Cover photo credit: Wikimedia

Which comes first, a damaged liver or obesity? That’s like a chicken and egg conundrum! In his blog ‘Insulin and Fatty Liver Disease’, Dr. Jason Fung, M.D. accounts an interesting observation made in the late-nineteenth century by the University of Vienna’s Dr. Alfred Frohlich that eventually paved the way to the connection between the liver and obesity. He found that obese vertebrates with hypothalamus injury shared a common feature of having a damaged liver, suggesting a complex link between the brain, liver, and obesity. Despite his findings, the answer to the causality question was still in haze and the fact that excess fat in the body can lead to liver damage did not start gaining interest until the mid-twentieth century.

When obesity is not associated with alcohol consumption and there is significant liver damage due to accumulation of fat, a condition called Non-alcoholic Fatty Liver Disease (NAFLD) develops. When NAFLD is associated with damage in the liver due to severe inflammation, a sub-condition of NAFLD called Non-alcoholic steatohepatitis (NASH) develops. Implications that dietary changes to control obesity could subdue the development or progression of NAFLD are not surprising. In a recent study, a positive correlation between trunk/limb fat mass ratio and severity in liver disease has been suggested. Interestingly, bariatric surgery at an early age seems to reverse the conditions of liver pathologies later in life. This is primarily due to a shift in the storage of fat from subcutaneous to visceral adipose tissue with aging. Therefore, fat storage in visceral adipose tissue is a major driver towards disease pathology accompanied by inflammatory responses. Such conditions could eventually develop into insulin resistance or cirrhosis (due to NASH), which accounts for 30-40% of deaths due to a non-functioning liver (Figure 1).

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Figure 1: Illustration that depicts the natural history in the context of NAFLD. Disease spectrum can range from inflammatory cascades that happens in steatohepatitis to hepatocellular carcinoma (HCC), complications that could prevent liver functioning and account for 30-40% liver related mortality.

 

The incidence of NAFLD is at a steady increase globally with predominance in the Western countries, possibly due to diet and lifestyle. In the United States, nearly 80 – 100 million people have been estimated to suffer from some kind of NAFLD. Utilizing information from the American Liver Foundation, if we segment the patient population for NASH by age, the majority of the disease incidence occurs between 40 and 60 years of age with a higher prevalence in women. Interestingly, in contrast to hepatitis C that affects 3.2 million Americans, NASH has been projected to afflict greater than 25 million Americans by the year 2025. That’s an alarming prediction and is potentially due to the significant rise in childhood obesity. Therefore, if we try to crystallize our present understanding on the staggering growth of NAFLD in the US, it is not difficult to make our judgement that a carbohydrate-rich diet could be a key player behind all of these troubles! The figure below (Figure 2) nicely illustrates fat and sugar consumption in the global context and shows that per capita sugar consumption is significantly higher (~126 g/ person / day) in US compared to the WHO recommended baseline.

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Figure 2. Global fat and sugar consumption in grams. The data based on a market research study carried out by Euromonitor and covered in the Washington Post suggests higher intake of fat and sugar in US compared to Asian and European countries.

 

Diseases such as NAFLD that display clear association with daily sugar consumption bear far-reaching implications, the impact of which is driven by socio-economic scenarios. Interestingly, with rare exceptions, countries with a dietary regimen inclined towards the consumption of high fat and sugar have a counter-balancing and relatively steady infrastructure for early diagnosis that determines the reimbursement policies for severe liver conditions such as steatohepatitis. A liver biopsy is the preferred route to diagnosis of these conditions unless there have been subsidiary tests to confirm the progression of the diseased state. Lifestyle plays a crucial role in NAFLD, particularly because of the link to alcohol consumption under certain circumstances (which could be shaped by society, culture and lifestyle). Therefore, reimbursement policies are tightly influenced by the underlying cause of the disease, at least if alcohol-mediated or not.

Disease diagnosis and understanding the severity of these diseases are still at their inception, mostly due to the asymptomatic nature of NAFLD that could progress to severe condition such as hepatocellular carcinoma (HCC) if not diagnosed early. Besides invasive techniques to assess the level of histologic lesions in conditions such as steatohepatitis, state-of-the-art imaging-based non-invasive strategies are yet to gain sufficient traction in the clinics. The World Gastroenterology Organization (WGO) has generated guidelines to streamline the assessment of the disease pathology and its progression as documented in the diagram below (Figure 3).

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Figure 3: Illustration that delineates the guideline to test NAFLD. Diagnostic guidelines to assess NAFLD recommended by WGO. ALT, alanine aminotransferase; AMA, antimitochondrial antibody; ANA, antinuclear antibody; anti-LKM Ab, anti-liver–kidney microsomal antibody; ASMA, antismooth muscle antibody; AST, aspartate aminotransferase; BMI, body mass index; CT, computed tomography; FBG, fasting blood glucose; GGT, γ-glutamyl transferase; HBsAg, hepatitis B surface antigen; HCV, hepatitis C virus; LFT, liver function tests; NAFLD, nonalcoholic fatty liver disease; OGTT, oral glucose tolerance test. (Adapted from WGO guidelines.)

 

Due to its global epidemiological impact across countries both rich and poor, from a macro-therapeutic perspective there is a huge demand for viable treatment strategies. This creates a significant market value for finding a treatment for NASH. Current efforts are directed towards finding an FDA-approved treatment for a condition derived from NAFLD. Drugs with therapeutic affects with regards to insulin resistance have been suggested as potential areas of investigation for future development NAFLD treatments. The role of mitochondria in energy homeostasis and fat metabolism is another attractive area of interest that may shed light in the context of fatty liver disease.

However, the largest problem lies in the complexity of fat metabolism and the vicious cycle that drives the severity in NAFLD conditions derived from diet and lifestyle. Uncoupling these elements through better proof-of-concept studies and developing experimental models, many of which are already underway, could possibly be the route to follow to get a treatment in the near future. Additionally, early diagnosis through the development of non-invasive imaging strategies could also help prevent disease progression.

Until then, let’s focus on a healthy diet and keep running on that treadmill!