Mohamed H. Ahmed

Bariatric Surgery as Potential Treatment for Nonalcoholic Fatty Liver Disease: A Future Treatment by Choice or by Chance?

Morbid obesity is strongly associated with nonalcoholic fatty liver disease (NAFLD) which is one of the most common causes of chronic liver disease worldwide. The current best treatment of NAFLD and NASH is weight reduction through life style modifications, antiobesity medication, and bariatric surgery. Importantly, bariatric surgery is the best alternative option for weight reduction if lifestyle modifications and pharmacological therapy have not yielded long-term success. Bariatric surgery is an effective treatment option for individuals who are grossly obese and associated with marked decrease in obesity-related morbidity and mortality. The most common performed bariatric surgery is Roux-en-Y gastric bypass (RYGB). The current evidence suggests that bariatric surgery in these patients will decrease the grade of steatosis, hepatic inflammation, and fibrosis. NAFLD per se is not an indication for bariatric surgery. Further research is urgently needed to determine (i) the benefit of bariatric surgery in NAFLD patients at high risk of developing liver cirrhosis (ii) the role of bariatric surgery in modulation of complications of NAFLD like diabetes and cardiovascular disease. The outcomes of the future research will determine whether bariatric surgery will be one of the recommended choice for treatment of the most progressive type of NAFLD.

Nonalcoholic Fatty Liver Disease and Cardiovascular Disease: Has the Time Come for Cardiologists to Be Hepatologists?

Nonalcoholic fatty liver disease (NAFLD) is prevalent in people with the metabolic syndrome and type 2 diabetes and is present in up to one-third of the general population. Evidence is now accumulating that NAFLD is associated with obesity and diabetes and may serve as a predictor of cardiovascular disease (CVD). The possible mechanisms linking NAFLD and CVD include inflammation and oxidative stress, hyperlipidaemia, insulin resistance, and direct impact of NAFLD on coronary arteries and left ventricular dysfunction. In addition, several studies suggest that NAFLD is associated with high risk of CVD and atherosclerosis such as carotid artery wall thickness and lower endothelial flow-mediated vasodilation independently of classical risk factors and components of the metabolic syndrome. It is not yet clear how treatment of NAFLD will modulate the risk of CVD. Furthermore, studies are urgently needed to establish (i) the pathophysiology of CVD with NAFLD and (ii) the benefit of early diagnosis and treatment of CVD in patients with NAFLD. In the absence of biochemical markers, it is crucial that screening and surveillance strategies are adopted in clinical practice in the growing number of patients with NAFLD and at risk of developing CVD. Importantly, the current evidence suggest that statins are safe and effective treatment for CVD in individuals with NAFLD.

Current treatment of non-alcoholic fatty liver disease

Non‐alcoholic fatty liver disease (NAFLD) is the most common cause of liver disease in Western World and frequently associated with insulin resistance and overweight and occurs often with type 2 diabetes. Interestingly, NAFLD is not only regarded as a hepatic component of the metabolic syndrome but also as an independent risk factor and a marker for increase in cardiovascular disease (CVD). Significantly, NAFLD is associated with an increased risk of all‐cause mortality and predicts future CVD events independent of age, sex, LDL‐cholesterol and features of metabolic syndrome. Although there was initial concern about drug toxicity with NAFLD, increasing evidence suggests that commonly used drugs such as metformin and statins do not cause harm and the thiazolidinediones (TZDs) may even confer a therapeutic benefit in NAFLD. Interestingly, medical and surgical treatments of obesity show potential benefit in treating NAFLD. In this review, we have focused on the safety and therapeutic impact of TZDs, statins, metformins and obesity medications in NAFLD. The potential benefit of bariatric surgery and the role of weight loss per se in treating NAFLD are also discussed.

Non-Alcoholic Fatty Liver Disease (NAFLD): new challenge for general practitioners and important burden for health authorities?

Non-alcoholic fatty liver disease (NAFLD) is the most common cause of hepatic dysfunction encountered in general practice. A large proportion of individuals with type 2 diabetes and the metabolic syndrome develop NAFLD. NAFLD is associated with severe insulin resistance and increased risk of cardiovascular disease and can progress to non-alcoholic steato-hepatitis, liver cirrhosis and cancer. Currently the only known effective treatments for NAFLD are lifestyle changes including stable weight loss and a diet low in calories. General practitioners will increasingly play a key role in dealing with this evolving but serious epidemic of NAFLD and associated metabolic complications. However, success will depend on the appropriate systems and mechanisms being in place in primary care and the proper motivation, support and education of the patient. This review provides the primary care physician with: (a) a step-by step guide of how to identify NAFLD, (b) information to exclude common other causes of liver fat accumulation and (c) additional insight into relationships between NAFLD and other conditions such as obesity, cardiovascular disease and type 2 diabetes.

Bariatric surgery and renal function: a precarious balance between benefit and harm

Medical treatment of obesity and lifestyle modification have limited effectiveness in treating it in morbidly obese individuals. Importantly, bariatric surgery is regarded as the only therapy that is effective in maintaining significant weight loss in morbidly obese individuals. Despite the fact that bariatric surgery-induced weight loss is associated with a significant decrease in morbidity and mortality and improvement in renal function, bariatric surgery has recently been shown to be associated with a significant risk of nephrolithiasis. The main risk factor for nephrolithiasis is increased excretion of urinary oxalate. In this review, we discuss the association between bariatric surgery, an increased risk of renal stone formation and oxalate nephropathy.

Tamoxifen-induced non-alcoholic steatohepatitis: where are we now and where are we going?

Tamoxifen is a cheap and effective estrogen-receptor antagonist, used as the adjuvant hormonal treatment of choice in women with estrogen-receptor-positive breast cancer. Tamoxifen-induced non-alcoholic steatohepatitis (NASH) may increase the demand on oncologists, not only with regard to screening for diabetes, but also for the suggested link of NASH with high incidence of coronary heart disease. At present, there is no guideline for treatment of hyperlipidaemia associated with tamoxifen-induced NASH. However, exemstane (and other aromatase inhibitors) has been shown to lower triglyceride and have a neutral effect on low-denisty lipoprotein and cholesterol levels. These may be alternative agents if severe progressive liver disease or hyperlipidaemia were encountered with tamoxifen administration. Other lipid-lowering medications may have potential benefits in the treatment of tamoxifen-induced NASH and is discussed in this article.

The Relationship between Nonalcoholic Fatty Liver Disease and Colorectal Cancer: The Future Challenges and Outcomes of the Metabolic Syndrome

Nonalcoholic fatty liver disease (NAFLD) is closely related to insulin resistance, metabolic syndrome, obesity, type 2 diabetes, and dyslipidaemia. Obesity and metabolic syndrome are associated with an increased cancer risk, and recent evidence demonstrated an association between NAFLD and colorectal cancer (CRC). The mechanism of how NAFLD can be associated with increased risk of CRC is not fully understood; however, NAFLD represents a condition of profound insulin resistance and a proinflammatory state. Insulin and insulin-like growth factors may promote the development of CRC through their proliferative and antiapoptotic effects. Patients with NAFLD have reduced expression of adiponectin, an adipokine with anti-inflammatory effects. Importantly, hypoadiponectinemia is associated with an increased risk of CRC. Decreased levels of adiponectin lead to increased insulin levels due to marked insulin resistance and in turn increased insulin growth factor-1 (IGF-1). Insulin binds to IGF-1 receptors and plays an important role in cell proliferation, apoptosis, and increased production of vascular endothelial growth factor, an angiogenic factor that supports cancer growth. Further studies are needed to establish (i) the pathophysiology of NAFLD with colorectal cancer, (ii) the benefit of early screening of CRC in NAFLD patients, and (iii) the impact of treatment of NAFLD in the modulation of the risk of colorectal cancer.

Biochemical markers: the road map for the diagnosis of nonalcoholic fatty liver disease.

Fatty liver is a common histologic finding in human liverbiopsy specimens. It affects 10% to 24% of the general popu-lation and is believed to be a marker of risk of later chronicliver disease. Nonalcoholic fatty liver disease (NAFLD) is themost common cause of liver dysfunction, as determined byliver function testing, and it has been estimated that, withincreasing levels of obesity in the United States, 20 millionpatients are affected.NAFLD represents a spectrum of diseases, ranging fromsimple fatty liver (steatosis) to steatosis with inflammationand necrosis to cirrhosis that occurs in people who drink littleor no alcohol. Nonalcoholic steatohepatitis (NASH) repre-sents the more severe end of this spectrum and is associatedwith progressive liver disease, fibrosis, and cirrhosis.

Potential therapeutic uses for ezetimibe beyond lowering LDL-c to decrease cardiovascular events.

Ezetimibe is a relatively new drug that inhibits the absorption of dietary cholesterol in the small intestine. It is a low density lipoprotein‐cholesterol (LDL‐C) lowering medication that acts directly on the intestine by inhibiting Niemann‐Pick C1 Like1 (NPC1L1). Recently, results of the ARBITER 6–HALTS trial (Arterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol 6–HDL and LDL Treatment Strategies) and the ENHANCE trial (Ezetimibe and Simvastatin in Hypercholesterolemia Enhances Atherosclerosis Regression) showed that ezetimibe had no effect on atherosclerosis despite producing a marked decrease in LDL‐C. Recent studies show a potential benefit of ezetimibe in treating insulin resistance, non‐alcoholic fatty liver disease (NAFLD), gallstones and dyslipidaemia associated with chronic renal failure and organ transplantation. All of these conditions are known to be associated with an increase in risk of cardiovascular disease (CVD) and further studies are needed to assess the potential benefits of ezetimibe in these therapeutics areas.

Ezetimibe as a potential treatment for non-alcoholic fatty liver disease: is the intestine a modulator of hepatic insulin sensitivity and hepatic fat accumulation?

Non-alcoholic fatty liver disease (NAFLD) is the hepatic component of the metabolic syndrome and is known to be associated with marked insulin resistance and increased risk of cardiovascular disease. Ezetimibe, an inhibitor of intestinal cholesterol absorption, inhibits Niemann-Pick C1-like 1 (NPC1L1). Interestingly, NPC1L1 is abundantly expressed in human liver, as well as in the intestine. Recent reports suggest a potential benefit of ezetimibe in improving hepatic insulin sensitivity and decreasing hepatic inflammation and lipid accumulation. Insulin resistance and excess hepatic fat accumulation are regarded as key factors in the pathogenesis of NAFLD. We suggest, therefore, that urgent studies are needed to assess the potential therapeutic benefit of ezetimibe in treating NAFLD.