NAFLD: A Practical Approach to Treatment
Patients with NASH cirrhosis are at risk of the same complications of cirrhosis as with any other aetiology of liver disease. The yearly cumulative incidence of HCC is 2.6% per year in patients with NASH cirrhosis. Therefore, surveillance with abdominal ultrasonography (USS) should be performed every 6 months. In unselected cirrhotic patients, USS has a sensitivity ranging from 58% to 89% with a specificity >90% when used as a surveillance test. Ultrasound can be technically difficult in obese patients so it is likely that ultrasound is less sensitive as a surveillance modality in patients with NAFLD, but currently there are no data to support the routine use of CT or MRI for surveillance. CT or MRI could be considered in subjects where ultrasound has failed to produce adequate examination of the liver, but these modalities have their own limitations in obese patients.
α-Fetoprotein is a tumour biomarker and has recently been removed from the European guidelines but is still widely used in clinical practise alongside 6-monthly ultrasound. Although rare, HCC can occur on a background of non-cirrhotic NAFLD.
There is a clear association between obesity and malignancy and hyperinsulinaemia is well recognised as an independent risk factor for many malignancies. Aberrant genes involved in metabolic pathways, such as the AMP-activated protein kinase (AMPK)–LKB1 pathway, are emerging as therapeutic targets in cancer treatment. Metformin acts by inhibiting hepatic glucose production through an LKB1–AMPK-mediated mechanism. There is emerging evidence that metformin reduces the risk of cancer (including HCC) in patients with diabetes in a dose-dependent manner. The mechanisms of the anticancer effects of metformin may include triggering of the LKB1-mediated AMPK pathway, resulting in cancer cell death under conditions of nutrient deprivation, and reducing proliferation of cancer cell lines.
Donadon et al found that metformin treatment was associated with a statistically significant reduction of HCC risk (OR 0.33; CI 0.1 to 0.7, p=0.006) in diabetic patients. The benefit of metformin was confirmed by Hassan et al who found the use of metformin or thiazolidinediones in diabetic patients was associated with a 70% risk reduction of HCC compared with the use of insulin or sulfonylureas. A recent large Taiwanese nationwide case-control study demonstrated a 7% risk reduction per year for HCC in diabetics treated with metformin (adjusted OR=0.93, 95% CI 0.91 to 0.94, p<0.0001).
There is also evidence that statins might reduce the incidence of HCC. An American case-control study examining HCC in diabetic patients found an adjusted OR for statin use of 0.74 (95% CI 0.64 to 0.87). There were no significant associations with non-statin cholesterol- or triglyceride-lowering medications. A Taiwanese population-based case-control study found an adjusted OR of 0.62 (95% CI 0.42 to 0.91) for HCC in patients prescribed statins. Singh et al conducted a systematic review and meta-analysis and found that statin users were less likely to develop HCC than non-users (adjusted OR, 0.63; 95% CI 0.52 to 0.76). The risk reduction was most marked in Asian populations but was also observed in Western populations.
Statins appear to have anticancer effects through both 3-hydroxy-3-methyl-glutaryl-CoA (HMG-CoA) reductase dependent and HMG-CoA reductase independent pathways. They have a variety of actions including: anti-inflammatory and immunomodulatory effects, inhibiting downstream production of mediators of cell growth and promoting programmed cell death. Studies have shown that inactivation of Myc can induce remission of HCC and atorvastatin blocks Myc activation resulting in suppression of tumour growth.
Cirrhotic patients with NASH are at risk of varices as with other liver diseases and their presence correlates with the severity of liver disease (40%–44% if Child–Pugh grade A, 75%–85% if Child–Pugh grade C). Therefore, patients with NASH cirrhosis should undergo endoscopic screening for oesophageal and gastric varices at the time of diagnosis and at regular intervals according to British Society of Gastroenterology or American Association for the Study of Liver Diseases guidelines (see Table 4).
Patients with cirrhosis are at increased risk of osteoporosis and fractures. Cirrhotic patients should have a dual x-ray absorptiometry scan to assess bone mineral density and have their fracture risk assessed using the FRAX tool (http://www.shef.ac.uk/FRAX/tool). The FRAX tool has an easy online link to the National Osteoporosis Guideline Group website which provides management advice according to the patient's risk of fracture. Table 4 summarises the management of the complications of NASH cirrhosis.
NASH cirrhosis is now the third commonest indication for liver transplantation in the USA and accounted for 12% of patients listed for transplantation in the UK in 2009. Patient and graft survival in liver transplantation for NASH are comparable with other indications. Although recurrence of NASH is common post-transplant, occurring in 4%–25% of patients, it does not appear to impact on graft survival. Patients who are transplanted for NASH cirrhosis frequently have multiple cardiovascular risk factors that should be managed aggressively post-transplant to prevent cardiovascular-related mortality. UK guidelines on liver transplantation suggest that bariatric surgery can be considered at the time of liver transplantation for patients with NASH and morbid obesity.
Lifestyle interventions aimed at weight loss and increased activity are essential for all patients with NAFLD and if sustained are effective in the treatment of NAFLD. For patients who fail lifestyle intervention, liver-directed pharmacotherapy with pioglitazone or vitamin E can be considered for those with advanced, but pre-cirrhotic, NASH. Features of the metabolic syndrome and cardiovascular risk factors are very common in NAFLD, so all patients should be screened for these and have them managed aggressively. For patients who develop advanced disease, they require surveillance for and management of the complications of cirrhosis (HCC, varices, osteoporosis).
Managing the Complications of Cirrhosis
Hepatocellular Carcinoma
Patients with NASH cirrhosis are at risk of the same complications of cirrhosis as with any other aetiology of liver disease. The yearly cumulative incidence of HCC is 2.6% per year in patients with NASH cirrhosis. Therefore, surveillance with abdominal ultrasonography (USS) should be performed every 6 months. In unselected cirrhotic patients, USS has a sensitivity ranging from 58% to 89% with a specificity >90% when used as a surveillance test. Ultrasound can be technically difficult in obese patients so it is likely that ultrasound is less sensitive as a surveillance modality in patients with NAFLD, but currently there are no data to support the routine use of CT or MRI for surveillance. CT or MRI could be considered in subjects where ultrasound has failed to produce adequate examination of the liver, but these modalities have their own limitations in obese patients.
α-Fetoprotein is a tumour biomarker and has recently been removed from the European guidelines but is still widely used in clinical practise alongside 6-monthly ultrasound. Although rare, HCC can occur on a background of non-cirrhotic NAFLD.
There is a clear association between obesity and malignancy and hyperinsulinaemia is well recognised as an independent risk factor for many malignancies. Aberrant genes involved in metabolic pathways, such as the AMP-activated protein kinase (AMPK)–LKB1 pathway, are emerging as therapeutic targets in cancer treatment. Metformin acts by inhibiting hepatic glucose production through an LKB1–AMPK-mediated mechanism. There is emerging evidence that metformin reduces the risk of cancer (including HCC) in patients with diabetes in a dose-dependent manner. The mechanisms of the anticancer effects of metformin may include triggering of the LKB1-mediated AMPK pathway, resulting in cancer cell death under conditions of nutrient deprivation, and reducing proliferation of cancer cell lines.
Donadon et al found that metformin treatment was associated with a statistically significant reduction of HCC risk (OR 0.33; CI 0.1 to 0.7, p=0.006) in diabetic patients. The benefit of metformin was confirmed by Hassan et al who found the use of metformin or thiazolidinediones in diabetic patients was associated with a 70% risk reduction of HCC compared with the use of insulin or sulfonylureas. A recent large Taiwanese nationwide case-control study demonstrated a 7% risk reduction per year for HCC in diabetics treated with metformin (adjusted OR=0.93, 95% CI 0.91 to 0.94, p<0.0001).
There is also evidence that statins might reduce the incidence of HCC. An American case-control study examining HCC in diabetic patients found an adjusted OR for statin use of 0.74 (95% CI 0.64 to 0.87). There were no significant associations with non-statin cholesterol- or triglyceride-lowering medications. A Taiwanese population-based case-control study found an adjusted OR of 0.62 (95% CI 0.42 to 0.91) for HCC in patients prescribed statins. Singh et al conducted a systematic review and meta-analysis and found that statin users were less likely to develop HCC than non-users (adjusted OR, 0.63; 95% CI 0.52 to 0.76). The risk reduction was most marked in Asian populations but was also observed in Western populations.
Statins appear to have anticancer effects through both 3-hydroxy-3-methyl-glutaryl-CoA (HMG-CoA) reductase dependent and HMG-CoA reductase independent pathways. They have a variety of actions including: anti-inflammatory and immunomodulatory effects, inhibiting downstream production of mediators of cell growth and promoting programmed cell death. Studies have shown that inactivation of Myc can induce remission of HCC and atorvastatin blocks Myc activation resulting in suppression of tumour growth.
Varices
Cirrhotic patients with NASH are at risk of varices as with other liver diseases and their presence correlates with the severity of liver disease (40%–44% if Child–Pugh grade A, 75%–85% if Child–Pugh grade C). Therefore, patients with NASH cirrhosis should undergo endoscopic screening for oesophageal and gastric varices at the time of diagnosis and at regular intervals according to British Society of Gastroenterology or American Association for the Study of Liver Diseases guidelines (see Table 4).
Osteoporosis and Fracture Risk
Patients with cirrhosis are at increased risk of osteoporosis and fractures. Cirrhotic patients should have a dual x-ray absorptiometry scan to assess bone mineral density and have their fracture risk assessed using the FRAX tool (http://www.shef.ac.uk/FRAX/tool). The FRAX tool has an easy online link to the National Osteoporosis Guideline Group website which provides management advice according to the patient's risk of fracture. Table 4 summarises the management of the complications of NASH cirrhosis.
Liver Transplantation
NASH cirrhosis is now the third commonest indication for liver transplantation in the USA and accounted for 12% of patients listed for transplantation in the UK in 2009. Patient and graft survival in liver transplantation for NASH are comparable with other indications. Although recurrence of NASH is common post-transplant, occurring in 4%–25% of patients, it does not appear to impact on graft survival. Patients who are transplanted for NASH cirrhosis frequently have multiple cardiovascular risk factors that should be managed aggressively post-transplant to prevent cardiovascular-related mortality. UK guidelines on liver transplantation suggest that bariatric surgery can be considered at the time of liver transplantation for patients with NASH and morbid obesity.
Summary
Lifestyle interventions aimed at weight loss and increased activity are essential for all patients with NAFLD and if sustained are effective in the treatment of NAFLD. For patients who fail lifestyle intervention, liver-directed pharmacotherapy with pioglitazone or vitamin E can be considered for those with advanced, but pre-cirrhotic, NASH. Features of the metabolic syndrome and cardiovascular risk factors are very common in NAFLD, so all patients should be screened for these and have them managed aggressively. For patients who develop advanced disease, they require surveillance for and management of the complications of cirrhosis (HCC, varices, osteoporosis).