OBES SURG DOI 10.1007/s11695-015-1664-0
ORIGINAL CONTRIBUTIONS
Functional Liver Recovery After Bariatric Surgery—a Prospective Cohort Study with the LiMAx Test Patrick H. Alizai 1 & Janica Wendl 1 & Anjali A. Roeth 1 & Christian D. Klink 1 & Tom Luedde 2 & Inga Steinhoff 3 & Ulf P. Neumann 1 & Maximilian Schmeding 1 & Florian Ulmer 1
# Springer Science+Business Media New York 2015
Abstract Background Bariatric surgery provides long-term weight loss and improvement of obesity-associated diseases such as nonalcoholic steatohepatitis (NASH). Histologic improvement of NASH has been reported in some studies after bariatric surgery. This study was designed to assess the liver function in obese patients as well as its recovery after bariatric surgery with a noninvasive test method. Methods In a prospective cohort study from October 2011 to May 2014, morbidly obese individuals receiving bariatric surgery were investigated for functional liver recovery (n=34). Liver function was determined by the LiMAx test (enzymatic capacity of cytochrome P450 1A2) preoperatively, 6 and 12 months postoperatively. Liver biopsy specimens were obtained from 18 participants and classified according to the nonalcoholic fatty liver disease (NAFLD) activity score (NAS).
Results The mean age of participants was 44 years, and the mean body mass index (BMI) was 52 kg/m2. The mean percent excess BMI loss (%EBMIL) was 53 % after 6 months and 68 % after 1 year. Mean liver function capacity increased significantly from 255 μg/kg/h preoperative to 324 μg/kg/h after 6 months and 342 μg/kg/h after 12 months. A negative correlation was observed between %EBMIL and alteration of liver function capacity in the first 6 months. Finally, the median NAS showed a negative correlation with liver function capacity. Conclusions Bariatric surgery leads to a significant functional recovery of the liver. An initial marked weight loss may negatively influence functional liver recovery.
Keywords NAFLD . NASH . Liver regeneration . Bariatric surgery . Liver function . LiMAx
* Patrick H. Alizai [email protected]
Maximilian Schmeding [email protected]
Janica Wendl [email protected] Anjali A. Roeth [email protected]
Florian Ulmer [email protected] 1
Department of General, Visceral and Transplantation Surgery, RWTH Aachen University Hospital, Pauwelsstr. 30, 52074 Aachen, Germany
2
Department of Gastroenterology, Digestive Diseases and Intensive Care Medicine, RWTH Aachen University Hospital, Pauwelsstr. 30, 52074 Aachen, Germany
3
Institute of Pathology, RWTH Aachen University Hospital, Pauwelsstr. 30, 52074 Aachen, Germany
Christian D. Klink [email protected] Tom Luedde [email protected] Inga Steinhoff [email protected] Ulf P. Neumann [email protected]
OBES SURG
Abbreviations ALT Alanine aminotransferase AP Alkaline phosphatase AST Aspartate aminotransferase BMI Body mass index γ-GT γ-Glutamyltransferase IQR Interquartile range LiMAx Liver maximum capacity test MPF Medium-power field NAFLD Nonalcoholic fatty liver disease NAS NAFLD activity score NASH Nonalcoholic steatohepatitis %EBMIL Percent excess BMI loss %LiMAx Percentage change of LiMAx value RYGB Roux-en-Y gastric bypass SG Sleeve gastrectomy
Introduction The prevalence of overweight and obesity has increased dramatically in recent years. Approximately half or more than half of the Western world’s population is overweight (body mass index (BMI) ≥25 kg/m2) or obese (BMI ≥30 kg/m2) [1]. Morbid obesity is associated with increased risks of type 2 diabetes, hypertension, cardiovascular disease, dyslipidemia, sleep-apnea syndrome, and various other comorbidities, which may lead to further morbidity and mortality [2–5]. The hepatic manifestation of the metabolic syndrome is nonalcoholic fatty liver disease (NAFLD), which is among the most common causes of chronic liver disease in Western countries [6]. NAFLD includes a wide clinicopathological spectrum ranging from simple steatosis to nonalcoholic steatohepatitis (NASH), which may progress to liver cirrhosis [7]. Over a follow-up of 10–15 years, about 20 % of patients with NAFLD will progress to NASH and about 10 % of patients with NASH will develop cirrhosis [8, 9]. In Western countries, the prevalence of NAFLD is approximately 25 % and that of NASH is 3 %, while in obese individuals, up to 85 % have NAFLD and over 50 % may have NASH [8]. Bariatric surgery has proved to be the most effective weight reduction treatment for morbidly obese individuals [3, 10, 11]. It is safe and provides long-term weight loss and significant reduction or remission of most obesity-associated diseases [5, 11–14]. Furthermore, bariatric procedures have also been shown to improve NAFLD and NASH [15]. In recent studies, a decrease in liver steatosis, hepatocyte ballooning, and inflammation could be demonstrated and some studies found improvement in liver fibrosis [8, 15]. Histological examination is certainly the gold standard for diagnosis and staging of NAFLD, but liver biopsies are not without risk [16]. Moreover, histological findings do not necessarily reflect the liver function and its changes after bariatric surgery and
consecutive weight loss. Different approaches toward an effective measurement of the liver function were described in the literature, but a consensus concerning the appropriate test has yet to be established [17–19]. The LiMAx test has recently been introduced and can validly determine liver function capacity [18, 20–22]. It is based on hepatic 13C-methacetin metabolism by the cytochrome P450 1A2 system and provides an interindividually comparable and quantitative value of enzymatic liver function capacity [18, 20, 21]. So far, the LiMAx test is used in liver surgery, liver transplantation, and sepsis [20–23]. The aim of this study was to evaluate the changes in liver function capacity after bariatric surgery determined by the LiMAx test.
Patients and Methods Study Design This prospective study was conducted at the interdisciplinary bariatric center of the RWTH Aachen University Hospital between October 2011 and May 2014. The study protocol included visits preoperatively, 6 and 12 months after bariatric surgery. At every study visit, clinical data (age, body weight, excess BMI loss, comorbidities) and biochemical parameters were recorded. Liver function capacity was monitored by the LiMAx test. Additionally, liver biopsy specimens were obtained at the time of surgery. Retrieved data were pseudonymized and saved in a secured database. The study was conducted in accordance with the 1964 Declaration of Helsinki and its later amendments and had received prior approval by the Local Ethics Committee (EK 312/11). Written informed consent was obtained from each patient before enrolment. Patients Participants were bariatric surgery candidates with body mass indices of >40 or >35 kg/m2 with weight-related comorbidities. Exclusion criteria were minority, heavy smoking (>15 cigarettes per day), alcohol consumption (>20 g/day for men and >10 g/day for women), and participation in another clinical trial and causes of liver disease other than NAFLD (e.g., viral hepatitis). All patients received the standard clinical management independent of the study protocol. Surgical procedures were laparoscopic Roux-en-Y gastric bypass (RYGB) and laparoscopic sleeve gastrectomy (SG). For RYGB, a small (30–40 ml) gastric pouch was created and an antecolic end-toside gastrojejunostomy was constructed as a 25-mm circular stapler anastomosis. The alimentary limb was measured, and a side-to-side jejunojejunostomy was performed with a linear stapler 120–140 cm below the gastrojejunostomy.
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The SG was created along a 36 F calibration bougie using linear staplers. Resection was initiated 5 cm proximal to the pylorus and carried out upward until the angle of His. In all cases, the stapler line was reinforced by oversewing.
(IQR) unless otherwise specified. Significance was calculated using the pair-sample or two-sample t test. A two-sided p value 315 μg/kg/h [18, 20]. Liver Biopsy Liver specimens were obtained at the time of surgery by wedge biopsy. A single hepatopathologist reviewed and classified the liver biopsies. Grading and staging of NASH was conducted according to Kleiner et al. [24, 25]. The NAFLD activity score (NAS) comprises different histological features: steatosis (0–3), lobular inflammation (0–3), and hepatocellular ballooning (0–2). Cases with NAS of 0–2 were considered not diagnostic of NASH, cases with 3–4 were considered as borderline and cases with NAS ≥5 were considered diagnostic of NASH. Fibrosis was divided into five stages: none (F0), perisinusoidal or periportal (F1), perisinusoidal and periportal (F2), bridging fibrosis (F3), and cirrhosis (F4) [24]. Laboratory Tests Blood samples were collected prior to surgery, 6 and 12 months postoperatively. Biochemical parameters (aspartate aminotransferase (AST), alanine aminotransferase (ALT), γglutamyltransferase (γ-GT), bilirubin, alkaline phosphatase (AP)) were determined at the Institute of Clinical Chemistry of the RWTH Aachen University Hospital. Normal range of ALT and AST is 10–50 U/l. For γ-GT 10–71 U/l and AP 40– 130 U/l is considered normal. Normal value of bilirubin is 14 months. Detailed clinical and demographic data are summarized in Table 1. Nine patients underwent laparoscopic RYGB and 25 patients laparoscopic SG. Twenty-two of the34 patients (65 %) were female. The average age of all patients was 44 ± 12 years. Comorbidities were as follows: type 2 diabetes mellitus (44 %), hypertension (74 %), dyslipidemia (41 %), obstructive sleep apnea syndrome (24 %), and coronary heart disease (9 %) (Table 1). Median length of stay in hospital was 7 days (IQR=3). Mortality rate was 0 %; postoperative complications as assessed by the Clavien-Dindo classification were two grade I complications (wound infections) and one grade III complication (suture insufficiency). The mean preoperative BMI was 52±7 kg/m2. Bariatric surgery led to a significant reduction of mean BMI to 38± 6 kg/m2 after 6 months and 34±7 kg/m2 after 12 months. Mean percent excess BMI loss (%EBMIL) was 53 % after 6 months and 68 % after 1 year. %EBMIL was not significantly different for RYGB and SG after 6 months (56 vs 51 %; p=0.754) and 12 months (78 vs 65 %; p=0.15). Liver Function Capacity Mean liver function capacity was calculated from the available patients: 34 preoperatively, 25 after 6–7 months and 23 after 12–14 months. Mean liver function capacity increased significantly from 255 μg/kg/h (±90) preoperatively to 324 μg/kg/h (±94) after 6 months (p=0.003). After 12 months, liver function capacity rose to 342 μg/kg/h (±103), which was
OBES SURG Table 1
Patients’ characteristics
Demographic data Male Female Age (years) BMI (kg/m2) Comorbidities
12 22 44 52
35 % 65 % ±12 ±7
Type 2 diabetes mellitus Hypertension Dyslipidemia Obstructive sleep apnea syndrome Coronary heart disease Surgery Sleeve gastrectomy Roux-en-Y gastric bypass Mortality Morbiditya
15 25 14 8 3
44 % 74 % 41 % 24 % 9%
25 9 0
74 % 26 % 0%
Grade I Grade III NAFLD activity score No NASH Borderline Manifest NASH Median NAS
2 1
6% 3%
8 6 4 3
44 % 33 % 22 % IQR=4
a
According to Clavien-Dindo classification of surgical complications
significantly different from the preoperative value (p80 %) showed almost no improvement of the liver function or even deterioration. This effect could not be observed after 1 year, possibly indicating a stabilization of metabolic processes. Liver biopsy is certainly the gold standard for grading and staging of NAFLD, but unfortunately, it has several negative aspects: biopsies are invasive, unpleasant for patients, often technically challenging in obese individuals and cost- and time-consuming procedures [26]. Furthermore, it underlies a sampling variability as a biopsy only represents approximately 1/50,000 part of the organ [26, 38]. Because of the high prevalence of NAFLD and the invasiveness of liver biopsy, much effort is being expended on developing noninvasive diagnostic tools. Various methods have been investigated, e.g., laboratory tests, imaging techniques, or transient elastography. Conventional biochemical parameters have the advantage that they are easily and cheaply obtained. ALT elevation, after exclusion of recognized causes of hepatic inflammation, is a marker of NAFLD [8]. In our study, ALT, AST, and γ-GT decreased significantly within months. However, preoperative levels of these parameters were already within the normal ranges. Other studies observed the whole spectrum of NAFLD including advanced fibrosis and cirrhosis in patients with completely normal laboratory findings [26, 39, 40]. Fracanzani et al. compared histological data from 458 patients to liver enzymes and found that ALT is not a valid criterion for excluding patients from liver biopsy [41]. The authors of the study suggest considering insulin resistance in subjects with normal ALT for histological assessment, which underlines the importance of glucose metabolism in NAFLD [41]. Noninvasive imaging methods such as ultrasound, magnetic resonance imaging (MRI), and computed tomography can be employed to further investigate the liver. These techniques are sensitive (80–100 %) [42], but negative imaging studies do not rule out NAFLD [15]. Furthermore, CT examinations are expensive, sometimes technically not feasible because of scanner weight limitations and associated to radiation exposure. Transient elastography is a relatively new technique which measures liver tissue elasticity. Elasticity shows significant correlation with the degree of liver fibrosis [43, 44]. Unfortunately, in obese individuals, the subcutaneous fat layer often hampers liver stiffness measurement [45]. Wong and
colleagues obtained valid liver stiffness measurements in 98 % of the patients with normal BMI, but only in 75 % of the subjects with BMI greater than 30 kg/m2 [43]. Hence, the current noninvasive approaches to diagnosis, staging, and management of NAFLD and NASH are deficient. This study provides the first comparison of liver biopsy and liver function measured by the LiMAx test method. The liver specimens were evaluated according to Kleiner et al. and indicated with NAS and stage of fibrosis [24, 25]. NAS score correlated negatively with liver function capacity; furthermore, patients with a normal liver function did not show a manifest NASH. The LiMAx testing as a noninvasive tool may potentially be able to distinguish NASH from simple steatosis. This could facilitate screening of obese individuals and of other suspect cases for NASH. Furthermore, repetitive LiMAx testing might enable monitoring of disease course and evaluation of response to bariatric surgery. NAFLD per se is today not an indication for bariatric surgery, but further research is urgently needed to determine the benefit of bariatric surgery in these patients. A limitation of the study is the relatively small number of patients undergoing RYGB, which limits the conclusions regarding varieties between SG and RYGB. Furthermore, follow-up data were incomplete as approximately one third of the patients were not available for evaluation after 1 year. It would certainly be interesting to obtain additional histologic specimens 6 and 12 months after surgery and correlate the results with liver function capacity. Therefore, these data have to be regarded as preliminary and further studies have to be conducted. The pandemic prevalence of NAFLD in Western countries necessitates a noninvasive approach to staging and monitoring of therapy. In our study, we were able to show that the LiMAx value correlates to NAS score and may be a useful method for the staging of NAFLD. Furthermore, this study demonstrated that bariatric surgery leads to a functional recovery of the liver. Today, NAFLD per se is not an indication for bariatric surgery. Future research will determine the benefit of bariatric surgery in NAFLD patients at high risk of developing liver cirrhosis.
Conflict of Interest The authors (Patrick H. Alizai, Janica Wendl, Anjali A. Roeth, Christian D. Klink, Tom Luedde, Inga Steinhoff, Ulf P. Neumann, Maximilian Schmeding, Florian Ulmer) declare that they have no conflict of interest. Funding Funding played no role in this study. Informed Consent Informed consent was obtained from all individual participants included in the study. Statement of Human Rights The study was conducted in accordance with the 1964 Declaration of Helsinki and its later amendments and had received prior approval by the Local Ethics Committee.
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ORIGINAL CONTRIBUTIONS
Functional Liver Recovery After Bariatric Surgery—a Prospective Cohort Study with the LiMAx Test Patrick H. Alizai 1 & Janica Wendl 1 & Anjali A. Roeth 1 & Christian D. Klink 1 & Tom Luedde 2 & Inga Steinhoff 3 & Ulf P. Neumann 1 & Maximilian Schmeding 1 & Florian Ulmer 1
# Springer Science+Business Media New York 2015
Abstract Background Bariatric surgery provides long-term weight loss and improvement of obesity-associated diseases such as nonalcoholic steatohepatitis (NASH). Histologic improvement of NASH has been reported in some studies after bariatric surgery. This study was designed to assess the liver function in obese patients as well as its recovery after bariatric surgery with a noninvasive test method. Methods In a prospective cohort study from October 2011 to May 2014, morbidly obese individuals receiving bariatric surgery were investigated for functional liver recovery (n=34). Liver function was determined by the LiMAx test (enzymatic capacity of cytochrome P450 1A2) preoperatively, 6 and 12 months postoperatively. Liver biopsy specimens were obtained from 18 participants and classified according to the nonalcoholic fatty liver disease (NAFLD) activity score (NAS).
Results The mean age of participants was 44 years, and the mean body mass index (BMI) was 52 kg/m2. The mean percent excess BMI loss (%EBMIL) was 53 % after 6 months and 68 % after 1 year. Mean liver function capacity increased significantly from 255 μg/kg/h preoperative to 324 μg/kg/h after 6 months and 342 μg/kg/h after 12 months. A negative correlation was observed between %EBMIL and alteration of liver function capacity in the first 6 months. Finally, the median NAS showed a negative correlation with liver function capacity. Conclusions Bariatric surgery leads to a significant functional recovery of the liver. An initial marked weight loss may negatively influence functional liver recovery.
Keywords NAFLD . NASH . Liver regeneration . Bariatric surgery . Liver function . LiMAx
* Patrick H. Alizai [email protected]
Maximilian Schmeding [email protected]
Janica Wendl [email protected] Anjali A. Roeth [email protected]
Florian Ulmer [email protected] 1
Department of General, Visceral and Transplantation Surgery, RWTH Aachen University Hospital, Pauwelsstr. 30, 52074 Aachen, Germany
2
Department of Gastroenterology, Digestive Diseases and Intensive Care Medicine, RWTH Aachen University Hospital, Pauwelsstr. 30, 52074 Aachen, Germany
3
Institute of Pathology, RWTH Aachen University Hospital, Pauwelsstr. 30, 52074 Aachen, Germany
Christian D. Klink [email protected] Tom Luedde [email protected] Inga Steinhoff [email protected] Ulf P. Neumann [email protected]
OBES SURG
Abbreviations ALT Alanine aminotransferase AP Alkaline phosphatase AST Aspartate aminotransferase BMI Body mass index γ-GT γ-Glutamyltransferase IQR Interquartile range LiMAx Liver maximum capacity test MPF Medium-power field NAFLD Nonalcoholic fatty liver disease NAS NAFLD activity score NASH Nonalcoholic steatohepatitis %EBMIL Percent excess BMI loss %LiMAx Percentage change of LiMAx value RYGB Roux-en-Y gastric bypass SG Sleeve gastrectomy
Introduction The prevalence of overweight and obesity has increased dramatically in recent years. Approximately half or more than half of the Western world’s population is overweight (body mass index (BMI) ≥25 kg/m2) or obese (BMI ≥30 kg/m2) [1]. Morbid obesity is associated with increased risks of type 2 diabetes, hypertension, cardiovascular disease, dyslipidemia, sleep-apnea syndrome, and various other comorbidities, which may lead to further morbidity and mortality [2–5]. The hepatic manifestation of the metabolic syndrome is nonalcoholic fatty liver disease (NAFLD), which is among the most common causes of chronic liver disease in Western countries [6]. NAFLD includes a wide clinicopathological spectrum ranging from simple steatosis to nonalcoholic steatohepatitis (NASH), which may progress to liver cirrhosis [7]. Over a follow-up of 10–15 years, about 20 % of patients with NAFLD will progress to NASH and about 10 % of patients with NASH will develop cirrhosis [8, 9]. In Western countries, the prevalence of NAFLD is approximately 25 % and that of NASH is 3 %, while in obese individuals, up to 85 % have NAFLD and over 50 % may have NASH [8]. Bariatric surgery has proved to be the most effective weight reduction treatment for morbidly obese individuals [3, 10, 11]. It is safe and provides long-term weight loss and significant reduction or remission of most obesity-associated diseases [5, 11–14]. Furthermore, bariatric procedures have also been shown to improve NAFLD and NASH [15]. In recent studies, a decrease in liver steatosis, hepatocyte ballooning, and inflammation could be demonstrated and some studies found improvement in liver fibrosis [8, 15]. Histological examination is certainly the gold standard for diagnosis and staging of NAFLD, but liver biopsies are not without risk [16]. Moreover, histological findings do not necessarily reflect the liver function and its changes after bariatric surgery and
consecutive weight loss. Different approaches toward an effective measurement of the liver function were described in the literature, but a consensus concerning the appropriate test has yet to be established [17–19]. The LiMAx test has recently been introduced and can validly determine liver function capacity [18, 20–22]. It is based on hepatic 13C-methacetin metabolism by the cytochrome P450 1A2 system and provides an interindividually comparable and quantitative value of enzymatic liver function capacity [18, 20, 21]. So far, the LiMAx test is used in liver surgery, liver transplantation, and sepsis [20–23]. The aim of this study was to evaluate the changes in liver function capacity after bariatric surgery determined by the LiMAx test.
Patients and Methods Study Design This prospective study was conducted at the interdisciplinary bariatric center of the RWTH Aachen University Hospital between October 2011 and May 2014. The study protocol included visits preoperatively, 6 and 12 months after bariatric surgery. At every study visit, clinical data (age, body weight, excess BMI loss, comorbidities) and biochemical parameters were recorded. Liver function capacity was monitored by the LiMAx test. Additionally, liver biopsy specimens were obtained at the time of surgery. Retrieved data were pseudonymized and saved in a secured database. The study was conducted in accordance with the 1964 Declaration of Helsinki and its later amendments and had received prior approval by the Local Ethics Committee (EK 312/11). Written informed consent was obtained from each patient before enrolment. Patients Participants were bariatric surgery candidates with body mass indices of >40 or >35 kg/m2 with weight-related comorbidities. Exclusion criteria were minority, heavy smoking (>15 cigarettes per day), alcohol consumption (>20 g/day for men and >10 g/day for women), and participation in another clinical trial and causes of liver disease other than NAFLD (e.g., viral hepatitis). All patients received the standard clinical management independent of the study protocol. Surgical procedures were laparoscopic Roux-en-Y gastric bypass (RYGB) and laparoscopic sleeve gastrectomy (SG). For RYGB, a small (30–40 ml) gastric pouch was created and an antecolic end-toside gastrojejunostomy was constructed as a 25-mm circular stapler anastomosis. The alimentary limb was measured, and a side-to-side jejunojejunostomy was performed with a linear stapler 120–140 cm below the gastrojejunostomy.
OBES SURG
The SG was created along a 36 F calibration bougie using linear staplers. Resection was initiated 5 cm proximal to the pylorus and carried out upward until the angle of His. In all cases, the stapler line was reinforced by oversewing.
(IQR) unless otherwise specified. Significance was calculated using the pair-sample or two-sample t test. A two-sided p value 315 μg/kg/h [18, 20]. Liver Biopsy Liver specimens were obtained at the time of surgery by wedge biopsy. A single hepatopathologist reviewed and classified the liver biopsies. Grading and staging of NASH was conducted according to Kleiner et al. [24, 25]. The NAFLD activity score (NAS) comprises different histological features: steatosis (0–3), lobular inflammation (0–3), and hepatocellular ballooning (0–2). Cases with NAS of 0–2 were considered not diagnostic of NASH, cases with 3–4 were considered as borderline and cases with NAS ≥5 were considered diagnostic of NASH. Fibrosis was divided into five stages: none (F0), perisinusoidal or periportal (F1), perisinusoidal and periportal (F2), bridging fibrosis (F3), and cirrhosis (F4) [24]. Laboratory Tests Blood samples were collected prior to surgery, 6 and 12 months postoperatively. Biochemical parameters (aspartate aminotransferase (AST), alanine aminotransferase (ALT), γglutamyltransferase (γ-GT), bilirubin, alkaline phosphatase (AP)) were determined at the Institute of Clinical Chemistry of the RWTH Aachen University Hospital. Normal range of ALT and AST is 10–50 U/l. For γ-GT 10–71 U/l and AP 40– 130 U/l is considered normal. Normal value of bilirubin is 14 months. Detailed clinical and demographic data are summarized in Table 1. Nine patients underwent laparoscopic RYGB and 25 patients laparoscopic SG. Twenty-two of the34 patients (65 %) were female. The average age of all patients was 44 ± 12 years. Comorbidities were as follows: type 2 diabetes mellitus (44 %), hypertension (74 %), dyslipidemia (41 %), obstructive sleep apnea syndrome (24 %), and coronary heart disease (9 %) (Table 1). Median length of stay in hospital was 7 days (IQR=3). Mortality rate was 0 %; postoperative complications as assessed by the Clavien-Dindo classification were two grade I complications (wound infections) and one grade III complication (suture insufficiency). The mean preoperative BMI was 52±7 kg/m2. Bariatric surgery led to a significant reduction of mean BMI to 38± 6 kg/m2 after 6 months and 34±7 kg/m2 after 12 months. Mean percent excess BMI loss (%EBMIL) was 53 % after 6 months and 68 % after 1 year. %EBMIL was not significantly different for RYGB and SG after 6 months (56 vs 51 %; p=0.754) and 12 months (78 vs 65 %; p=0.15). Liver Function Capacity Mean liver function capacity was calculated from the available patients: 34 preoperatively, 25 after 6–7 months and 23 after 12–14 months. Mean liver function capacity increased significantly from 255 μg/kg/h (±90) preoperatively to 324 μg/kg/h (±94) after 6 months (p=0.003). After 12 months, liver function capacity rose to 342 μg/kg/h (±103), which was
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Patients’ characteristics
Demographic data Male Female Age (years) BMI (kg/m2) Comorbidities
12 22 44 52
35 % 65 % ±12 ±7
Type 2 diabetes mellitus Hypertension Dyslipidemia Obstructive sleep apnea syndrome Coronary heart disease Surgery Sleeve gastrectomy Roux-en-Y gastric bypass Mortality Morbiditya
15 25 14 8 3
44 % 74 % 41 % 24 % 9%
25 9 0
74 % 26 % 0%
Grade I Grade III NAFLD activity score No NASH Borderline Manifest NASH Median NAS
2 1
6% 3%
8 6 4 3
44 % 33 % 22 % IQR=4
a
According to Clavien-Dindo classification of surgical complications
significantly different from the preoperative value (p80 %) showed almost no improvement of the liver function or even deterioration. This effect could not be observed after 1 year, possibly indicating a stabilization of metabolic processes. Liver biopsy is certainly the gold standard for grading and staging of NAFLD, but unfortunately, it has several negative aspects: biopsies are invasive, unpleasant for patients, often technically challenging in obese individuals and cost- and time-consuming procedures [26]. Furthermore, it underlies a sampling variability as a biopsy only represents approximately 1/50,000 part of the organ [26, 38]. Because of the high prevalence of NAFLD and the invasiveness of liver biopsy, much effort is being expended on developing noninvasive diagnostic tools. Various methods have been investigated, e.g., laboratory tests, imaging techniques, or transient elastography. Conventional biochemical parameters have the advantage that they are easily and cheaply obtained. ALT elevation, after exclusion of recognized causes of hepatic inflammation, is a marker of NAFLD [8]. In our study, ALT, AST, and γ-GT decreased significantly within months. However, preoperative levels of these parameters were already within the normal ranges. Other studies observed the whole spectrum of NAFLD including advanced fibrosis and cirrhosis in patients with completely normal laboratory findings [26, 39, 40]. Fracanzani et al. compared histological data from 458 patients to liver enzymes and found that ALT is not a valid criterion for excluding patients from liver biopsy [41]. The authors of the study suggest considering insulin resistance in subjects with normal ALT for histological assessment, which underlines the importance of glucose metabolism in NAFLD [41]. Noninvasive imaging methods such as ultrasound, magnetic resonance imaging (MRI), and computed tomography can be employed to further investigate the liver. These techniques are sensitive (80–100 %) [42], but negative imaging studies do not rule out NAFLD [15]. Furthermore, CT examinations are expensive, sometimes technically not feasible because of scanner weight limitations and associated to radiation exposure. Transient elastography is a relatively new technique which measures liver tissue elasticity. Elasticity shows significant correlation with the degree of liver fibrosis [43, 44]. Unfortunately, in obese individuals, the subcutaneous fat layer often hampers liver stiffness measurement [45]. Wong and
colleagues obtained valid liver stiffness measurements in 98 % of the patients with normal BMI, but only in 75 % of the subjects with BMI greater than 30 kg/m2 [43]. Hence, the current noninvasive approaches to diagnosis, staging, and management of NAFLD and NASH are deficient. This study provides the first comparison of liver biopsy and liver function measured by the LiMAx test method. The liver specimens were evaluated according to Kleiner et al. and indicated with NAS and stage of fibrosis [24, 25]. NAS score correlated negatively with liver function capacity; furthermore, patients with a normal liver function did not show a manifest NASH. The LiMAx testing as a noninvasive tool may potentially be able to distinguish NASH from simple steatosis. This could facilitate screening of obese individuals and of other suspect cases for NASH. Furthermore, repetitive LiMAx testing might enable monitoring of disease course and evaluation of response to bariatric surgery. NAFLD per se is today not an indication for bariatric surgery, but further research is urgently needed to determine the benefit of bariatric surgery in these patients. A limitation of the study is the relatively small number of patients undergoing RYGB, which limits the conclusions regarding varieties between SG and RYGB. Furthermore, follow-up data were incomplete as approximately one third of the patients were not available for evaluation after 1 year. It would certainly be interesting to obtain additional histologic specimens 6 and 12 months after surgery and correlate the results with liver function capacity. Therefore, these data have to be regarded as preliminary and further studies have to be conducted. The pandemic prevalence of NAFLD in Western countries necessitates a noninvasive approach to staging and monitoring of therapy. In our study, we were able to show that the LiMAx value correlates to NAS score and may be a useful method for the staging of NAFLD. Furthermore, this study demonstrated that bariatric surgery leads to a functional recovery of the liver. Today, NAFLD per se is not an indication for bariatric surgery. Future research will determine the benefit of bariatric surgery in NAFLD patients at high risk of developing liver cirrhosis.
Conflict of Interest The authors (Patrick H. Alizai, Janica Wendl, Anjali A. Roeth, Christian D. Klink, Tom Luedde, Inga Steinhoff, Ulf P. Neumann, Maximilian Schmeding, Florian Ulmer) declare that they have no conflict of interest. Funding Funding played no role in this study. Informed Consent Informed consent was obtained from all individual participants included in the study. Statement of Human Rights The study was conducted in accordance with the 1964 Declaration of Helsinki and its later amendments and had received prior approval by the Local Ethics Committee.
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