt S, Mowafi H, Ghattas T. Gender-Related Difference in Postoperative Pain After Laparoscopic Roux-En-Y Gastric Bypass in Morbidly Obese Patients. Obes surg. 2013; 23:1880–1884.

[22] Nguyen NT, Braley S, Fleming NW, Lambourne L, Rivers R, Wolfe BM. Comparison of postoperative hepatic function after laparoscopic versus open gastric bypass. Am J Surg. 2002 Nov; 186:40–44.

[23] Morino M, Giraudo G, Festa V. Alterations in hepatic function during laparoscopic surgery: an experimental clinical study. Surg Endosc. 1998 Jul; 12(7):968–972.

[24] Lai H, Mo X, Yang Y, Xiao J, He K, Chen J, et al. Association between duration of carbon dioxide pneumoperitoneum during laparoscopic abdominal surgery and hepatic injury: a meta-analysis. PLoS One. 2014 Aug 11; 9(8).

[25] Glantzounis GK, Tselepis AD, Tambaki AP, Trikalinos TA, Manataki AD, Galaris DA, et al. Laparoscopic surgery-induced changes in oxidative stress markers in human plasma. Surg Endosc. 2001 Nov; 15(11):1315-1319.

[26] Kitajima T, Shinohara H, Haruta S, Momose K, Ueno M, Udagawa H. Prevention of transient liver damage after laparoscopic gastrectomy via modification of the liver retraction technique using the Nathanson liver retractor. Asian J Endosc Surg. 2015 Nov; 8(4):413-418.

(26)

[27] Williams MR, McMeekin S, Wilson RJ, Miller GV, Langlands FE, Wong W, et al. Predictive Value of C-Reactive Protein for Complications Post-Laparoscopic Roux-En-Y Gastric Bypass. Obes surg. 2017 Mar; 27(3):709–715.

[28] Straatman J, Harmsen AMK, Cuesta MA, Berkhof J, Jansma EP, van der Peet DL. Predictive Value of C-Reactive Protein for Major Complications after Major Abdominal Surgery: A Systematic Review and Pooled-Analysis. PLoS One. 2015 Jul 15; 10(7).

[29] Romain B, Chemaly R, Meyer N, Chilintseva N, Triki E, Brigand C, et al. Diagnostic markers of postoperative morbidity after laparoscopic Roux-en-Y gastric bypass for obesity. Langenbecks Arch Surg. 2014 Apr; 399(4):503-508.

[30] Warschkow R, Tarantino I, Folie P, Beutner U, Schmied BM, Bisang P, et al. C-reactive protein 2 days after laparoscopic gastric bypass surgery reliably indicates leaks and

moderately predicts morbidity. J Gastrointest Surg. 2012 Jun; 16(6):1128-1135.

[31] Matthiessen P, Henriksson M, Hallböök O, Grunditz E, Norén B, Arbman G. Increase of serum C-reactive protein is an early indicator of subsequent symptomatic anastomotic leakage after anterior resection. Colorectal Dis. 2008 Jan; 10(1):75-80.

[32] Consensus Development Conference Panel. NIH conference, Gastrointestinal surgery for severe obesity, Consensus Development Conference Panel. Ann Intern Med. 1991 Dec; 115(12):956-961.

[33] Olbers T, Lönroth H, Fagervik-Olsén M, Lundell L. Laparoscopic Gastric Bypass: Development of Technique, Respiratory Function, and Long-Term Outcome. Obes Surg. 2003 Jun; 13(3):364-370.

[34] Hasson HM. Open laparoscopy as a method of access in laparoscopic surgery. Gynaecol Endosc. 1999; 8:353–362.

[35] Wong LFA, Anglim B, Wahab NA, Gleeson N. A review of the open laparoscopic Hasson technique and retrieval of adnexal specimen via umbilicus. J Obstet Gynaecol. 2017 May; 37(4):487-491.

(27)

[36] Lal P, Singh L, Agarwal PN, Kant R. Open port placement of the first laparoscopic port: a safe technique. JSLS. 2004 Oct-Dec; 8(4):364-366.

[37] Rosenthal RJ; International Sleeve Gastrectomy Expert Panel, Diaz AA, Arvidsson D, Baker RF, Basso N, Bellanger D, et al. International Sleeve Gastrectomy Expert Panel Consensus Statement: best practice guidelines based on experience of >12,000 cases. Surg Obes Relat Dis. 2012 Jan-Feb; 8(1):8-19.

[38] Peterli R, Wölnerhanssen BK, Vetter D, Nett P, Gass M, Borbely Y et al. Laparoscopic Sleeve Gastrectomy Versus Roux-Y-Gastric Bypass for Morbid Obesity-3-Year Outcomes of the Prospective Randomized Swiss Multicenter Bypass Or Sleeve Study (SM-BOSS). Ann Surg. 2017 Mar; 265(3):466-473.

[39] Tagaya N, Kasama K, Kikkawa R, Kanahira E, Umezawa A, Oshiro T, et al. Experience with laparoscopic sleeve gastrectomy for morbid versus super morbid obesity. Obes Surg. 2009 Oct; 19(10):1371-1376.

[40] Kragsbjerg P, Holmberg H, Vikerfors T. Serum concentrations of interleukin-6, tumour necrosis factor-alpha, and C-reactive protein in patients undergoing major operations. Eur J Surg. 1995 Jan; 161(1):17-22.

[41] Csendes A, Burgos AM, Roizblatt D, Garay C, Bezama P. Inflammatory response measured by body temperature, C-reactive protein and white blood cell count 1, 3, and 5 days after laparotomic or laparoscopic gastric bypass surgery. Obes Surg. 2009 Jul; 19(7):890-893.

[42] Lohlun J, Guirguis A, Wise L. Elevated liver enzymes following open Roux-en-Y gastric bypass for morbid obesity - does timing of liver retraction affect the rise in the levels of transaminases? Obes Surg. 2004 Apr; 14(4):505-508.

[43] Gupta R, Kaman L, Dahiya D, Gupta N, Singh R. Effects of varying intraperitoneal pressure on liver function tests during laparoscopic cholecystectomy. J Laparoendosc Adv Surg Tech A. 2013 Apr; 23(4):339-342.

(28)

[44] Jeong GA, Cho GS, Shin EJ, Lee MS, Kim HC, Song OP. Liver function alterations after laparoscopy-assisted gastrectomy for gastric cancer and its clinical significance. World J Gastroenterol. 2011 Jan; 17(3):372-378.

[45] Tiwari MM, Goede MR, Reynoso JF, Tsang AW, Oleynikov D, McBride CL.

Differences in outcomes of laparoscopic gastric bypass. Surg Obes Relat Dis. 2011 May-Jun; 7(3):277-282.

Laparoscopic bariatric surgery - The normal course of liver values after surgery. A prospective cohort study