At least 30% of the Western population estimated to have Non-alcoholic fatty liver disease (NAFLD).  It is the commonest cause of abnormal liver tests in the community and is closely associated with his ‘big brother’ metabolic syndrome (MS), which comprised of central obesity, type 2 diabetes mellitus (type 2 DM), hypertension and hyperlipidemia. NAFLD may be present in at least 50-70% of patients with type 2 DM. India being the ‘diabetic capital’ one would anticipate a much higher prevalence of NAFLD. In patients with NAFLD the prevalence of MS is around 40%.  NAFLD is emerging as an important health issue of concern in both adults and children because it increases the risk of type 2 diabetes mellitus, hypertension, ischaemic heart disease, and death.  

Dr. Dinesh Jothimani talks about fatty liver

NAFLD, the liver manifestation of MS is characterized by steatosis (fatty liver). Progressive steatosis leads to non-alcoholic steatohepatitis (NASH) in at least 40% of patients, which is characterized by hepatic inflammation. Long-standing inflammatory mileu leads to fibrosis and eventually to approximately 10% of patients. Studies show that many cases of ‘cryptogenic cirrhosis’ is probably due to ‘burnt out’ NASH.

In addition, NASH cirrhosis increases the risk of hepatocellular carcinoma by several folds. The presence of diabetes increases the risk of fibrosis. In addition, obesity also results in progressive liver damage leading to cirrhosis.

Clinical presentation

Like most chronic liver conditions, patients with NAFLD are asymptomatic until late. The majority of them are detected rather incidentally. ‘Fatigue’ may be observed in some patients but being a non-specific symptom, it may not always trigger the thought of NAFLD. The most commonly observed abnormality is slightly elevated transaminases such as aspartate aminotransferase (AST or SGOT) and alanine aminotransferase (ALT or SGPT). However, the sensitivities of the liver enzymes are poor for the detection of NAFLD. Furthermore, these enzymes do not differentiate between simple steatosis and steatohepatitis. In a recent Italian study, biopsy-proven NASH was present in up to 60% of patients with type 2 diabetes with normal liver enzymes. Ultrasound abdomen may show a ‘bright liver’. The advantages of ultrasound are it is readily available, non-invasive and inexpensive. However, the limitations are that it is not a sensitive until the steatosis is moderate to severe, a result may vary depending on the observer. The presence of abdominal obesity can further reduce its sensitivity. To further complicate this issue, other rare conditions such as iron overload can also increase the brightness of the liver.  In addition, ultrasound lacks specificity for excluding hepatic steatosis.

Magnetic resonance spectroscopy (MRS) is emerging as a non-invasive tool for detecting hepatic steatosis and is superior to ultrasound. However, it is not readily available and is expensive. None of these above tests differentiate between simple steatosis and steatohepatitis, as the prognosis considerably different between these two groups.

Liver biopsy is considered to be the ‘gold standard’ for the detection and assessment of NAFLD. It is readily available and helps to classify steatosis as mild, moderate and severe depending on the presence of <5%, 5 to 33% and >33% fat, respectively. It is the only investigation that differentiates between steatosis and steatohepatitis. However, it is an invasive procedure with some rare but significant complications such as pain, bleeding, pneumothorax, bile leak and very rarely, death.

Fibroscan (Transient elastography) is the latest tool developed by French scientists to measure ‘liver stiffness’. It works on the principle that firmer the liver propagates low-frequency waves (50 Hz) quicker than normal liver tissue. It is simple to use, non-invasive, reproducible, less inter and intraobserver variability and is not expensive. It quantifies fibrosis indirectly with a sensitivity of 80% for mild, moderate fibrosis and cirrhosis, respectively. It helps to assess fibrosis progression as a consequence of NAFLD but does not differentiate steatosis from steatohepatitis.

The current trend around the world is to utilize combinations of liver enzymes, ultrasound, and fibroscan in the management of NAFLD.

Pathogenesis of NAFLD:

The key pathogenesis in the development of NAFLD is insulin resistance

Pathogenesis of NAFLD steatosis

The pathogenesis of NAFLD is complex. There is wary of metabolic imbalance in adipocytes and liver. Increased intake of carbohydrate and fructose-containing diet results in hyperinsulinemia. This results in adipose tissue insulin resistance, which subsequently causes lipolysis resulting in increased FFA. This FFA is utilized for hepatic triglyceride synthesis resulting in steatosis. In the liver, hepatic insulin resistance and increased dietary carbohydrates result in lipogenesis.

Steatohepatitis

Hyperlipidemia and hepatic steatosis activate proinflammatory cytokines TNF alpha secreted by activated Kupffer cells through mitochondria dysfunction, lysosomal disruption and endoplasmic reticulum (ER) stress resulting steatohepatitis. Chronic liver injury results in hepatocyte death.

Fibrosis and cirrhosis

Chronic inflammation and reduced adiponectin stimulate stellate cells resulting in scarring (fibrosis). Reduced Persistent fibrosis leads to the development of cirrhosis.

Treatment of NAFLD

Measures to improve insulin sensitivity is the key for both NAFLD and MS management. However, the lack of single effective therapy led to a multi-dimensional treatment approaches such as lifestyle modification, weight loss, change in dietary habit and exercise. Unfortunately, most studies are only performed to evaluate and there is a lack of long term data in the management of NAFLD. Weight loss of 5-10% over 6 months has been shown to improve NAFLD and indeed obesity. Rapid weight loss ironically exacerbates NAFLD and hence not recommended.

Diet

Diet and exercise are shown to reduce hepatic steatosis and obesity. Diet rich in carbohydrates and saturated fats should be avoided. Most of the fast-food contain that trans-fat has shown to worsen the liver injury and increase hepatic triglycerides. Polyunsaturated fatty acid seems to improve liver enzymes. Many soft drinks contain fructose that increases lipogenesis, insulin resistance, and NAFLD. Hence, excessive soft drinks generally not recommended. Diet with the low glycemic index, rich in fruits & vegetables with limited meat consumption is recommended.

Exercise

Both the ‘brothers’ are susceptible to exercise. It aids weight reduction, improvement in liver enzymes and decreases the risk of type 2 DM. Moderate exercise with an expenditure of 400 calories for at least 3-4 times a week has shown to improve NAFLD in the short term.

Drugs

Various drugs have been studied with varying results.

Metformin is an insulin-sensitizing agent. Apart from improving insulin sensitivity, it helps weight reduction. When used for NAFLD patients there was some reduction in liver enzymes, however, randomized controlled studies showed no improvement in liver histology.

Pioglitazone increases insulin sensitivity, improves steatosis, and inflammation. However, it is associated with weight gain. Rosiglitazone improves liver histology (FLIRT trial) but only in the short term but not in the long term. This drug has been suspended by the FDA due to cardiovascular risks.

Orlistat is a lipase inhibitor. Studies show that improves transaminases, steatosis and weight reduction of 8% over 3 months. Long term studies are required to confirm their benefit. Side effects are bloating and diarrhea.

Sibutramine is a serotonin reuptake inhibitor that increases satiety leading to moderate weight reduction. This drug has been withdrawn from the UK due to cardiovascular risks.

Rimonaobant is a cannabanoid receptor antagonist that was shown to improve insulin sensitivity, but this drug was withdrawn from the market due to severe psychiatric effects.

A new glucagon-like peptide (GLP-1) analogue, Exanetide has been studied. In patients with type 2 DM, it has been shown to improve glycemic control, suppresses appetite and also induces weight reduction. This may be beneficial in patients with MS and NAFLD in the future.

Angiotensin receptor blocker (ARB) such as Losartan has been shown to inhibit proinflammatory cytokines and stellate activation. Human studies in small numbers showed improved liver enzymes and histology in NASH patients. Long term data is not available.

Pentoxyphylline, Vitamin E and UDCA failed to show any benefit in NAFLD patients.

Surgery

Bariatric surgery has been increasingly performed throughout the world. A recent meta-analysis suggested improvement in steatosis and steatohepatitis of 90% and 80%, respectively, but the varying outcomes on fibrosis. Various options include Roux-en Y gastric bypass, laparoscopic gastric banding.  It should be considered for morbidly obese (BMI>40) patients who are otherwise unable to lose weight by other measures.

Endoscopically placed Intragastric Balloon (IB) is an attractive alternative to bariatric surgery. This is a temporary measure that has shown to improve liver enzymes, insulin sensitivity if the weight reduction was >10%. Long term data are needed to confirm its efficacy.

                                                                                                         - Dr. Dinesh Jothimani MRCP (UK), FRCP(Glasgow), is a DirectorTransplant Hepatologist, Dr. Rela Institute & Medical Centre, Chennai