A B S T R A C T Eight normal subjects were administered tracer amounts of a 14C-labeled thyroxine, L-[tyrosyl-14C] T4, by multiple injections. Then serial blood samples were collected for isolation of the thyroxine, triiodothyronine, and tetraiodothyroacetic acid fractions by a combination of column and paper chromatographies. The chromatographic artifacts were corrected by adding to the sera a purified 3H-labeled thyroxine, D,L-[a,,f-3H] T4 immediately after the separation of sera from blood. 1-2% of the serum 14C radioactivity was observed in the triiodothyronine fraction and 2-4% of the serum 14C radioactivity was observed in the tetraiodothyroacetic acid fraction. Complete kinetic studies of thyroxine and triiodothyronine were compared in the same individual in four of the subjects. The extrathyroidal conversion rates of thyroxine to triiodothyronine were calculated from data obtained during both the injection and the postinjection periods as functions of the 14C-labeled thyroxine and triiodothyronine remaining in the body at time t and their fractional turnover rates. The average daily rate of the extrathyroidal conversion of thyroxine to triiodothyronine was 4% of the extrathyroidal thyroxine pool or 33% of the total thyroxine production. The amount of triiodothyronine generated by this pathway (22 ,ug/day) was found to contribute 31% of the extrathyroidal triiodothyronine pool or 41% of the daily triiodothyronine production. This pathway is a major source of triiodothyronine production. The extrathyroidal conversions of thyroxine to triiodothyronine and tetraiodothyroacetic acid are major metabolic pathways of thyroxine in normal man.

A B S T R A C T The role of liver in the peripheral conversion of thyroxine (T4) to triiodothyronine (Ts) was studied in normal subjects and patients with alcoholic liver disease by measurement of thyrotrophin (TSH) and total and free T4 and T3 in random and serial serum samples. Also, T4 to Ts conversion rates and Ts disposal rates were compared by noncompartmental analysis. While the mean total serum T4 values were similar for the two groups, 8.6 and 8.1 ug/dl, the mean free To value was significantly higher in the cirrhotic patients (3.3 ng/dl) than in the normal subjects (2.1 ng/dl, P < 0.001). The mean serum T3 value, 85 ng/dl, was significantly reduced in the hepatic patients as compared to a mean serum T8 value of 126 ng/dl in the normal subjects (P < 0.001), while the free T3 value was 0.28 ng/dl in both groups. The reduction of the serum total and free Ts values were closely correlated with the degree of liver damage, as indicated by elevation of serum bilirubin (r = -0.547) and reduction of serum albumin (r = 0.471). The mean serum TSH level was 3.1 AiU/ml in the normals and 7.1 tU/ ml in the cirrhotic patients (P < 0.001). 15% of the hepatic patients had serum TSH values above 10 AU/ ml, which, however, did not correlate with any of the four liver function tests studied. Serial blood sampling from two convalescing patients with alcoholic hepatitis showed a gradual normalization of serum TSH and Ts levels as the liver function improved. After oral T4 administration, 0.25 mg/day for 10 days, three of four cirrhotic patients studied failed to raise their serum Ts values. The mean T4 to Ts conversion rate of seven normal subjects was 35.7%. The mean T4 to T3 conversion rate of four cirrhotic patients studied was significantly reduced to 15.6% (P < 0.001). The mean Received for publication 12 March 1974 and in revised form 22 May 1975. disposal rates of T4 and T3 of the normal subjects were 114 and 34 ,ig/day, respectively. The ratio of T, disposal to T3 disposal was 3.5. In contrast, the mean T4 disposal rate, 82 Ag/day, and the mean Ts disposal rate, 10 ug/day, were both reduced in the cirrhotic patients. Their ratio of T4 disposal to Ts disposal was 7.9. These findings suggest that impairment of T4 conversion in patients with advanced hepatic cirrhosis may lead to reduced Ts production and lowered serum Ts level. Therefore, the liver is one of the major sites of T4 conversion to Ts.

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