Non-Alcoholic Fatty Liver Disease: A silent pandemic

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Non-alcoholic fatty liver disease commonly known as NAFLD is the most prevalent liver disease in human history, with prevalence estimates indicating it affects almost two billion people globally. NAFLD has become the leading cause of chronic liver disease and the number one indication for liver transplantation worldwide. Alongside progressive liver damage, NAFLD is becoming an established risk factor for other leading causes of death and disability in the twenty-first century, namely cancer, cardiovascular disease, and type 2 diabetes mellitus (T2DM). Despite the already staggering number, NAFLD burden is expected to grow in the coming decades, compromising individual health, burdening health- care systems, and causing substantial economic and well-being losses. First identified in the 1980s, NAFLD is an umbrella term, the essential component of which is excess (>5%) fat in the liver (Non-alcoholic fatty liver-NAFL). Excess fat in the liver can induce liver inflammation in the form of ballooning of liver cells, inflammation of lobules, apoptotic bodies, and Mallory-Denk bodies (Non-alcoholic Steatohepatitis-NASH).

NASH is associated with varying degrees of scarring or liver fibrosis (F), which is conventionally scored under METAVIR (Meta-analysis of Histological Data in Viral Hepatitis) scoring system as F0—no fibrosis, F1—portal fibrosis, F2—periportal fibrosis, F3—bridging fibrosis, and F4— nodule formation (Liver cirrhosis). It is believed that most patients with cryptogenic cirrhosis may have what is considered “burned-out” NAFLD. Patients with NASH +Fibrosis and those with cirrhosis (F4) can progress to develop liver cancer (Hepatocellular carcinoma-HCC) and NAFLD is the third most common cause of HCC in the United States and is increasing at a rate of 9% annually (Fig 1). NAFLD is a disease of exclusion and all other possible causes of fat in the liver must be excluded before a diagnosis of NAFLD is made. This includes excessive alcohol consumption (alcoholic fatty liver disease-AFLD), chronic hepatitis C infection (genotype 3), Wilson’s disease, lipodystrophies, starvation, parenteral nutrition, abetalipoproteinemia, and drugs (amiodarone, methotrexate, tamoxifen, lomitapide, and corticosteroids). Another form of fatty liver called microvesicular steatosis occurs in Reye’s syndrome, drugs (valproate and antiretroviral medication), acute fatty liver of pregnancy, and HELLP syndrome and is unrelated to NAFLD. NAFLD is associated with several comorbidities which may be related to obesity or independent of it. Obesity (excessive body mass index [BMI] and visceral obesity) is the most common and well-documented risk factor for NAFLD.

The entire spectrum of obesity, ranging from overweight to obese and severely obese, is associated with NAFLD. There is a very high prevalence of NAFLD in individuals with T2DM. Some studies have suggested that around one-third to two-thirds of diabetic patients have NAFLD. It is also important to remember the importance of the bidirectional association between NAFLD and T2DM. In this context, T2DM, and NAFLD can develop almost simultaneously in a patient, which confounds the 2 prevalence of NAFLD in patients with T2DM or the prevalence of T2DM in patients with NAFLD. High serum triglyceride (TG) levels and low serum high-density lipoprotein (HDL) levels are also common in patients with NAFLD. The prevalence of NAFLD in individuals with dyslipidemia attending lipid clinics has been estimated to be 50%. Metabolic syndrome, as defined by a constellation of (1) waist circumference greater than 102 cm in men or greater than 88 cm in women; (2) TG level 150 mg/dL or greater; (3) HDL cholesterol level less than 40 mg/dL in men and less than 50 mg/dL in women; (4) systolic blood pressure 130 mm Hg or greater or diastolic pressure 85 mm Hg or greater; and (5) fasting plasma glucose level 110 mg/dL or greater, is an important determinant of NAFLD. NAFLD is frequent in patients with polycystic ovary syndrome (PCOS). Obesity and insulin resistance are considered the main factors related to NAFLD in PCOS. Androgen excess may be an additional contributing factor to the development of NAFLD. Age, sex, and ethnicity also play a role as risk factors for NAFLD. NAFLD increases with age, is more common in males, and has a higher prevalence in South America, the Middle East, and Asia and a low prevalence in Africa.

The South Asian phenotype of NAFLD is distinctive as patients have lower BMI and obesity rates with an ethnic disparity in visceral fat distribution (Lean NAFLD). Hypothyroidism, obstructive sleep apnoea, hypopituitarism, hypogonadism, pancreatoduodenal resection, and psoriasis have also been associated with NAFLD. Diet has been thought of as an independent risk factor for the development of NAFLD, specifically, a diet high in fats. It has been shown that dietary modifications can reduce metabolic syndrome through energy restriction and manipulation of dietary macronutrients, namely, restriction of carbohydrates, fat, or enrichment with monounsaturated fatty acids. Diets that model after a Westernized pattern, such as those high in red meat consumption, refined grains, pastries, and sugar-laden beverages are associated with a greater likelihood of the development of the metabolic syndrome and subsequent NAFLD. A diet high in fructose may increase the risk of developing NAFLD. Fructose is one of the ingredients in common table sugar and is the dominant ingredient in high fructose corn syrup, a common sweetener. It’s highly linked to metabolic syndrome.

NAFLD is emerging as an important cause of liver disease in India and occurs in 9-32% of the general population. Kashmir is in the middle of an epidemic of metabolic syndrome and NAFLD. NAFLD is a potentially progressive liver disease and shall pose a serious health problem to our community in near future. What could be the possible reasons for introducing metabolic syndrome and NAFLD in our community of late? The focus has to be our changing sedentary lifestyle and food habits. It is shocking to know that a plate of wazwan shared by 4 persons serves around 40,000 kilo-calories and indulgence in this delicacy shall throw anybody’s metabolic system into disarray and load the liver with fat, similar to what binge drinking can do in the West (Fig 2). So, if we need to fight this metabolic syndrome and liver disease caused by NAFLD, we need to be on roads and gyms rather than driving luxurious cars, go back to our delicious Haak (Cabbage) and rice rather than the delicacy of Wazwan and maintain a body mass index at least under 25. The pathogenesis of NAFLD is possibly based on insulin resistance which plays a key role in the accumulation of excessive fat in the liver. This leads to adipose tissue dysfunction and the production and secretion of adipokines and inflammatory cytokines with consequent steatohepatitis.

The gut microbiota has been recognized as one of the key players in the pathogenesis of NAFLD. Gut microbiota not only influences the absorption and disposal of nutrients to the liver but also conditions hepatic inflammation by supplying toll-like receptor 3 ligands, which can stimulate liver cells to produce proinflammatory cytokines. Accordingly, the modification of intestinal bacterial flora by specific probiotics has been proposed as a therapeutic approach for the treatment of NASH. A majority (up to two-thirds) of patients with NAFLD have no symptoms and are not aware of the disease. Early symptoms include fatigue related to sleep apnoea, RUQ pain and bloating caused by distension of the liver capsule, and skin manifestations of Insulin resistance namely acanthosis nigricans, skin tags, hirsutism, (ovarian hyperandrogenism), and androgenetic alopecia. The mortality from NAFLD with NASH and early fibrosis comes from cardiovascular rather than liver-related outcomes.

Furthermore, cancer-related mortality is among the leading causes of mortality in NAFLD patients, mainly driven by extrahepatic malignancies followed by HCC. Once a diagnosis of NASH and/or advanced fibrosis (i.e., fibrosis stage 3 or cirrhosis) and/or portal hypertension is confirmed patients are at an increased risk for liver-related complications (i.e., hepatic decompensation and hepatocellular carcinoma) and liver-related mortality. Evaluation of NAFLD includes tools to identify NAFL, diagnose NASH and identify fibrosis and its severity (F0-F4). All possible competing causes of steatosis and alternative causes of liver disease must be explored. A liver biopsy is a gold standard for the diagnosis of NAFLD. However, due to the risk involved and the availability of non-invasive tests, liver biopsy is indicated in a select group of patients who will benefit and include those with competing or unclear diagnoses and conflicting clinical data. Hepatic steatosis is commonly detected on ultrasound or computed tomography (CT). These modalities have poor sensitivity, detect fat when 20-33% of the liver parenchyma is involved, and cannot accurately quantify the amount of fat. Patients with NAFLD have higher levels of liver transaminases. However, up to 60% of patients with NASH have persistently or intermittently normal liver enzymes. Serum biomarkers such as NashTest predict hepatocyte apoptosis, oxidative stress, and inflammation and may predict NASH. Hepatic fibrosis can be assessed by serum biomarkers for fibrosis (NAFLD fibrosis score, Fibrosis 4 index, and AST-ALT ratio) and/or imaging tools like transient elastography (Fibroscan or fibrotouch), Shear wave elastography, and MR elastography. Remarkable progress in the understanding of the pathogenesis of NAFLD has led to an explosion of medical therapies targeting various aspects of fat accumulation and injury pathways.

For NAFL, a combination of a hypocaloric diet, moderate-intensity exercise, and weight loss of 3 to 10% is recommended. Drugs to lower body weight (Orlistat) may be used and are helpful in select cases. Pharmacological treatment options are limited and should be employed in only patients with NASH with advanced fibrosis or those who are likely to progress to advanced fibrosis because of comorbidities.

These include the administration of Pioglitazone, Vitamin E, Saroglitazar, and Obeticholic acid. Statins and fenofibrate to target high cholesterol and/or TG may be used. Metformin, ursodeoxycholic acid, and Omega-3 fatty acids are not effective in NAFLD and are not recommended for treatment. Bariatric surgery is an option for morbidly obese and may be effective in those with progressive NASH with fibrosis. Hepatologists, cardiologists, and endocrinologists have a significant role to play to manage progressive liver disease, cardiac events, and T2DM. Patients need screening for HCC and early intervention if detected. A liver transplant is an option for those with end-stage liver disease with or without HCC and NAFLD is now the number one indication for liver transplant in most liver transplant centers.

(PROF. MOHAMMAD SULTAN KHUROO MD, DM, FRCP (Edin), FACP, Master American College of Physicians (MACP, Emeritus). Former Director, Professor and Head Gastroenterology, Chairman Dept. Medicine, Sher-IKashmir Institute of Medical Sciences, Soura, Srinagar, Kashmir, India. Director, Digestive Diseases Centre, Dr.Khuroo’s Medical Clinic, Srinagar, Kashmir, India. E-mail: khuroo@yahoo.com, mohammad.khuroo@gmail.com, Website: www.drkhuroo.com. )

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