The global obesity epidemic has dramatically increased the prevalence of NAFLD and made it the leading cause of chronic liver disease in Western nations. NAFLD is considered the hepatic manifestation of the metabolic syndrome and shares a strong association with type 2 diabetes mellitus, obstructive sleep apnea (OSA), and cardiovascular disease. Although cardiovascular disease is the leading cause of death in patients with NAFLD, the subset of patients who meet histopathologic criteria for NASH are those at greatest risk of liver-related morbidity and mortality. Ludwig and colleagues coined the term NASH in 1980 to describe a cohort of middle-aged patients with elevated serum liver enzyme levels who had evidence of alcohol-associated hepatitis on biopsy specimens in the absence of alcohol consumption. Subsequent study led to the proposed “2-hit” hypothesis in which a sequential progression from isolated fatty liver (IFL) to NASH involved the initial “hit” of hepatic steatosis followed by a second “hit” of oxidative stress resulting in liver injury. It was subsequently recognized that patients who have steatohepatitis on a liver biopsy specimen are at greatest risk for progression to cirrhosis compared with those who have IFL. Correspondingly, our understanding of the pathogenesis of NAFLD has evolved from the 2-hit hypothesis. NASH is expected to become the most common cause of cirrhosis and the leading indication for LT in the USA in the 2020s. As a major public health concern, an understanding of its epidemiology and pathogenesis is paramount to facilitate our ability to effectively diagnose and treat patients with NAFLD and NASH.
NAFLD is an increasingly frequent cause of cirrhosis and HCC. In fact, a report published in 2018 listed NAFLD as the second leading non-neoplastic indication for LT in adults in the USA, following alcohol-associated liver disease. Obesity (BMI ≥30 kg/m2) and type 2 diabetes mellitus are commonly encountered in patients with NAFLD; these 2 diseases have been recognized as risk factors for HCC, irrespective of the presence or etiology of cirrhosis. Although BMI is not necessarily a reliable indicator of adiposity in patients with end-stage liver disease, particularly in those with fluid retention and ascites, it is commonly used by many LT centers during the patient selection process. Morbid obesity (BMI ≥40 kg/m2 without significant obesity-related comorbidities or BMI ≥35 kg/m2 associated with obesity-related comorbidities) is commonly regarded as a relative contraindication to LT; however, data from the Organ Procurement and Transplantation Network demonstrate that 16.5% and 5% of patients who underwent LT in 2016 had a BMI greater than or equal to 35 kg/m2 and greater than or equal to 40 kg/m2, respectively.
NAFLD and Liver Transplantation
Analysis of data from the UNOS registry has suggested that the risk of primary graft nonfunction is increased and short- and long-term survival is poorer in morbidly obese liver transplant recipients with various causes of end-stage liver disease. However, when analyzed as an entire cohort and not stratified by BMI, patients with NAFLD have patient and graft survival rates that are comparable to those for other indications for LT. Many of the key precipitants of NAFLD (obesity, hyperlipidemia, and insulin resistance) are exacerbated by immunosuppression. Recurrence of NAFLD after LT causes graft injury, although graft loss does not typically occur. De novo NAFLD after LT has also been described. In the absence of specific therapy for NAFLD, therapeutic efforts after LT should center on weight control, optimal diabetic management, and use of a lipid-lowering agent, if indicated. Intensive noninvasive weight loss interventions pre-LT appear to be successful (reduction of BMI to <35 kg/m2) in a large proportion of patients (84%) enrolled in carefully monitored multidisciplinary protocols; however, 60% of patients regained weight to a BMI ≥35 kg/m2 post-LT. Although bariatric surgery is feasible in selected patients with NAFLD, this intervention is typically reserved for patients with early stages of liver disease and, as is the case for many other abdominal surgical procedures, is contraindicated in those with decompensated cirrhosis because of high morbidity and mortality. A strategy of combining LT with sleeve gastrectomy during the same operation has only been evaluated in small prospective series. The mean surgical time was not significantly different between LT and combined LT/sleeve gastrectomy, and the mean BMI reduction with the combined surgical approach was 20 kg/m2. Metabolic complications, such as post-transplant diabetes mellitus, as well as steatosis of the graft noted by US were significantly less frequent in patients undergoing LT/sleeve gastrectomy compared with patients who lost weight noninvasively pre-LT. The safety and efficacy of this combined surgical approach and other combinations of less invasive weight loss interventions, such as endoscopic techniques, pre-LT must be confirmed by large prospective studies before they can be recommended. Bariatric interventions are still an option post-LT; however, the procedure should be performed by an experienced surgeon, and the role of less invasive endoscopic techniques postLT is still under investigation.
Sleeve Gastrectomy vs NAFLD
Bariatric surgery leads to substantial weight loss that results in improved metabolic parameters and hepatic histology in patients with NAFLD, according to numerous large retrospective and prospective cohort studies. In one study of 109 patients with NASH who underwent follow-up liver biopsy one year after bariatric surgery, 85% of patients had resolution of NASH, and 33% had improvement in fibrosis. Initial concerns that fibrosis would worsen with rapid weight loss were unfounded, as demonstrated in a meta-analysis in which fibrosis improved by 11.9% from baseline after bariatric surgery. Although bariatric surgery is not recommended as a treatment for NASH, the abundant positive data in its favor suggest that surgical weight loss is a viable option for patients with comorbid conditions that would warrant the surgery for other reasons. Patients with NASH cirrhosis are at potentially higher risk for surgical complications, although some centers have demonstrated encouraging results with sleeve gastrectomy in patients with Child-Pugh class A cirrhosis.
The absence of oxygen and nutrients during ischaemia affects all tissues with aerobic metabolism. Ischaemia of these tissues creates a condition which upon the restoration of circulation results in further inflammation and oxidative damage (reperfusion injury). Restoration of blood flow to an ischaemic organ is essential to prevent irreversible tissue injury, however reperfusion of the organ or tissues may result in a local and systemic inflammatory response augmenting tissue injury in excess of that produced by ischaemia alone. This process of organ damage with ischaemia being exacerbated by reperfusion is called ischaemia-reperfusion (IR). Regardless of the disease process, severity of IR injury depends on the length of ischaemic time as well as size and pre-ischaemic condition of the affected tissue. The liver is the largest solid organ in the body, hence liver IR injury can have profound local and systemic consequences, particularly in those with pre-existing liver disease. Liver IR injury is common following liver surgery and transplantation and remains the main cause of morbidity and mortality.
The liver has a dual blood supply from the hepatic artery (20%) and the portal vein (80%). A temporary reduction in blood supply to the liver causes IR injury. This can be due to a systemic reduction or local cessation and restoration of blood flow. Liver resections are performed for primary or secondary tumours of the liver and carry a substantial risk of bleeding especially in patients with chronic liver disease. Significant blood loss is associated with increased transfusion requirements, tumour recurrence, complications and increased morbidity and mortality. Several methods of hepatic vascular control have been described in order to minimise blood loss during elective liver resection. The simplest and most common method is inflow occlusion by applying a tape or vascular clamp across the hepatoduodenal ligament (Pringle Manoeuvre). This occludes both the arterial and portal vein inflow to the liver and leads to a period of warm ischaemia (37 °C) to the liver parenchyma resulting in ‘warm’ IR injury when the temporary inflow occlusion is relieved. In major liver surgery, extensive mobilisation of the liver itself without inflow occlusion results in a significant reduction in hepatic oxygenation.
3. PATOPHYSIOLOGY and RISK FACTORS
A complex cellular and molecular network of hepatocytes, Kupffer cells, liver sinusoidal endothelial cells (LSEC), leukocytes and cytokines play a role in the pathogenesis of IR injury. In general, both warm and cold ischaemia share similar mechanisms of injury. Hepatocyte injury is a predominant feature of warm ischaemia, whilst endothelial cells are more susceptible to cold ischaemic injury. There are currently no proven treatments for liver IR injury. Understanding this complex network is essential in developing therapeutic strategies in prevention and treatment of IR injury. Identifying risk factors for IR injury are extremely important in patient selection for liver surgery and transplantation. The main factors are the donor or patient age, the duration of organ ischaemia, presence or absence of liver steatosis and in transplantation whether the donor organ has been retrieved from a brain dead or cardiac death donor.
4. PREVENTION and TREATMENT
There is currently no accepted treatment for liver IR injury. Several pharmacological agents and surgical techniques have been beneficial in reducing markers of hepatocyte injury in experimental liver IR, however, they are yet to show clinical benefit in human trials. The following is an outline of current and future strategies which may be effective in reducing the detrimental effects of liver IR injury in liver surgery and transplantation.
4.1 SURGICAL STRATEGIES
Inflow occlusion or portal triad clamping (PTC) can be continuous or intermittent; alternating between short periods of inflow occlusion and reperfusion. Intermittent clamping (IC) increases parenchymal tolerance to ischaemia. Hence, prolonged continuous inflow occlusion rather than short intermittent periods results in greater degree of post-operative liver dysfunction. IC permits longer total ischaemia times for more complex resections. Alternating between 15 min of inflow occlusion and 5 min reperfusion cycles can be performed safely for up to 120 min total ischaemia time. There is a potential risk of increased blood loss during the periods of no inflow occlusion. However, these intervals provide an opportunity for the surgeon to check for haemostasis and control small bleeding areas from the cut surface of the liver. The optimal IC cycle times are not clear, although intermittent cycles of up to 30 min inflow occlusion have also been reported with no increase in morbidity, blood loss or liver dysfunction compared to 15 min cycles. IC is particularly beneficial in reducing post-operative liver dysfunction in patients with liver cirrhosis or steatosis.
In liver surgery, IPC ( Ischaemic Preconditioning) involves a short period of ischaemia (10 min) and reperfusion (10 min) intraoperatively by portal triad clamping prior to parenchymal transection during which a longer continuous inflow occlusion is applied to minimise blood loss. It allows continuous ischaemia times of up to 40 min without significant liver dysfunction. However, the protective effect of IPC decreases with increasing age above 60 years old and compared to IC it is less effective in steatotic livers. Moreover, IPC may impair liver regeneration capacity and may not be tolerated by the small remnant liver in those with more complex and extensive liver resections increasing the risk of post-operative hepatic insufficiency.
In order to avoid direct ischaemic insult to the liver by inflow occlusion, remote ischaemic preconditioning (RIPC) has been used. RIPC involves preconditioning a remote organ prior to ischaemia of the target organ. It has been shown to be reduce warm IR injury to the liver in experimental studies. A recent pilot randomised trial of RIPC in patients undergoing major liver resection for colorectal liver metastasis used a tourniquet applied to the right thigh with 10 min cycles of inflation-deflation to induce IR injury to the leg for 60 min. This was performed after general anaesthesia prior to skin incision. A reduction in post-operative transaminases and improved liver function was shown without the use of liver inflow occlusion. These results are promising but require validation in a larger trial addressing clinical outcomes.
5. FUTURE PERSPECTIVES
Hepatic IR injury remains the main cause of morbidity and mortality in liver surgery and transplantation. Despite over two decades of research in this area, therapeutic options to treat or prevent liver IR are limited. This is primarily due to the difficulties in translation of promising agents into human clinical studies. Recent advances in our understanding of the immunological responses and endothelial dysfunction in the pathogenesis of liver IR injury may pave the way for the development of new and more effective and targeted pharmacological agents.
Hepatocellular carcinoma is the second most common cause of cancer mortality worldwide and its incidence is rising in North America, with an estimated 35,000 cases in the U.S. in 2014. The best chance for cure is surgical resection in the form of either segmental removal or whole organ transplantation although recent survival data on radiofrequency ablation approximates surgical resection and could be placed under the new moniker of “thermal resection”. The debate between surgical resection and transplantation focuses on patients with “within Milan criteria” tumors, single tumors, and well compensated cirrhosis who can safely undergo either procedure. Although transplantation historically has had better survival outcomes, early diagnosis, reversal of liver disease, and innovations in patient selection and neo-adjuvant therapies have led to similar 5-year survival. Transplantation clearly has less risk of tumor recurrence but exposes recipients to long term immunosuppression and its side effects. Liver transplantation is also limited by the severe global limit on the supply of organ donors whereas resection is readily available. The current data does not favor one treatment over the other for patients with minimal or no portal hypertension and normal synthetic function. Instead, the decision to resect or transplant for HCC relies on multiple factors including tumor characteristics, biology, geography, co-morbidities, location, organ availability, social support and practice preference.
Resection Versus Transplantation
The debate between resection and transplantation revolves around patients who have well compensated cirrhosis with Milan criteria resectable tumors. Patients within these criteria represent a very small proportion of those who initially present with HCC. This is especially true in western countries where hepatitis C is the most common cause of liver failure and HCC is a result of the progressive and in most cases advanced cirrhosis.
Given the need for a large number of patients to show statistical significance, it would be difficult to perform a high-quality prospective randomized controlled trial comparing resection and transplantation. In fact the literature revealed that no randomized controlled trials addressing this issue exist. Instead, outcomes of surgical treatment for HCC stem from retrospective analyses that have inherent detection, selection and attrition biases.
Given the numerous articles available on this subject, several meta-analyses have been published to delineate the role of transplantation and resection for treatment of HCC. However, there is reason to be wary of these meta-analyses because they pool data from heterogeneous populations with variable selection criteria and treatment protocols. One such meta-analysis by Dhir et al. focused their choice of articles to strict criteria which excluded studies with non-cirrhotic patients, fibrolamellar HCC and hepato-cholangiocarcinomas but included those with HCC within Milan criteria and computation of 5-year survival; between 1990 and 2011 they identified ten articles that fit within these criteria, of which six were ITT analyses, six included only well-compensated cirrhotics (Child-Pugh Class A without liver dysfunction) and three were ITT analyses of well-compensated cirrhotics.
Analysis of the six ITT studies that included all cirrhotics (n = 1118) (Child-Pugh Class A through C) showed no significant difference in survival at 5 years (OR = 0.600, 95 % CI 0.291– 1.237 l; p=0.166) but ITT analysis of only well-compensated cirrhotics (Child- Pugh Class A) revealed that patients undergoing transplant had a significantly higher 5-year survival as compared to those with resection (OR=0.521, 95 % CI 0.298–0.911; p=0.022).
A more recent ITT retrospective analysis from Spain assessed long-term survival and tumor recurrence following resection or transplant for tumors <5 cm in 217 cirrhotics (Child-Pugh Class A, B and C) over the span of 16 years. Recurrence at 5 years was significantly higher in the resection group (71.6 % vs. 16 % p<0.001) but survival at 4 years was similar (60 % vs. 62 %) which is likely explained by the evolving role of adjuvant therapies to treat post-resection recurrence.
- Patients with anatomically resectable single tumors and no cirrhosis or Child-Pugh Class A cirrhosis with normal bilirubin, HVPG (<10 mmHg), albumin and INR can be offered resection (evidence quality moderate; strong recommendation).
- Patients with Milan criteria tumors in the setting of Child- Pugh Class A with low platelets and either low albumin or high bilirubin or Child-Pugh Class B and C cirrhosis, especially those with more than one tumor, should be offered liver transplantation over resection (evidence quality moderate; strong recommendation).
- Those with Milan criteria tumors and Child-Pugh Class A cirrhosis without liver dysfunction should be considered for transplantation over resection (evidence quality low; weak recommendation).
- No recommendation can be made in regard to transplanting tumors beyond Milan criteria (evidence quality low) except to follow regional review board criteria.
- Pre-transplant therapies such as embolic or thermal ablation are safe and by expert opinion considered to be effective in decreasing transplant waitlist dropout and bridging patients to transplant (evidence quality low, weak recommendation). These interventions should be considered for those waiting longer than 6 months (evi- dence quality low, moderate recommendation).
- Living donor liver transplantation is a safe and effective option for treatment of HCC that are within and exceed Milan criteria (evidence quality moderate, weak recommendation).