Nonalcoholic Fatty Liver Disease: Thyroid Function and Gut Health as Disease Risk Factors

With increasing rates of obesity and diabetes, the associated condition of nonalcoholic fatty liver disease (NAFLD) has become increasingly common, such that it is now the number one cause of liver disease in Western countries.[1] NAFLD affects 10 to 46% of the U.S. population, with a worldwide prevalence of 10 to 40%.[2] NAFLD is subdivided into nonalcoholic fatty liver (NAFL) and nonalcoholic steatohepatitis (NASH). The former presents without significant liver inflammation, while the latter is associated with hepatic inflammation that cannot be distinguishable histologically from its alcoholic counterpart. About 30 and 40% of adults in the U.S. have NAFL, while about 3 to 12% of US adults have the more severe form of NASH.[3]

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.[4] 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.[5] 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.[6],[7]

NAFLD is considered a “silent” liver disease: with its asymptomatic nature and oftentimes normal labs, it is easy to miss clinically even with proper screening. In addition to this, there are additional reasons why NAFLD may be underdiagnosed, particularly in the population without known risk factors such as diabetes and obesity where screening may be less stringent.

One contributor to underdiagnosis is that the standard laboratory ranges to which the alanine aminotransferase (ALT) and aspartate aminotransferase (AST) 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.[8]

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 alcohol consumption of more than 15 drinks a week for men and 10 drinks a week for women), however, liver ultrasounds are optimally sensitive to detecting liver changes only when fat percentage is greater than 12.5%.[9] Ultrasound has even worse sensitivity for diagnosing NAFLD in the obese.[10]

One thing that may contribute to a lack of rigorous screening is the lack of a well-studied efficacious medication for the treatment of NAFLD. Beyond providing immunizations for hepatitis A and B viruses to prevent further liver-affecting complications, the only recommendations typically suggested that may impact elevated liver enzymes are alcohol abstinence, weight loss, and the proper medical management of blood sugar and cholesterol.[11] However, the race to develop an FDA-approved medication is on, with a phase 2 study recently completed which shows promise for a medication known as VK2809.[12] This medication, a thyroid receptor β-agonist, selectively affects hepatic thyroid receptors that play a role in cholesterol metabolism.[13] In the phase II studies, it was shown to significantly reduce low density lipoprotein (LDL) cholesterol and reduce hepatic fat content between 56.5 to 59.7% depending on the dose studied. However, similar thyromimetics have made it this far only to fail in phase III, so if this drug makes it to the clinic remains to be seen.

As we seek natural treatment strategies for NAFLD, it is important to consider the underlying conditions that may contribute to fatty liver changes and hepatic inflammation. Not surprisingly, one factor may be thyroid function, and the other, the health of the gut.

Hypothyroidism 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.[14] 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.[15] In one study, individuals with hypothyroidism were approximately twice as likely to have NAFLD, and about four times as likely to have NASH.[16] From these and other findings, hypothyroidism has even been suggested as an independent risk factor for NAFLD.[17]

Hypothyroidism is associated with metabolic changes, including insulin resistance,[18] dyslipidemia,[19] and obesity,[20] each being factors that can contribute to the increased risk of NAFLD. In addition to these factors, higher levels of oxidative stress have been seen in patients with hypothyroidism,[21],[22] which can contribute to the development of NAFLD.[23] Both animal and human studies have shown that treatment with thyroid hormone has the ability to improve NAFLD.[24],[25],[26]

Hypothyroidism also is a contributing factor to gut dysbiosis. Hypothyroidism contributes to prolonged gastric and intestinal transit times[27],[28] and diminished bile secretion,[29] both of which play a role in the development of small intestinal bacterial overgrowth (SIBO).[30] In the other direction, digestive diseases associated with malabsorption and even Helicobacter pylori infection can be factors that make hypothyroidism resistant to treatment with typical oral therapies.[31],[32]

The Gut–Liver Connection

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.[33] Liver enzyme elevation and fatty liver changes are commonly seen in gastrointestinal conditions such as SIBO,[34] celiac disease,[35] and inflammatory bowel disease (IBD).[36] A recent meta-analysis also found that patients with gastroesophageal reflux disease were at a significantly increased risk of developing NAFLD.[37] It doesn’t stop there; an association has also been shown with H. pylori infection and NAFLD as well.[38]

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 alike to connect this common underpinning with NAFLD.[39],[40]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.[41]

In addition to alterations in the gut microbiome such as SIBO or H. pylori infection, a high-fat diet (HFD) also contributes to increased intestinal permeability and related endotoxemia.[42] Endotoxemia contributes to the backup of bile flow at the level of the hepatocytes and related cellular inflammation and damage.[43] 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.[44]

Finally, an additional mechanism that dysbiotic gut 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[45] while mice protected from dysbiosis have decreased liver disease despite leaky gut.[46] Increased levels of alcohol-producing gut bacteria as well as elevated blood alcohol levels have been seen in children with NASH,[47] while alcohol production attributable Candida albicans or Saccharomyces cerevisiae overgrowth has also been reported.[48]

Much like many medical conditions, NAFLD is a multifactorial issue, impacted by metabolic function, the endocrine system, and gut health as well. Given the many interweaving pathways connecting each of these conditions, a holistic plan of management should include comprehensive evaluation and appropriately selected treatment strategies which attempt to address the cause, and not just the symptom, of the underlying disease.

Dr. Carrie Decker, ND graduated with honors from the National College of Natural Medicine (now the National University of Natural Medicine) in Portland, Oregon. Dr. Decker sees patients remotely, with a focus on gastrointestinal disease, mood imbalances, eating disorders, autoimmune disease, and chronic fatigue. Prior to becoming a naturopathic physician, Dr. Decker was an engineer, and obtained graduate degrees in biomedical and mechanical engineering from the University of Wisconsin-Madison and University of Illinois at Urbana-Champaign respectively. Dr. Decker continues to enjoy academic research and writing and uses these skills to support integrative medicine education as a writer and contributor to various resources. Dr. Decker supports Allergy Research Group as a member of their education and product development team.
Sources:
[1] Review Team, LaBrecque DR, et al. World Gastroenterology Organisation global guidelines: Nonalcoholic fatty liver disease and nonalcoholic steatohepatitis. J Clin Gastroenterol. 2014;48:467-73.
[2] Lazo M, et al. Prevalence of nonalcoholic fatty liver disease in the United States: the Third National Health and Nutrition Examination Survey, 1988-1994. Am J Epidemiol. 2013;178(1):38-45.
[3] Brunt EM, et al. Nonalcoholic fatty liver disease. Nature Reviews Disease Primers. 2015;1:15080.
[4] Vanni E, et al. From the metabolic syndrome to NAFLD or vice versa? Dig Liver Dis. 2010 May;42(5):320-30.
[5] 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.
[6] Silverman JF, et al. Liver pathology in morbidly obese patients with and without diabetes. Am J Gastroenterol. 1990 Oct;85(10):1349-55.
[7] Clain DJ, Lefkowitch JH. Fatty liver disease in morbid obesity. Gastroenterol Clin North Am. 1987 Jun;16(2):239-52.
[8] Kwo PY, et al. ACG Clinical Guideline: Evaluation of Abnormal Liver Chemistries. Am J Gastroenterol. 2017;112(1):18.
[9] 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.
[10] 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.
[11] Ahmed A, et al. Nonalcoholic Fatty Liver Disease Review: Diagnosis, Treatment, and Outcomes. Clin Gastroenterol Hepatol. 2015;13:2062-70.
[12] CISION PR Newswire. Viking Therapeutics Announces Positive Top-Line Results from Phase 2 Study of VK2809 in Patients with Non-Alcoholic Fatty Liver Disease (NAFLD) and Elevated LDL-Cholesterol. Published September 18, 2018. Accessed October 9, 2018. Available from: https://tinyurl.com/ybfymmvl
[13] Jakobsson T, et al. Potential Role of Thyroid Receptor β Agonists in the Treatment of Hyperlipidemia. Drugs. 2017 Oct;77(15):1613-1621.
[14] 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.
[15] 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.
[16] Pagadala MR, et al. Prevalence of hypothyroidism in nonalcoholic fatty liver disease. Dig Dis Sci. 2012 Feb;57(2):528-34.
[17] 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.
[18] Maratou E, et al. Studies of insulin resistance in patients with clinical and subclinical hypothyroidism. Eur J Endocrinol. 2009 May;160(5):785-90.
[19] 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.
[20] Verma A, et al. Hypothyroidism and obesity. Cause or effect? Saudi Med J. 2008;29(8):1135-8.
[21] 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.
[22] 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.
[23] 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.
[24] 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.
[25] Liu L, et al. Benefits of Levothyroxine Replacement Therapy on Nonalcoholic Fatty Liver Disease in Subclinical Hypothyroidism Patients. Int J Endocrinol. 2017;2017:5753039.
[26] Kowalik MA, et al. Thyroid Hormones, Thyromimetics and Their Metabolites in the Treatment of Liver Disease. Front Endocrinol (Lausanne). 2018 Jul 10;9:382.
[27] Yaylali O, et al. Does hypothyroidism affect gastrointestinal motility? Gastroenterol Res Pract. 2009;2009:529802.
[28] O’Mahony D, et al. Aging and intestinal motility: a review of factors that affect intestinal motility in the aged. Drugs Aging. 2002;19(7):515-27.
[29] Laukkarinen J, et al. The underlying mechanisms: how hypothyroidism affects the formation of common bile duct stones-a review. HPB Surg. 2012;2012:102825.
[30] Patil AD. Link between hypothyroidism and small intestinal bacterial overgrowth. Indian J Endocrinol Metab. 2014 May;18(3):307-9.
[31] Ruchała M, et al. The influence of lactose intolerance and other gastro-intestinal tract disorders on L-thyroxine absorption. Endokrynol Pol. 2012;63(4):318-23.
[32] Bugdaci MS, et al. The role of Helicobacter pylori in patients with hypothyroidism in whom could not be achieved normal thyrotropin levels despite treatment with high doses of thyroxine. Helicobacter. 2011 Apr;16(2):124-30.
[33] Vajro P, et al. Microbiota and gut-liver axis: their influences on obesity and obesity-related liver disease. J Pediatr Gastroenterol Nutr. 2013 May;56(5):461-8.
[34] 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.
[35] 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.
[36] 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.
[37] 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.
[38] 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.
[39] 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.
[40] Miele L, et al. Increased intestinal permeability and tight junction alterations in nonalcoholic fatty liver disease. Hepatology. 2009 Jun;49(6):1877-87.
[41] 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.
[42] 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.
[43] 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.
[44] Hellström PM, et al. Role of bile in regulation of gut motility. J Intern Med. 1995 Apr;237(4):395-402.
[45] Cope K, et al. Increased gastrointestinal ethanol production in obese mice: implications for fatty liver disease pathogenesis. Gastroenterology. 2000;119:1340–1347.
[46] Hartmann P, et al. Deficiency of intestinal mucin-2 ameliorates experimental alcoholic liver disease in mice. Hepatology. 2013;58:108–119.
[47] 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.
[48] 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.