Factors beyond diabetes and obesity which may contribute to the development of non-alcoholic fatty liver disease
Perhaps you had a recent screening physical for work, or you hit that magic age of 50 when your doctor suddenly wanted to test “everything” to assess your overall health and disease risk factors. Either way, one of the tests that likely was done (or should have been done) when these tests were performed is a fasting comprehensive metabolic panel. Within this panel, in addition to your fasting blood sugar and electrolytes, additional parameters are assessed that gage your basic kidney and liver function. The values your physician looks at to evaluate your liver function are the albumin (ALB), bilirubin (BILI), alkaline phosphatase (ALK PHOS), aspartate aminotransferase (AST), and alanine aminotransferase (ALT). Your physician also may have included a test known as the gamma-glutamyltransferase (GGT) as well, which also is a marker for liver or gallbladder disease.
Providing your ALB, BILI, and ALK PHOS were in normal range, the two markers which serve to assess liver inflammation are the AST and ALT. ALK PHOS gives indication of if there is biliary tract or gallbladder involvement (e.g. gallbladder stones or bile duct obstruction) among other things, while abnormal levels of ALB and BILI may indicate multiple problems including gallstones, liver infection or cirrhosis, and even malnutrition. Significant abnormalities of ALB and BILI will likely trigger further testing and are also evaluated in the context of the AST, ALT, and ALK PHOS values.
Most often, the majority of these numbers are within normal ranges in healthy people without chronic liver or gallbladder disease who do not use alcohol or drink only moderately. However, at times, even in the absence of these factors, there is liver enzyme (ALT and/or AST) elevation. In fact, a population-based survey from 1999 to 2002 showed that abnormalities of ALT existed in approximately 8.9 percent of respondents. After exclusion of significant alcohol use (more than 15 drinks a week for men, and 10 drinks a week for women), the most common condition leading to AST and ALT elevation is non-alcoholic fatty liver disease (NAFLD).
Increased levels of triglycerides are common in type 2 diabetes, and correspondingly between about 60 to 75% of individuals with type 2 diabetes also have been shown to have NAFLD.
NAFLD is a condition predominantly characterized by fatty infiltration of the liver. Fat, in the form of triglycerides, accumulates in the cells of the liver. This triglyceride accumulation may be due to increased levels in circulation which eventually deposit in the liver, decreased export out of the liver, or decreased fatty acid breakdown. Increased levels of triglycerides are common in type 2 diabetes, and correspondingly between about 60 to 75% of individuals with type 2 diabetes also have been shown to have NAFLD. Obesity plays a role in both the development of both type 2 diabetes and NAFLD, and NAFLD has been shown to be present in 30 to 90% of individuals who are obese.,
There are many reasons why NAFLD also may even be underdiagnosed, particularly in the population without known risk factors such as diabetes and obesity. One of these is that the standard laboratory ranges to which the AST and ALT values are compared often utilize “normal” upper limits which are too high, usually around 40 IU/L, when in fact, the normal upper limit of ALT ranges from 29 to 33 IU/L in men and 19 to 25 IU/l in women. Another factor is the poor sensitivity of diagnostic ultrasound, the most common tool used to evaluate for fatty liver changes. NAFLD is diagnosable by having liver fat of more than 5% (in absence of significant alcohol consumption), however, liver ultrasounds are optimally sensitive to detecting liver changes only when fat percentage is greater than 12.5%. Ultrasound has even worse sensitivity for diagnosing NAFLD in the obese.
NAFLD is diagnosable by having liver fat of more than 5% (in absence of significant alcohol consumption), however, liver ultrasounds are optimally sensitive to detecting liver changes only when fat percentage is greater than 12.5%.
Individuals with diabetes and obesity are not the only people who may present with liver enzyme elevation – there are many other contributory factors which are common among the generally healthy population. Two of these are hypothyroidism and gut dysbiosis, the latter commonly seen as a condition known as small intestinal bacterial overgrowth (SIBO). Gut dysbiosis further gives rise to increased intestinal permeability, which also has been connected with NAFLD.
Hypothyroid and NAFLD
Hypothyroidism is very common condition population-wide with up to 2% of the population experiencing overt hypothyroidism, and numbers as high as 10% affected by subclinical hypothyroidism. A 2017 meta-analysis of 13 studies assessing the possible relationship between NAFLD and hypothyroidism found that both overt hypothyroidism and subclinical hypothyroidism were independently correlated with NAFLD. In one study, individuals with hypothyroidism were approximately twice as likely to have NAFLD, and about four times as likely to have the variant of NAFLD known as non-alcoholic steatohepatitis (NASH), characterized by inflammation accompanying the fatty infiltration. From these and other findings, hypothyroidism has been suggested as an independent risk factor for NAFLD.
Individuals with hypothyroidism were approximately twice as likely to have NAFLD, and about four times as likely to have the variant of NAFLD known as non-alcoholic steatohepatitis (NASH).
Hypothyroidism is associated with metabolic changes, including insulin resistance, dyslipidemia, and obesity, each being a factor which can contribute to the increased risk of NALFD. In addition to these factors, higher levels of oxidative stress have been seen in patients with hypothyroidism,, which can contribute to the development of NAFLD. Both animal and human studies have shown that treatment with thyroid hormone has the ability to improve NAFLD.,,
Gut dysbiosis and NAFLD
Increasing evidence shows that the gut and liver have multiple levels of associated interdependence, and disturbance of the gut–liver axis has been implicated in several conditions linked to obesity, including NAFLD. Liver enzyme elevation and fatty liver changes are commonly seen in gastrointestinal conditions such as SIBO, celiac disease, and inflammatory bowel disease (IBD). A recent meta-analysis also found that patients with gastroesophageal reflux disease were at a significantly increased risk of developing NAFLD (pooled odds ratio of 2.07). It doesn’t stop there; an association has also been shown with Helicobacter pylori infection, a common cause of gastric ulcers.
One common denominator among these conditions is the integrity, or lack thereof, of the gut mucosal barrier. “Leaky gut,” the common term for increased intestinal permeability, has been demonstrated in each of these conditions, and it has not been a stretch for hepatologists and gastroenterologists to connect this common underpinning with NAFLD., With the compromised intestinal barrier that is hallmark to leaky gut, bacterial-derived endotoxin, also known as lipopolysaccharide (LPS), is able to pass into circulation and trigger a defensive inflammatory response.
Increased levels of alcohol-producing gut bacteria as well as elevated blood alcohol levels have been seen in children with NASH, while alcohol production attributable Candida albicans or Saccharomyces cerevisiae overgrowth has also been reported.
In addition to alterations in the gut microbiome such as SIBO or H. pylori infection, a high-fat diet (HFD) has been shown to contribute to increased intestinal permeability and related endotoxemia (high levels of endotoxin in the blood). Endotoxemia contributes to the backup of bile flow at the level of the liver cells and related cellular inflammation and damage. However, much like the gut-brain axis where there is communication in both directions, the biliary stasis related to endotoxemia can further contribute to an altered balance of gastrointestinal flora and diminished motility.
Finally, an additional mechanism that dysbiotic flora may contribute to fatty liver changes is through the production of alcohol or other toxic metabolites. Significantly higher levels of blood alcohol have been observed in obese animals while mice protected from dysbiosis have decreased alcoholic liver disease despite leaky gut. Increased levels of alcohol-producing gut bacteria as well as elevated blood alcohol levels have been seen in children with NASH, while alcohol production attributable Candida albicans or Saccharomyces cerevisiae overgrowth has also been reported.
Much like many medical conditions, NAFLD is a multifactorial issue, impacted by metabolic function, the endocrine system, and gut health as well. Thus, natural support which addresses these possible contributors in a variety of fashions may be useful. Botanicals such as milk thistle and berberine both have evidence of improving fatty liver changes, and stimulate a receptor in the liver known as farnesoid X receptor (FXR) which serves to regulate bile acid, glucose, and lipid balance in the body. Bile acids help to prevent bacterial overgrowth and they also improve metabolism by binding FXR. Nutritional support such as antioxidants, phosphatidylcholine, and curcumin also have evidence for improving fatty liver changes and the oxidative damage which may accompany this condition. Finally, addressing leaky gut (and the dysbiosis which contributes to it) is another strategy to implement that may help restore the liver to a state of health.
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