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.

A B S T R A C T Studies were carried out to determine the chemical structures of thyroxine metabolites after total deiodination. Normal subjects were given thyroxine labeled with "C on the nonphenolic ring and the alanine side chain, 8-11 Ag/day for 10 days. By paper chromatography of fresh urine, six or more "C-labeled compounds were separated. The "C-labeled metabolites were concentrated by passing the urine through a nonionic polymeric adsorbent. Two major thyroxine metabolites were identified. The identification was made by three different methods: (a) chromatography, (b) synthesis of derivatives, and (c) recrystallization to constant specific activity. One "C-labeled metabolite was identified as thyroacetic acid or 4-phenoxy-(4'-hydroxy) phenylacetic acid. Another one was identified as thyronine. Of the total urinary "C radioactivity, 43.7% was recovered as thyroacetic acid and 19.8% was recovered as thyronine. Approximately one-fifth of each of these metabolites was present in the urine in bound form which released the free metabolites during acid hydrolysis. The average daily excretion of thyroacetic acid was 13.7% of the renal disposal rate of thyroxine, or approximately 7.5 ig/day. The average daily excretion of thyronine was 6.5% of the renal disposal rate of thyroxine or approximately 3.9 ug/day while the urinary iodide made up 64.7% of the renal disposal rate of thyroxine. Our findings provide the needed proof that the major metabolic pathways of thyroxine remove the iodine atoms by substituting hydrogen for iodine and leave the diphenyl ether nucleus intact.

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