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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 Pratt DS, Kaplan MM. Evaluation of abnormal liver-enzyme results in asymptomatic patients. N Engl J Med. 2000 Apr 27;342(17):1266-71.
 Estes C, et al. Modeling the epidemic of nonalcoholic fatty liver disease demonstrates an exponential increase in burden of disease. Hepatology. 2018 Jan;67(1):123-133.
 Cusi K, et al. Non-alcoholic fatty liver disease (NAFLD) prevalence and its metabolic associations in patients with type 1 diabetes and type 2 diabetes. Diabetes Obes Metab. 2017 Nov;19(11):1630-1634.
 Silverman JF, et al. Liver pathology in morbidly obese patients with and without diabetes. Am J Gastroenterol. 1990 Oct;85(10):1349-55.
 Clain DJ, Lefkowitch JH. Fatty liver disease in morbid obesity. Gastroenterol Clin North Am. 1987 Jun;16(2):239-52.
 Kwo PY, et al. ACG Clinical Guideline: Evaluation of Abnormal Liver Chemistries. Am J Gastroenterol. 2017;112(1):18.
 Bril F, et al. Clinical value of liver ultrasound for the diagnosis of nonalcoholic fatty liver disease in overweight and obese patients. Liver Int. 2015 Sep;35(9):2139-46.
 de Moura Almeida A, et al. Fatty liver disease in severe obese patients: diagnostic value of abdominal ultrasound. World J Gastroenterol. 2008 Mar 7;14(9):1415-8.
 Hollowell JG, et al. Serum TSH, T(4), and thyroid antibodies in the United States population (1988 to 1994): National Health and Nutrition Examination Survey (NHANES III). J Clin Endocrinol Metab. 2002;87(2):489.
 He W, et al. Relationship between Hypothyroidism and Non-Alcoholic Fatty Liver Disease: A Systematic Review and Meta-analysis. Front Endocrinol (Lausanne). 2017 Nov 29;8:335.
 Pagadala MR, et al. Prevalence of hypothyroidism in nonalcoholic fatty liver disease. Dig Dis Sci. 2012 Feb;57(2):528-34.
 Xu L, et al. Impact of subclinical hypothyroidism on the development of non-alcoholic fatty liver disease: a prospective case-control study. J Hepatol. 2012 Nov;57(5):1153-4.
 Maratou E, et al. Studies of insulin resistance in patients with clinical and subclinical hypothyroidism. Eur J Endocrinol. 2009 May;160(5):785-90.
 Diekman T, et al. Prevalence and correction of hypothyroidism in a large cohort of patients referred for dyslipidemia. Arch Intern Med. 1995 Jul 24;155(14):1490-5.
 Verma A, et al. Hypothyroidism and obesity. Cause or effect? Saudi Med J. 2008;29(8):1135-8.
 Chakrabarti SK, et al. Oxidative stress in hypothyroid patients and the role of antioxidant supplementation. Indian J Endocrinol Metab. 2016 Sep-Oct;20(5):674-678.
 Erdamar H, et al. The effect of hypothyroidism, hyperthyroidism, and their treatment on parameters of oxidative stress and antioxidant status. Clin Chem Lab Med. 2008;46(7):1004-10.
 Köroğlu E, et al. Role of oxidative stress and insulin resistance in disease severity of non-alcoholic fatty liver disease. Turk J Gastroenterol. 2016 Jul;27(4):361-6.
 Perra A, et al. Thyroid hormone (T3) and TRbeta agonist GC-1 inhibit/reverse nonalcoholic fatty liver in rats. FASEB J. 2008 Aug;22(8):2981-9.
 Liu L, et al. Benefits of Levothyroxine Replacement Therapy on Nonalcoholic Fatty Liver Disease in Subclinical Hypothyroidism Patients. Int J Endocrinol. 2017;2017:5753039.
 Kowalik MA, et al. Thyroid Hormones, Thyromimetics and Their Metabolites in the Treatment of Liver Disease. Front Endocrinol (Lausanne). 2018 Jul 10;9:382.
 Kapil S, et al. Small intestinal bacterial overgrowth and toll-like receptor signaling in patients with non-alcoholic fatty liver disease. J Gastroenterol Hepatol. 2016 Jan;31(1):213-21.
 Reilly NR, et al. Increased risk of non-alcoholic fatty liver disease after diagnosis of celiac disease. J Hepatol. 2015 Jun;62(6):1405-11.
 Chao CY, et al. Co-existence of non-alcoholic fatty liver disease and inflammatory bowel disease: A review article. World J Gastroenterol. 2016 Sep 14;22(34):7727-34.
 Wijarnpreecha K, et al. Association between gastroesophageal reflux disease and nonalcoholic fatty liver disease: A meta-analysis. Saudi J Gastroenterol. 2017 Nov-Dec;23(6):311-7.
 Wijarnpreecha K, et al. Helicobacter pylori and Risk of Nonalcoholic Fatty Liver Disease: A Systematic Review and Meta-analysis. J Clin Gastroenterol. 2017 Jan 17.
 Ilan Y. Leaky gut and the liver: a role for bacterial translocation in nonalcoholic steatohepatitis. World J Gastroenterol. 2012 Jun 7;18(21):2609-18.
 Miele L, et al. Increased intestinal permeability and tight junction alterations in nonalcoholic fatty liver disease. Hepatology. 2009 Jun;49(6):1877-87.
 Ferolla SM, et al. The role of intestinal bacteria overgrowth in obesity-related nonalcoholic fatty liver disease. Nutrients. 2014 Dec 3;6(12):5583-99.
 Moreira AP, et al. Influence of a high-fat diet on gut microbiota, intestinal permeability and metabolic endotoxaemia. Br J Nutr. 2012 Sep;108(5):801-9.
 Whiting JF, et al. Tumor necrosis factor-alpha decreases hepatocyte bile salt uptake and mediates endotoxin-induced cholestasis. Hepatology. 1995 Oct;22(4 Pt 1):1273-8.
 Hellström PM, et al. Role of bile in regulation of gut motility. J Intern Med. 1995 Apr;237(4):395-402.
 Cope K, et al. Increased gastrointestinal ethanol production in obese mice: implications for fatty liver disease pathogenesis. Gastroenterology. 2000;119:1340-1347.
 Hartmann P, et al. Deficiency of intestinal mucin-2 ameliorates experimental alcoholic liver disease in mice. Hepatology. 2013;58:108-119.
 Zhu L, et al. Characterization of gut microbiomes in nonalcoholic steatohepatitis (NASH) patients: a connection between endogenous alcohol and NASH. Hepatology. 2013 Feb;57(2):601-9.
 Spinucci G, et al. Endogenous ethanol production in a patient with chronic intestinal pseudo-obstruction and small intestinal bacterial overgrowth. Eur J Gastroenterol Hepatol. 2006 Jul;18(7):799-802.