Metabolic syndrome and hepatic surgery

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Metabolic syndrome and hepatic surgery C. Hobeika a, M. Ronot b, A. Beaufrere c, V. Paradis c, O. Soubrane a, F. Cauchy a,∗ a

Service de chirurgie hépato-bilio-pancréatique et transplantation hépatique, Hôpital Beaujon, AP—HP et Université de Paris, 100, boulevard du Général Leclerc, 92110, Clichy, France b Service de radiologie, Hôpital Beaujon, AP—HP et Université de Paris, 100, boulevard du Général Leclerc, 92110, Clichy, France c Service d’anatomo-pathologie, Hôpital Beaujon, AP—HP et Université de Paris, 100, boulevard du Général Leclerc, 92110, Clichy, France

HIGHLIGHTS • • • •

Non-alcoholic fatty liver disease (NAFLD), a hepatic manifestation of metabolic syndrome, currently represents a major problem in liver disease. Metabolic syndrome and NAFLD are major risk factors for the development of hepatocellular carcinoma and intrahepatic cholangiocarcinoma. Non-alcoholic steatohepatitis (NASH) is becoming the most frequent cause of liver transplantation in Western countries. Patients with metabolic syndrome and/or NAFLD are subject to heightened operative risk after liver resection and transplantation and need to be provided with adequately targeted evaluation and perioperative management.

KEYWORDS Metabolic syndrome; Nonalcoholic fatty liver diseases; Hepatocellular carcinoma; Hepatic resection; Liver transplant

Summary In Europe, the prevalence of metabolic syndrome (MS) has reached the endemic rate of 25%. Non-alcoholic fatty liver disease (NAFLD) is the hepatic manifestation of MS. Its definition is histological, bringing together the different lesions associated with hepatic steatosis (fat deposits on more than 5% of hepatocytes) without alcohol consumption and following exclusion of other causes. MS and NAFLD are implicated in the carcinogenesis of hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC). At present, HCC and ICC involving MS represent 15—20% and 20—30% respectively of indications for hepatic resection in HCC and ICC. Moreover, in the industrialized nations NAFLD is tending to become the most frequent indication for liver transplantation. MS patients combine the operative risk associated with their general condition and comorbidities and the risk associated with the presence and/or severity of NAFLD. Following hepatic resection in cases of HCC and ICC complicating MS, the morbidity rate ranges from 20 to 30%, and due to cardiovascular and infectious complications, post-transplantation mortality is heightened. The operative risk incurred by MS patients necessitates appropriate management including: (i) precise characterization of the subjacent liver; (ii) an accurately targeted approach privileging detection and optimization of treatment taking into account the relevant cardiovascular risk factors; (iii) a surgical strategy adapted to the histology of the underlying liver, with optimization of the volume of the remaining (postoperative) liver. © 2019 Elsevier Masson SAS. All rights reserved.

∗ Corresponding author at: Department of HPB surgery and liver transplantation, Beaujon Hospital, University of Paris, 100, boulevard du Général Leclerc, Clichy, 92110, France. E-mail address: [email protected] (F. Cauchy).

https://doi.org/10.1016/j.jviscsurg.2019.11.004 1878-7886/© 2019 Elsevier Masson SAS. All rights reserved.

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Introduction Over the course of the last two decades, the prevalence of metabolic syndrome (MS) has reached endemic proportions in Western countries, with rates as high as 25% in Europe and 33% on the United States [1]. As concerns abdominal disease, increased MS in the industrialized nations has led to the emergence of a new nosological framework, and MS has become a major public health problem. For one thing, non-alcoholic fatty liver disease (NAFLD), the hepatic manifestation of MS, is becoming the most frequent cause of chronic liver disease in the industrialized nations. For another thing, it is now a recognized fact that MS and NAFLD are major risk factors for hepatic carcinogenesis insofar as 15 to 30% of the cases of hepatocellular carcinomas (HCC) with ‘‘cryptogenic etiology’’ reported in the literature could in all likelihood be imputed to these pathologies [2]. Liver surgery for MS patients has become quite frequent in clinical practice. In today’s France, 15 to 20% of liver resections in HCC involve MS patients [3], and in the industrialized countries, NAFLD is tending to become the most frequent indication for liver transplantation (LT) [4]. The elevated risk of postoperative complications incurred by these patients necessitates treatment in a specialized setting [3]. More precisely, improved liver surgery outcomes in MS patients presuppose precise assessment of comorbidities and non-tumor liver tissue along with anticipation of operative risk and perioperative strategy.

Metabolic syndrome and NAFLD MS pathophysiology is largely explained by insulin resistance [5], which is defined as reduction of insulin’s ability to absorb blood glucose in peripheral tissues. The five clinicalbiological criteria defining MS (Table 1) were validated in 2009 [6]; SM diagnosis requires applicability of at least 3 out of the 5 criteria. That much said, definition of the criteria in clinical practice and in relevant studies is not always in accordance with the consensus definition [7]. At times it is erroneously supposed that patients undergoing lipid-lowering treatment (fenofibrate, statins) present with dyslipidemia, while that those taking hyportensive drugs have high blood pressure, and those taking antidiabetic medication would present with diabetes. Threshold body mass index (BMI) values have been proposed as retrospective criteria defining central obesity. Nonalcoholic fatty liver disease (NAFLD) is the hepatic manifestation of the metabolic syndrome. Its definition is histological and brings together the different lesions associated with steatosis (fat deposits in more than 5% of hepatocytes) without alcohol consumption and after having excluded viral or autoimmune causes [8]. NAFLD prevalence is correlated with MS prevalence; in Europe, it is as high as 25% [9]. It is the most frequent cause of chronic liver disease in Western countries [10]. NAFLD comprises a spectrum of histological manifestations ranging from NAFL (Nonalcoholic fatty liver) or simple steatosis to HCC, and also including NASH (Nonalcoholic steatohepatitis) and cirrhosis [11] (Fig. 1). In 44% of cases, NAFL evolves into NASH and in 22% of cases, it evolves into severe fibrosis [11]. Mean durations of evolution from NAFL to NASH and cirrhosis are 28 and 57 years respectively [12]. The most widely utilized score for histological evaluation of NAFLD is the non-alcoholic liver disease activity score (NAS) proposed by Kleiner et al. [13]. As a semi-quantitative

score, it takes three parameters into account: steatosis (graded from 0 to 3), lobular inflammatory infiltrate (graded from 0 to 3) and hepatocellular ballooning (graded from 0 to 2). In 2012, a new NAFLD score was introduced. The SAF (steatosis, activity, fibrosis) score incorporates fibrosis evaluation and seems particularly suitable in assessment of histological NAFLD lesions in obese patients [14]. To summarize, this score takes into account steatosis (graded from 0 to 3), activity evaluated according to lobular inflammation (graded from 0 to 2) and hepatocyte ballooning (graded from 0 to 2), as well as fibrosis (graded from 0 to 4).

MS and primitive hepatic tumors While the mechanisms implicated in hepatic carcinogenesis associated with MS and NAFLD remain largely unknown, numerous studies have established a clear link between MS, NAFLD and the two most frequent primitive hepatic cancers, namely HCC and intrahepatic cholangiocarcinoma (ICC). Elevated prevalence of MS and NAFLD in the general population positions them as major risk factors for primary liver cancer. Indeed, increased HCC incidence in the industrialized countries may be partially explained by the growing prevalence of MS and NAFLD [15]. Presently, HCC involving MS accounts for 15 to 20% of hepatic resections in cases of HCC [3],[16]. Notwithstanding later diagnosis in the absence of systematic screening, prognosis for these lesions seems more favorable than prognosis for HCC complicating viral hepatitis C [16]. The cumulative risk of developing cirrhotic HCC associated with NAFLD approximates 2.6%/year. MS and diabetes are pro-tumoral [17] and intrinsic promoters of HCC. In a liver with NAFLD, HCC involving MS develops in only 50% of cases, without necessarily entailing severe fibrosis (less than 50% of cases), or even steatohepatitis (less than 30% of cases) [18]. While ICC is the second most frequent form of primitive liver cancer, it remains a rare and poorly understood disease. That much said, numerous studies have reported increased ICC incidence over recent decades [19]. By analogy with HCC, heightened ICC incidence could be correlated with heightened MS and NAFLD incidence in the industrialized countries. It has been reported that up to 35% of patients with resectable ICC presented with MS [20] and that MS and NASH-derived cirrhosis was independently associated with ICC occurrence [15,21]. Among MS patients resected due to ICC, 60% suffered from NAFLD and 20—25% from NASH [20,22].

Imagery and non-invasive evaluation of NAFLD While numerous experimental studies have analyzed the performances of different imaging modalities aimed at differentiating simple steatosis and NASH in animals, few comparable studies have been carried out in humans. As of now, imagery alone does not suffice to satisfactorily distinguish simple steatosis from NASH. Abdominal ultrasound remains the first-line radiological examination in NAFLD diagnosis [23]. Steatosis is defined as hyper-echogenicity with regard to the splenic parenchyma and the right renal cortex. Hepatomegaly can also be observed in cases of steatosis. In moderate steatosis, hyperechogenicity can blur the walls of the hepatic and portal veins; in severe steatosis, it can even blur the limits of the diaphragm. Several studies have shown that in detection of hepatic steatosis, ultrasound shows 60—94% sensitivity

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Metabolic syndrome and hepatic surgery Table 1

3

Criteria for clinical diagnosis of metabolic syndrome.

Criteria

Threshold values

Abdominal perimeter

Definition specific to a population and to a concerned country (94 cm for men and 80 cm for women in Europe) ≥150 mg/dL (1.7 mmol/L) <40 mg/dL (1.0 mmol/L) for men; <50 mg/dL (1.3 mmol/L) for women Systolic ≥ 130 and/or diastolic ≥ 85 mm Hg ≥ 100 mg/dL

Triglycerides (or treatment for hypertriglyceridemia) HDL-c (or treatment for low HDL-c) Arterial tension (or hypotension treatment Fasting blood glucose (or diabetes treatment) HDL-c: High-density cholesterol-transporting lipoprotein.

Figure 1.

Histological lesions observed during NAFLD as they evolve.

and 84—95% specificity [24]. Ultrasound sensitivity increases with severe steatosis. A CT-scan can also help to diagnose steatosis by measuring attenuation of the hepatic parenchyma on the quantitative Hounsfield scale (HU), which enables diagnosis and quantification of steatosis using slices without injection. Normal values range from 50 to 65 HU, about 8-10 HU more than the spleen. The greater the hypodensity of the liver, the more severe the steatosis (Fig. 2). It is generally recognized that steatosis can be diagnosed using CT-scan in cases where hepatic attenuation is at least 10 HU less than that of the spleen, or when the absolute value of hepatic attenuation is less than 40 HU [24]. The above values correspond to steatosis approximating 30%. The degrees of CT sensitivity and specificity required to detect moderate to severe steatosis are 100% and 82% respectively. Like ultrasound, a CT scan is not effective in detection of minimal or moderate steatoses (5—30% overload) [25]. In non-invasive NAFLD diagnosis, MRI and proton magnetic resonance spectroscopy (MRS) are much more effective. Almost by definition, MRS ensures direct measurement of the chemical composition of tissues, and can thereby detect even a very small amount of fatty substance. That is why, even though still in the experimental stage, it is already considered as the most sensitive method. Other MRI sequences based on chemical shift, known as imaging in phase or in phase opposition, are markedly simpler and routinely utilized by numerous teams. Several studies have demonstrated satisfactory correlation between sequentially evaluated steatosis severity and liver biopsy results [26]. Presently, replacement of liver biopsy by MRI as a

non-invasive means of stenosis assessment is an idea that is gradually taking hold [27].

Metabolic syndrome and hepatic surgery The different parameters of MS and their impacts on the postoperative sequelae of liver surgery have been extensively studied. Diabetes increases the risk of complications by a factor of 1.5 and doubles the risk of postoperative liver insufficiency after hepatic resection [28]. As regards the impact of obesity in postoperative sequelae, however, the literature is less unequivocal. While obesity seems to increase clamping time and transfusion rates [29], its degree of association with the occurrence of postoperative complications remains controversial. Some authors affirm that with the exception of parietal complications, obesity is not an independent factor for postoperative complications following hepatic resection for HCC [30]. In current practice, however, these patients require specialized management. In expert centers, the proportion of HCC involving cirrhosis in overweight and obese patients has reached 40% et 20% respectively [31]. In this dysmetabolic environment, the histology of a liver with NAFLD compounds the postoperative risks of MS patients. Indeed, from a broad-based histological standpoint NAFLD is independently associated in liver surgery with additional postoperative morbidity [32]. For many years, steatosis has been considered as a risk factor for complications subsequent to hepatectomy [33], the risk being proportionally correlated with NAFLD severity [32]. In reality, steatosis alone does not seem to have an impact in postoperative sequelae [34]; only

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Figure 2. Macroscopic aspect of a steatotic liver. A. Sonography aspect: Without injection, the liver spontaneously shows greater hypodensity than the spleen. Vessel contours are clearly outlined. B. intraoperative aspect.

steatohepatitis seems to be an independent risk factor for postoperative complications [35]. Following major hepatectomy, steatohepatitis aggravates inflammatory response, increases hepatocellular damage, reduces the regenerative capacities of the remaining liver [36] and causes microvascular dysfunction [37]. Livers with NASH consequently show less tolerance of extended resections, leading to a heightened risk of liver failure and postoperative mortality [35]. Overall, MS patients combine environmentally conditioned postoperative risk and the risk associated with NAFLD presence and/or severity (Table 2). After hepatic resection in cases of HCC involving MS, the rate of major complications increases by 20 to 30% [3,16], with over 20% of major cardiorespiratory events and major events involving the liver [3]. A NAS score exceeding 2, and a fortiori NASH, is an independent risk factor predictive of major postoperative complications [3,34]. After hepatic resection for ICC involving MS, the rate of major complications exceeds 50% and MS presence is independently associated with the occurrence of major, particularly cardiorespiratory complications [20].

MS and liver transplant Evolution of NAFLD toward cirrhosis can lead to an indication for liver transplantation (LT). It also seems that even when non-excessive, alcohol consumption may favor NAFLD progression. While there currently exist no precise data on the proportion of totally abstinent patients transplanted due to NASH, the frequency of NASH as an indication for LT rose between 2002 and 2011 from 3% to 19% and quintupled over a 10-year period [42]. In this context, in the industrialized countries NASH is presently becoming the first cause of LT [4]. A number of studies have shown that the long-term outcomes in cases of LT due to NASH were equivalent to those of LT with other etiologies. Survival rates of NASH patients at 1, 3 and 5 years following LT range from 84% to 87.6%, 75% to 82.2% and 70% to 76.7% respectively and are at least equivalent to those following LT carried out for other reasons [42]. However, cardiovascular comorbidities in MS patients [43] and their significantly higher age (> 65 years) at the time of LT raise questions regarding actual LT morbidity in these patients [44]. Some authors have identified a subgroup of high-risk NASH patients combining age > 60 years, obesity, high blood pressure and diabetes, and found that they have lower survival rates at 1 year and at 5 years [45]. By definition, these high-risk subjects present with MS. As observed with hepatic resections, short-term LT outcomes are influenced by NASH. More concretely, LT in NASH

patients is significantly longer in terms of operation and hospitalization duration [46]. Hepatic complications and acute rejection rates seem higher in recipients with NASH [47]; due to cardiovascular and infectious complications, their postLT mortality is particularly elevated [47], [48]. Indeed, the main cause of post-LT morbidity not graft-related is represented by cardiovascular complications (approximately 10% of transplanted patients [49]) due to accumulation of the cardiovascular risk intrinsic to MS and the myocardial dysfunction characterizing cirrhotic patients (‘‘cirrhotic cardiomyopathy’’ [50]). Following LT, NASH patients present with precarious renal function [51] and are at high risk of developing chronic renal disease [52]. Finally, risk of thromboembolic events seems to independently increase in NASH patients, with a significantly higher risk of pretransplantation portal vein thrombosis [53]. After transplantation, MS prevalence can be as high as 50% [54]. The increase seems multifactorial; while primarily drug-based, it is also associated with post-transplantation modification of dietary habits. MS is an independent risk factor for long-term mortality [55]; multiplied by 4, cardiovascular risk is responsible for 19% to 42% of mortality nonspecific to grafts in transplant patients [56]. Reduction of glomerular filtration flow and in micro-albuminuria due to high blood pressure and diabetes is aggravated by immunosuppressive drugs and explains the high rate of chronic renal insufficiency in these patients [54].

Metabolic syndrome and liver surgery: what are their implications in routine practice? MS and NAFLD have an impact on the short-term outcomes of hepatic surgery, and prevalence of these diseases will surely continue to grow over the coming years. Optimized management in hepatic surgery is consequently becoming a major priority. In these patients, a context propitious to cardiorespiratory complications necessitates optimized preoperative cardiovascular evaluation, preoperative conditioning and postoperative screening for cardiorespiratory events [3]. Even in the absence of severe fibrosis, MS patients should be considered as having underlying liver disease and as potentially affected by NASH with or without fibrosis; their regenerative capacities are lessened, as is their tolerance of reduced outflow; moreover, they are particularly exposed to postoperative hepatic insufficiency [36]. Surgical management must consequently combine oncological treatment and mini-invasive parenchymatous-sparing techniques [57]. Major right-side resection must be prepared by means of

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Metabolic syndrome and hepatic surgery Table 2

Summary of the mains studies pertaining to hepatic resection in a MS/NAFLD context.

Study

Wakai, 2011[38] Reddy, 2012[34]

Study objective

HR for HCC with NAFLD HR for NAFLD Steatosis vs. Normal NASH vs. normal

Evaluation of MS parameters

Obesity: n = 11 SM: n = 17

MS: n = 36 Bhayani, 2012[39]

Zarzavadjian Le Bian, 2012[40]

Hepatic resection with vs. without MS context

Right hepatectomy in MS context

Cauchy, 2013[3] Vigano, 2015[16]

HCC involving MS HCC involving MS vs. HCC involving HCV

Tian, 2018[41]

HCC involving MS vs. HCC involving MS + HBV vs. HCC involving HBV

MS: n = 256

ICC involving MS vs. ICC not involving MS

Underlying parenchyma

NAFLD: 100% (n = 17) Steatosis: 100% (n = 72)

Mortality

Morbidity Overall

Hepatic

Cardio-vascular

59%

47%

6%

12%

34.7%

19.4%

11.1%

4.2%

NASH: 100% (n = 102) NA

56.9%

28.4%

26.2%

3.9%

29%

—

22%

6%

NA

23%

—

15%

2%

NAFLD (n = 27)

60%

53%

NA

30%

NA

NA

NA

54%

No MS: n = 3717 > 2 MS parameters: n = 30 ≥ 3 MS parameters n = 13 MS: n = 62

NASH (n = 16)

58%

21%*

17%

11%

MS: n = 96

NASH: 25%

43.8%

31.2%

23.9%

1.0%

HCV: n = 96 MS: n = 81

NASH: 9.4% Steatosis: 45.7% Cirrhosis: 51.8%

38.5% 33.3%

40.6% 21.6%a

15.6% 3.4%

3.1% 2.5%

MS + HBV: n = 117

Steatosis: 41.9% Cirrhosis: 74.3% Steatosis: 17.9% Cirrhosis: 77.8% NASH: 25.0% Cirrhosis: 30%

21.4%

22.2%a

1.7%

2.6%

15.7%

22.8%a

0.8%

2.2%

62.5%a

27.5%a

52.5%

17.5%

29.3%a

18.7%a

17.3%

8.0%

HBV: n = 1154

Hobeika, 2019[20]

5

MS: n = 40

No MS: n = 75

NASH: 5.4% Cirrhosis: 17.3%

HR: Hepatic resection; MS: Metabolic syndrome; NAFLD: non-alcoholic fatty liver disease; HCC: Hepatocellular carcinoma; HCV: Hepatitis C virus; HBV: Hepatitis B virus; NASH: Non-alcoholic steatohepatitis; ICC: Intrahepatic cholangiocarcinoma. a Major complications.

portal embolization [3]. Conversely, in clinical practice simple steatosis without steatohepatitis should no longer be considered as a major risk factor for postoperative complication and does not need to limit surgical indications [34]. Finally, while a laparoscopic approach may reduce the rate of respiratory complications in at-risk patients, frequent

obesity and/or voluminous hepatic parenchyma renders this approach problematically doable. All in all, management of MS patients in hepatic surgery requires: • accurate characterization of the subjacent liver (steatosis vs. steatohepatitis with more or less severe fibrosis) in

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Figure 3. Preoperative evaluation strategy regarding metabolic syndrome patients with an indication of right hepatectomy (PH = portal hypertension; HPVG= hepatic vein portal gradient)

view of measuring the implications of pre-existing conditions in postoperative sequelae; • management specifically addressing the area of interest, with detection and optimization of cardiovascular risk factors; • a surgical strategy taking underlying liver histology into close account, including parenchymatous sparing, preoperative liver evaluation based on hepatic volumetry more or less associated with preoperative volumetric modulation strategies [58] (Fig. 3).

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Conclusions

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Progression of MS and NAFLD in the general population has been contributing to increased incidence of HCC and ICC, thereby creating a new nosological framework that is henceforth part and parcel of a major public health issue. The field of knowledge concerning these diseases has been expanding and management presently encompasses numerous disciplines. Several expert centers have recently reported outcomes of surgery in MS patients closely monitored from the outset of treatment. Given the incidence of metabolic syndrome in the overall population, a substantially increased number of patients is to be expected, and it will necessitate management addressing the areas of interest and, more specifically, the quality of the underlying hepatic parenchyma.

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Disclosure of interest The authors declare that they have no competing interest.

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