“The liver is the most affected organ in both hypo- and hyperthyroidism.”(Daher R, 2009)
Effects of Thyroid Hormones on the Liver
T4 and T3 regulate the metabolic activity of hepatocytes and have a central role in hepatic growth, development and function. Both are important in regulating permeability of vascular endothelial cells and are needed for bilirubin and bile secretion (Burra P, 2013.)
A number of diseases affect both the thyroid and liver. These include non-Hodgkin’s lymphoma, amyloidosis, hemochromatosis, alcoholic liver disease, hepatitis C and primary biliary cirrhosis (Elta GH, 1983).
TSH and cirrhosis
Although physicians might assume that improving functional thyroid activity would be beneficial in most disease states there is evidence that in cirrhotic patients a higher TSH level may increase albumin and INR (indicating improved hepatic synthetic function), and decrease ALT, alkaline phosphatase and bilirubin (indicating better hepatocyte health and less biliary congestion.) Therefore, in cirrhotic patients it may not be best to aggressively treat .
The Liver-Thyroid Continuum
The above cirrhosis research notwithstanding, in thyroid diseases liver function tests often may be altered and signs of cholestasis may increase. Liver function tests often return to normal with thyroid hormone repletion. Thyrotoxicosis increases transaminases in 30% of patients, alkaline phosphatase in 66% of patients and GGT in about 20% of patients (Burra P, 2013.) Clearly, thyroid dysfunction can affect liver function and liver disease is likely to alter thyroid hormone metabolism. Autoimmune diseases also impact the liver and thyroid – classic examples are autoimmune hepatitis and primary biliary cirrhosis, conditions in which celiac disease, Hashimoto’s thyroiditis and cirrhosis often occur as a triad (Muratori P, 2015.)
A number of drugs or treatments affect both thyroid and liver, These include alcohol, propylthiouracil, amiodarone, mefloquine (antimalarial), carbamazepine (antiseizure)
many chemotherapy agents, interferon in HCV treatment and radiation (Koh LH, 1997.)
Obesity, thyroid hormones, ALT and non-alcoholic steatohepatitis
In a study of 111 obese adolescents vs 42 lean controls, TSH > 4.0 was the cutoff for elevated normal range thyroid activity. In non-alcoholic steatohepatitis subjects with a TSH > 4.0, insulin resistance was significantly higher than the obese subjects with a lower TSH level. Total cholesterol, triglycerides, LDL-C and insulin were also higher in the subjects with TSH >4.0 (Sert A, 2013.) In another study of subjects with normal range TSH, ALT was higher and was inversely correlated with TSH in those with metabolic syndrome. Interestingly this relationship between TSH and ALT was not seen in subjects without metabolic syndrome (Dullaart RP, 2014.)
Thyroid levels in obese children and adolescents with non-alcoholic fatty liver disease
In a study of 109 obese subjects ages 9-15 compared to 44 normal weight controls markers of thyroid and liver function were compared to indicators of insulin resistance. Parameters measured included lipids, ALT, fasting glucose, TSH, fT4, fT3, HOMA-IR (insulin resistance), BMI and abdominal ultrasound imaging for the presence of steatosis. The results were that TSH levels were increased significantly as the degree of steatosis increased (p=0.04) but fT3 and fT4 levels were not different with normal vs liver steatosis. TSH was significantly correlated with ALT levels, BMI and the degree of steatosis (Torun E, 2014.)
The effect of weight loss via laparoscopic gastric band (LAGB) on thyroid hormone levels
258 obese subjects with normal range thyroid tests/99 controls
Assessed at baseline, 6 months, 1 and 2 years after LAGB. Markers were TSH, fT3, fT4, fT3/fT4, triglycerides, total cholesterol, HDL, BMI and waist circumference. Basal thyroid tests were normal range.
After weight loss: fT4 increased and fT3 decreased; TSH did not change, Triglycerides, total chol., insulin and HOMA-IR decreased. HDL increased (Dall’ Asta C, 2010.)
Thyroid values appear to be associated with non-alcoholic fatty liver disease (NAFLD) in euthyroid middle aged subjects. Ultrasound was used to differentiate fatty livers from normal livers in 2576 euthyroid subjects. fT3 was significantly higher in fatty liver, TSH was comparable in both groups and fT4 was inversely correlated with fatty liver in premenopausal women but not in postmenopausal women (Liu G. 2014.) This study did not evaluate reverse T3 levels and higher levels of this non-active form of T3 might be related to the elevated fT3 correlation with fatty liver.
Euthyroid markers in NAFLD
In another study of 196 NAFLD euthyroid subjects, which also employed ultrasound to determine the presence of fatty liver, low fT4 and high TSH were associated with fatty liver.
TSH had a positive correlation with BMI, waist circumference and LDL-C, while fT4 had a negative correlation with BMI and waist circumference. The researchers concluded “our findings suggest serum fT4 and TSH levels within the reference range are independent risk factors for NAFLD” (Tao Y, 2015.) Mehran et al found a similar relationship among TSH, fT4 and insulin resistance (Mehran L, 2014.)
Subclinical hypothyroidism (SCH), coronary artery calcification (CAC) and IR markers
In a study of 753 Mexican subjects ages 35-70 with no history of DM, renal, hepatic, overt thyroid or coronary artery disease, subclinical hypothyroidism defined as elevated TSH with normal fT4. Computed tomography was used to assess fatty liver, CAC and abdominal fat.
Subclinical hypothyroidism was found in 17.7% of these subjects! SCH and fatty liver together were found to increase the odds of metabolic syndrome and insulin resistance (Posades-Romero C, 2014.)
In frank hypothyroidism Misra et al found significantly higher insulin resistance and TSH in NAFLD. fT4 was significantly lower in these subjects (Misra S, 2014.)
Summary of thyroid issues in NAFLD
NAFLD is associated with:
• Elevated euthyroid TSH
• Elevated euthyroid TSH in obese adolescents
• Elevated fT3?
• Low euthyroid fT4 (especially in premenopausal women)