Hyperthyroxinaemia in hepatocellular carcinoma: Relation to thyroid binding globulin in the clinical and preclinical stages of the disease

Abstract

Summary Serum thyroxine was significantly higher in 59 patients with hepatocellular carcinoma than in normal subjects, patients with uncomplicated cirrhosis (48), or other primary tumours with or without hepatic metastases (50). Elevated thyroxine levels appeared attributable to high levels of thyroxine binding globulin which showed a positive linear correlation with serum thyroxine in all groups studied. Despite this hyperthyroxinaemia all patients appeared clinically euthyroid and, consistent with this, T3 was elevated in only one patient and the free thyroxine index was normal in all. Amongst a group of 25 cirrhotic patients who were followed-up for between 12 and 72 months, there was a striking dissociation between the TBG values of those destined to develop HCC and those who did not. In the former group TBG rose steadily with time whereas in the latter group levels remained stable, or, more often, fell. The rises in TBG occurred prior to any clinical signs of tumour development and may be one of the earliest serological changes to occur during carcinogenesis in the cirrhotic liver.Changes in the serum levels of thyroid hormones and their binding proteins in patients with cirrhosis are welldocumented (Chopra et al., 1974;Hepner & Chopra, 1979; Lumholtz et al., 1978;Nomura et al., 1975). Most studies have shown a normal thyroxine (T4) level with impaired conversion to triiodothyronine (T3) resulting in low levels of T3 and high levels of reverse T3 (rT3). Despite this, clinical evidence of hypothyroidism is uncommon and direct measurement of free T4 (fT4) or the free thyroxine index has usually given normal values (Green et al., 1970;Liewendahl et al., 1983). In contrast, hyperthyroxinaemia has been described in some patients with hepatocellular carcinoma (HCC), a frequent complication of long-standing cirrhosis (Gershengorn et al., 1976;Kalk et al., 1982;Nelson, 1979). The hyperthyroxinaemia has been attributed to elevated levels of thyroxine binding globulin (TBG) but whether abnormalities of other thyroid binding proteins such as albumin and prealbumin are also involved has not been determined. There are also no data on how levels of TBG change before diagnosis of HCC or whether such changes are specific for HCC or occur generally in malignant disease.In the present study we have measured the serum thyroid hormones together with their binding proteins in a large series of patients with HCC and various control groups including uncomplicated cirrhosis and other primary tumours with or without hepatic metastases. In healthy volunteers recruited from the ho6pital staff. None of the subjects studied was receiving drugs known to interfere with thyroid function. In all patients with HCC the serum samples studied were those collected at the time of diagnosis and prior to any treatment.The stored serial sera (which had been frozen once and not previously thawed before the assay) came from patients included in a prospective study of the development of HCC in cirrhosis (Zaman et al., 1985). These comprised 25 pati...

Variations in Thyroid Hormone Transport Proteins and Their Clinical Implications

“…The observation that serum TBG values are correlated with alanine aminotransferase levels in chronic active hepatitis but not in hepatocellular carcinoma (49) might suggest that the increase in serum TBG concentration is the result of hepatocellular damage in the former condition and of increased synthesis in the latter. This concept is supported by the observation that the elevated serum TBG concentration is relatively constant in patients with liver cirrhosis who do not develop hepatocellular carcinoma but increases progressively in those who develop the tumor (50). In addition, the finding that the differentiation-inducing agent, sodium butyrate, increases albumin synthesis and decreases TBG synthesis in human hepatoblastoma-derived Hep G2 cells (51 ) is consistent with enhanced TBG synthesis in hepatocellular carcinoma.…”

Application of Classification Tree and Neural Network Algorithms to the Identification of Serological Liver Marker Profiles for the Diagnosis of Hepatocellular Carcinoma

“…However, even AFP, the tumour marker which is most widely used for the diagnosis of HCC, is associated with liver cirrhosis, thereby decreasing its specificity for HCC [1, 4, 5]. Many attempts have been made to identify new diagnostic markers for HCC [8, 9, 10, 11, 12, 13, 14, 15, 16]. Unfortunately none of the available serological markers can be used alone to identify all the HCC cases while maintaining high specificity.…”

“…Apart from trials on tumour-specific AFP glycoforms [8, 9, 10], attempts have been made to identify other liver markers, including α1-antitrypsin (A1AT) [11], thyroxine-binding globulin (TBG) [12, 13], transferrin [14], des-γ-carboxy prothrombin [15]and transforming growth factor [16]for the diagnosis of HCC. Unfortunately, none of the available serological liver markers can be used alone to identify all the HCC cases among the liver cirrhosis patients while maintaining high specificity.…”

“…We attempted to apply the classification tree and neural network algorithms to identify the serological liver marker profiles comprising AFP, A1AT, α 2 -macroglobulin (A2MG), TBG, transferrin and albumin as well as sex and age, that might permit the diagnosis of HCC. The rationales for choosing these six serological markers were that (1) raised serum levels of AFP, A1AT [11]and TBG [12, 13]have been associated with HCC; (2) raised serum levels of A1AT [24], A2MG [25], TBG [26]and AFP [27, 28]have been associated with hepatic regeneration; (3) albumin [29]and transferrin [30]have been used as a measure of overall liver function; and (4) they could all be easily measured in routine laboratories.…”

Dysprealbuminemic Hyperthyroxinemia in a Patient with Hyperthyroid Graves Disease

“…Additional families with other mutations have subsequently been characterized (10 -12 ). An increase in T 4 binding by TTR has also been reported as an acquired paraneoplastic phenomenon in patients with pancreatic and hepatic tumors (13,14 ). Here we describe a patient with typical hyperthyroid Graves disease in whom coexistence of euthyroid dysprealbuminemic hyperthyroxine-mia masked the emergence and complicated the management of postablative hypothyroidism.…”