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enzime hati sbg nia valuable as diagnostic and prognostic guideline both in clinical

practice and occupational medicine; reflecting the status, size, structure and functions of liver

affected by age, sex, environmental factors, various diseases and drugs.

Thyroid hormones are essential for normal growth, development and function of all

tissues of the body by regulating BMR of all cells, including hepatocytes. The liver in turn

metabolises thyroid hormones and regulates their systemic endocrine effects. Therefore

thyroid dysfunction may disturb liver functions and liver diseases modulate thyroid hormones

metabolism.

The liver has an important role in thyroid hormone metabolism and the level of thyroid

hormones is also important to normal hepatic function and bilirubin metabolism. Besides the

associations between thyroid and liver diseases of an autoimmune nature, such as that

between primary biliary cirrhosis and hypothyroidism, thyroid diseases are frequently

associated with liver injuries or biochemical test abnormalities. For example, thyroid diseases

may be associated with elevation of alaniue aminotransferase and alkaline phosphatase,

which is mainly of bone origin, in hyperthyroidism and aspartate amhotransferase in

hypothyroidism, Liver diseases are also frequently associated with thyroid test abnormalities

or dysfunctions, particularly elevation of thyroxine-binding globulin and thyroxine. Hepatitis

C virus infection has been connected with thyroid abnormalities. In addition, antithyroid drug

therapy may result in hepatitis, cholestasis or transient subclinical hepatotoxicity, whereas

interferon (IFW) therapy in liver diseases may also induce thyroid dysfunctions. These

thyroid-liver associations may cause diagnostic confusions. Neglect of these facts may result

in over or under diagnosis of associated liver or thyroid diseases and thereby cause errors in
patient care. It is suggested to measure free thyroxine (FT4) and thyroid-stimulating hormone

(TSH) which are usually normal in euthyroid patients with liver disease, to rule out or rule in

coexistent thyroid dysfunctions, and consider the possibility of thyroid dysfunctions in any

patients with unexplained liver biochemical test abnormalities. It is also advisable to monitor

patients with autoimmune liver disease or those receiving IFN therapy for the development of

thyroid dysfunctions, and patients receiving antithyroid therapy for the development of

hepatic injuries.

The liver has an important role in thyroid hormone metabolism because it is the

manufacturer of proteins that bind thyroid hormone, such as thyroxine-binding globulin

(TBG), pre-albumin and albumin. It is also the major site of thyroid hormone peripheral

metabolism and is involved in its conjugation, biliary excretion, oxidative deamination

and the extrathyroidal deiodination of thyroxine (T4) to triiodothyronine (T3) and to reverse

T3.2 On the other hand, the level of thyroid hormones is also important to normal hepatic

function and bilirubin metaboli~rn.,C~o nceivably, the disorders of these two organs would

interact or influence each other. In fact, there are several clinical and laboratory associations

between thyroid and liver diseases.

Namely:

(i) liver damage secondary to the systemic effect of thyroid hormone excess or direct toxic

effects and subclinical physiological effects of thyroid hormone on liver function;

(ii) some patients with chronic liver diseases may have thyroiditis, hyperthyroidism or

hypothyroidism through autoimmune mechanisms;

(iii) alterations of thyroid hormone metabolism or tests secondary to liver disease,

And

(iv) liver or thyroid disorders related to the therapy of thyroid or liver disease.

Hypothyroidism
 Three features of hypothyroidism may mimic liver diseases: myalgias, fatigue and

muscle cramp together with AST elevation in cases with myopathy; ascites in cases with

myxoedema; and jaundice in cretinism.27A specifk central congestive fibrosis of the liver has

been described, particularly in cases with myxoedema ascites.2s ALT may also be elevated

occasionally and cholesterol elevation is as a rule due to hypometabolism. The latter may

result in fatty liver causing mild but prolonged AST andlor ALT elevation and, therefore, be

erroneously considered chronic hepatitis, particularly before the advent of hepatitis C virus

(HCV) assays. These biochemical changes, usually mild, are also reversible with adequate

thyroid replacement the rap. In addition, increased serum levels of creatine kinase, aldolase

and lactic dehydrogenase, high protein concentration in ascites and coexistence of pleural or

pericardial effusions may also help to reach a correct diagnosis of

hypothyroidi~rn.4A,~d*d~it~io nally, the biliary excretion of bilirubin is diminished, which

is associated with some subtle alterations of hepatic bilirubin metabolism. These changes

together with hypercholesterolaemia and the hypotonia of the gall-bladder seen in

hypothyroidism suggest the possibility of increased cholesterol saturation of bile and higher

incidence of gall~tones. Clearly, these biochemical abnormalities in patients with thyroid

disorders may pose diagnostic confusion. Proper use of currently available hepatitis markers

or other facilities, such as ultrasonography, could help to detect some associated hepatobiliary

disorder(s). Since the hepatic histological findings in thyroid disorders are non-specific,

concomitant liver disease cannot be excluded definetely. even if liver biopsy is done, until

biochemical changes resolve along with the adequate control of the thyroid disorders. On the

other hand, physicians should keep in mind the possibility of thyroid disorder(s) in patients

with unexplained abnormal biochemical changes.

Thyroid test abnormalities

 Several investigators have reported various, and even contradictory, thyroid
function test abnormalities in euthyroid patients with acute or chronic liver disease. Much of
the confusion in the published literature can be attributed to patients being studied at
different stages of their The most consistent fmrlmgs are elevation of T4 and TBG but normal
free T4 (FT4) and thyroid
stimulating hormone (TSH) in both acute and chronic liver
diseases, including alcoholic liver disease and hepatocellular carcinoma (HCC). The
elevation of T4 and TBG levels return to normal as the patients recover. While T4 elevation
in these conditions might be secondary to TBG elevation, TBG elevation in hepatitis has
been considered as the result of either increased TBG synthesis in regenerating
hepat~cytes,*d~ec reased TBG degradation or release of TBG by damaged
hepat0cytes.4~,I~n~ c*o~n~tra st, studies have shown that a human hepatoma cell line can
synthesize and secrete TBG and that the fall and rise of serum TBG coincide with resection
and recurrence of HCC in human. It is therefore suggested that TBG elevation in patients
with HCC is due to increased synthesis and secretion of TBG by HCC cells. In view of the
finding that TBG elevation in patients with hepatitis or cirrhosis parallels or correlates
positively with serum ALT elevati0n, high serum TBG without a concomitant rise of ALT
could be a useful marker of HCC, at least for
assessment of treatment re~ponse.
Serum T3 levels measured in hepatitis are extremely variable, ranging from
decreased, normal to increased l e~e l s . ~M ,o~s~t s tudies have shown that serum T3
levels correlate negatively with the severity of the liver diseases. Patients with advanced
decompensated liver disease may even have the low T3 syndrome. Diminished T4 to T3
conversion appears to be the likely mechanism for the low serum T3.40 However, our recent
study involving various categories of hepatitis B virus (HBV)-related acute and all categories
except asymptomatic carriers and patients with HCC, and suggested that serum T3 elevation
was related to hepatocyte damage and increased TBG. Itoher aL4* have demonstrated that
the T3/T4 ratio, which represents a marker of microsomal arylamidase activity of
hepatocytes, increased in HBV carriers but decreased in other liver diseases. They noticed
that the T3/T4 ratio is particularly low in fulminant hepatitis and suggested that it could be
used as a prognostic More confusion comes from the use of several drugs in patients with
hepatobiliary disorders, because these agents have been shown to influence the thyroid
hormone levels. Corticosteroid, propranolol in high doses (> 160 mg/day) and
cholecystographic agents [iopanoic acid (telepaque) and ipodate (oragrafim)] could inhibit
the hepatic enzymatic monodeiodination of T4 to T3 and result in an increased serum T4 and
decreased serum T3.57-5C9 holecystographic agents may even result in a rise in serum TSH
secondary to impaired T4 conversion in the pituitary. It is clear, then, that the conventional
thyroid tests may be difficult to interpret in the presence of liver disease. Since FT4 and TSH
are usually normal in these settings, in general it can be assumed that most patients are
euthyroid if they have normal TSH and FT4 levels no matter how remarkable the changes of
other thyroid tests are. On the other hand, the frequently raised TBG and related hormone
level changes in patients with liver disease could have falsely normal T4 and T3 despite
being hypothyroid, and therefore easily lead to missing the diagnosis of hypothyroidism
during long-term follow up. It has been suggested that the finding of normal or low normal
T4 in this patient population should alert the physician to the possibility of coexistent
hypothyroidism and TSH screening is therefore advisable.