Malabsorption of Thyroid Hormones After Jejunoileal Bypass for Obesity FEREIDOUN AZIZI, M.D.; ROY BELUR, M.S.; and JOSEPHINE ALBANO, M.D. St. Elizabeth's Hospital and Tufts University School of Medicine; Boston, Massachusetts T H E MALABSORPTION STATE caused by small intestinal
bypass surgery may result in nutritional deficiencies. The drastic loss of jejunum and ileum interferes with normal absorption of various substances, leading to metabolic derangement, vitamin deficiencies, and even nutritional cirrhosis of the liver (1). We have recently seen a patient with hypothyroidism and obesity who developed severe malabsorption of thyroid hormones after a bypass operation. A 38-year-old white woman was referred for evaluation of hypothyroidism in March 1977. She had been grossly obese ( > 160 kg) for most of her adult life and had undergone a small intestinal bypass in August 1974. Three months before her bypass operation, she was found to be hypothyroid and was treated with 0.2 mg of L-thyroxine (T4) per day. During the next 2 years she lost 73 kg. Dating from October 1976, the patient noted lethargy, dyspnea on exertion, cold intolerance, dry skin, ecchymosis, amenorrhea, and weight gain. The only abnormal physical findings were dry skin and ankle edema. The relaxation phase of deep tendon reflexes was slightly delayed. Liver function test findings were abnormal, and a liver biopsy showed fatty infiltration and some degree of fibrosis. Serum T4 and total triiodothyronine (T,) were repeatedly low and serum thyrotropin (TSH) elevated (Table 1). The dosage of L-T4 was gradually increased until it reached 0.6 mg. The clinical symptoms and signs of hypothyroidism were reversed, and serum TSH and its response to thyrotropin-releasing hormone (TRH) became normal, even though liver test findings remained abnormal. Studies of absorption of thyroid hormones were then done. Four months later, the patient underwent a surgical operation for restoration of gastrointestinal continuity. The required dosage of L-T4 dropped to 0.2 mg per day. This dosage has maintained thyroid function and TSH at a normal range. The concentration of T 3 in the serum of our patient and three patients with cirrhosis of the liver was measured before, and at frequent intervals after, a single oral dose of 100 jug of L-T3 (Cytomel ®). Absorption of [ 1 2 5 I]LT3 and [ 1 2 5 I]L-T 4 was assessed on separate days in the patient and in three normal volunteers. Blood samples were obtained at frequent intervals from 2 to 24 h after oral administration of radiothyronine. The percentage of the dose of each isotope per litre of serum was then calculated. Serum T 4 and T 3 were measured by radioimmunoassay, and free T 4 and free T 3 indices were calculated (2). Thyrotropin concentration in the serum was also measured by radioimmunoassay (3), using the human TSH standard 68/38 and reagents supplied by the National Institutes of Health. Brief Reports
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Table 1. Effect of Jejunoileal Bypass• on Serum Thyroxine (T4), Triiodothyronine (T3), and Thyrotropin (TSH) Concentrations in a Hypothyroid Patient Taking L-Thyroxine
Before bypass May 1974 Aug 1974 Bypass (Aug 1974) Sep 1974 Sep 1976 Dec 1976 Feb 1977 Mar 1977 May 1977 Reversal of shunt (Jul 1977) Jan 1978 Normal values
Duration of Treatment
Total Serum T 4
mg
mos.
ng/dL
0/ /o
0.2
3
4.1 6.8
31.5 39.0
3.2 6.6
64 160
50 156
0.2 0.2 0.2 0.4 0.6 0.6
4 28 31 2.5 1 3
3.6 1.6 0.6 2.7 5.5 5.4
36.5 45.9 49.9 58.7 65.2 56.1
3.3 1.8 0.7 4.0 9.0 7.6
10 10 32 17
12 15 47 24
0.2
5
7.6 4.5-12.7
38.0 35-45
7.2 4.5-12.2
130 90-205
123 85-205
T 3 Uptake
When the prescribed dosage of L-T4 was 0.4 mg daily, baseline serum TSH was 8.9 jLtU/mL and TSH response to T R H was prolonged and exaggerated, with a peak of 85 jLtU/mL at 30 minutes. Four weeks after the dosage of L-T4 was increased to 0.6 m g / d , serum T 4 increased to normal value, basal serum TSH decreased to 2.5 jiiU/mL (Table 1), and T S H response to T R H became normal, with a peak of 12.9 /LtU/mL at 10 minutes. Ingestion of 100 jxg of L-T3 by three patients with cirrhosis of the liver caused an increase in serum T 3 that reached a peak value of 470 ± 88 n g / d L in 4 h. T h e increase of serum T 3 in our patient, however, was slight, reaching a maximum of only 144 n g / d L in 2 h. The transport of labelled T 3 and T 4 was markedly decreased in our patient. The maximum percentage of dose per litre of [ 1 2 5 I]L-T 3 occurred 2 or 3 h after the dose was administered (control, 6.1 ± 1.2%; patient, 0.43%) and that of [ 1 2 5 I]L-T 4 occurred after 4 h (control, 14.5 ± 1.6%; patient, 5.9%). The absorption of various drugs in patients who undergo intestinal bypass has not been thoroughly studied; however, reduced plasma level of oral contraceptives has been reported after bypass surgery (4). In our patient, intestinal absorption of thyroid hormones was markedly diminished after intestinal bypass surgery and restored to normal after reversal of the shunt. After bypass surgery, elevated serum TSH responded to increasing dosages of L-T4, and both basal and TRH-stimulated serum T S H became normal 3 weeks after the dosage was increased to 0.6 mg. Serum T 4 also increased, but serum T 3 and the calculated free T 3 index remained in a subnormal range. The low T 3 was due to decreased conversion of T 4 to T 3 , which was caused by cirrhosis (5) and bypass-induced fasting state (6, 7). After bypass surgery, the absorption of labelled thyroid hormones was markedly diminished, and the serum concentration of T 3 after oral ingestion of L-T3 peaked at a level far below that of the cirrhotic patients and that of normal subjects (8). Therefore, it appears that malabsorption of thyroid hormones in our patient was not caused by cirrhosis.
9 4 2
Free T 3 Index
Daily Dose of Thyroxine
June 1979 • Annals of Internal Medicine • Volume 90 • Number 6
Downloaded from https://annals.org by Tulane University user on 01/16/2019
Free T 4 Index
Total T 3
Serum TSH
nU/mL
ng/dL
>50 1.8
36 8.9 2.5 2.0
1.6 < 1.2-5.0
Our finding that an intestinal bypass may result in significant malabsorption of T 4 and T 3 is in accord with findings from a previous report of impaired absorption of thyroid hormone in malabsorption and small intestinal disease (9). Patients with hypothyroidism who undergo this type of surgery should have periodic assessments of their thyroid hormone status. The exact intestinal site of absorption of thyroid hormones is not known. In-vitro studies have shown that in rats all three parts of the small intestine absorb labelled thyroxine; the absorption is least complete in the duodenum and most complete in the ileum (10). Present studies support the theory that thyroid hormones are absorbed throughout the small intestine, a large area of which is needed for complete absorption. This study was supported by grant 5S10RR 05587-07, General Research Support, National Institutes of Health, Bethesda, . Maryland. REFERENCES
1. D E W I N D LT, PAYNE JH: Intestinal bypass surgery for morbid obesity. Long-term results. JAMA 236:2298-2301, 1976 2. S A W I N CT, C H O P R A D, A L B A N O J, A Z I Z I F: The free triiodothyronine
(T,) index. Ann Intern Med 88:474-477, 1978 3. O D E L L W D , W I L B E R J F , U T I G E R R D : Studies of thyrotropin physiolo-
gy by means of radioimmunoassay. Recent Prog Horm Res 23:47-85, 1967 4. JOHANSSON EDB, K R A I JG: Oral contraceptives after intestinal bypass operations (letter). JAMA 236:2847, 1976 5. C H O P R A IJ, SOLOMON DH, C H O P R A U, Y O U N G RT, C H U A T E C O G N :
Alterations in circulating thyroid hormones and thyrotropin in hepatic cirrhosis: evidence for euthyroidism despite subnormal serum triiodothyronine. J Clin Endocrinol Metab 39:501-511, 1974 6. PORTNAY G I , O ' B R I A N JT, BUSH J, VAGENAKIS AG, A Z I Z I F, A R K Y RA, INGBAR SH, B R A V E R M A N LE: The effect of starvation on the con-
centration and binding of thyroxine and triiodothyronine in serum and on the response to TRH. J Clin Endocrinol Metab 39:191-194, 1974 7. AZIZI F: The effect of dietary composition on fasting induced changes in serum thyroid hormones and thyrotropin. Metabolism 27:935-942, 1978 8. LIEBLICH J, U T I G E R R D : Triiodothyronine radioimmunoassay. J Clin
Invest 51:157-166, 1972 9. HAYS MT, K A T Z L: Thyroxine (T4) absorption in small intestinal disease (abstract). J Nucl Med 14:406-407, 1973 10. C H U N G SJ, V A N M I D D L E S W O R T H L: Absorption of thyroxine from the
small intestine of rats. Endocrinology 74:694-700, 1964 © 1 9 7 9 American College of Physicians
bypass surgery may result in nutritional deficiencies. The drastic loss of jejunum and ileum interferes with normal absorption of various substances, leading to metabolic derangement, vitamin deficiencies, and even nutritional cirrhosis of the liver (1). We have recently seen a patient with hypothyroidism and obesity who developed severe malabsorption of thyroid hormones after a bypass operation. A 38-year-old white woman was referred for evaluation of hypothyroidism in March 1977. She had been grossly obese ( > 160 kg) for most of her adult life and had undergone a small intestinal bypass in August 1974. Three months before her bypass operation, she was found to be hypothyroid and was treated with 0.2 mg of L-thyroxine (T4) per day. During the next 2 years she lost 73 kg. Dating from October 1976, the patient noted lethargy, dyspnea on exertion, cold intolerance, dry skin, ecchymosis, amenorrhea, and weight gain. The only abnormal physical findings were dry skin and ankle edema. The relaxation phase of deep tendon reflexes was slightly delayed. Liver function test findings were abnormal, and a liver biopsy showed fatty infiltration and some degree of fibrosis. Serum T4 and total triiodothyronine (T,) were repeatedly low and serum thyrotropin (TSH) elevated (Table 1). The dosage of L-T4 was gradually increased until it reached 0.6 mg. The clinical symptoms and signs of hypothyroidism were reversed, and serum TSH and its response to thyrotropin-releasing hormone (TRH) became normal, even though liver test findings remained abnormal. Studies of absorption of thyroid hormones were then done. Four months later, the patient underwent a surgical operation for restoration of gastrointestinal continuity. The required dosage of L-T4 dropped to 0.2 mg per day. This dosage has maintained thyroid function and TSH at a normal range. The concentration of T 3 in the serum of our patient and three patients with cirrhosis of the liver was measured before, and at frequent intervals after, a single oral dose of 100 jug of L-T3 (Cytomel ®). Absorption of [ 1 2 5 I]LT3 and [ 1 2 5 I]L-T 4 was assessed on separate days in the patient and in three normal volunteers. Blood samples were obtained at frequent intervals from 2 to 24 h after oral administration of radiothyronine. The percentage of the dose of each isotope per litre of serum was then calculated. Serum T 4 and T 3 were measured by radioimmunoassay, and free T 4 and free T 3 indices were calculated (2). Thyrotropin concentration in the serum was also measured by radioimmunoassay (3), using the human TSH standard 68/38 and reagents supplied by the National Institutes of Health. Brief Reports
Downloaded from https://annals.org by Tulane University user on 01/16/2019
941
Table 1. Effect of Jejunoileal Bypass• on Serum Thyroxine (T4), Triiodothyronine (T3), and Thyrotropin (TSH) Concentrations in a Hypothyroid Patient Taking L-Thyroxine
Before bypass May 1974 Aug 1974 Bypass (Aug 1974) Sep 1974 Sep 1976 Dec 1976 Feb 1977 Mar 1977 May 1977 Reversal of shunt (Jul 1977) Jan 1978 Normal values
Duration of Treatment
Total Serum T 4
mg
mos.
ng/dL
0/ /o
0.2
3
4.1 6.8
31.5 39.0
3.2 6.6
64 160
50 156
0.2 0.2 0.2 0.4 0.6 0.6
4 28 31 2.5 1 3
3.6 1.6 0.6 2.7 5.5 5.4
36.5 45.9 49.9 58.7 65.2 56.1
3.3 1.8 0.7 4.0 9.0 7.6
10 10 32 17
12 15 47 24
0.2
5
7.6 4.5-12.7
38.0 35-45
7.2 4.5-12.2
130 90-205
123 85-205
T 3 Uptake
When the prescribed dosage of L-T4 was 0.4 mg daily, baseline serum TSH was 8.9 jLtU/mL and TSH response to T R H was prolonged and exaggerated, with a peak of 85 jLtU/mL at 30 minutes. Four weeks after the dosage of L-T4 was increased to 0.6 m g / d , serum T 4 increased to normal value, basal serum TSH decreased to 2.5 jiiU/mL (Table 1), and T S H response to T R H became normal, with a peak of 12.9 /LtU/mL at 10 minutes. Ingestion of 100 jxg of L-T3 by three patients with cirrhosis of the liver caused an increase in serum T 3 that reached a peak value of 470 ± 88 n g / d L in 4 h. T h e increase of serum T 3 in our patient, however, was slight, reaching a maximum of only 144 n g / d L in 2 h. The transport of labelled T 3 and T 4 was markedly decreased in our patient. The maximum percentage of dose per litre of [ 1 2 5 I]L-T 3 occurred 2 or 3 h after the dose was administered (control, 6.1 ± 1.2%; patient, 0.43%) and that of [ 1 2 5 I]L-T 4 occurred after 4 h (control, 14.5 ± 1.6%; patient, 5.9%). The absorption of various drugs in patients who undergo intestinal bypass has not been thoroughly studied; however, reduced plasma level of oral contraceptives has been reported after bypass surgery (4). In our patient, intestinal absorption of thyroid hormones was markedly diminished after intestinal bypass surgery and restored to normal after reversal of the shunt. After bypass surgery, elevated serum TSH responded to increasing dosages of L-T4, and both basal and TRH-stimulated serum T S H became normal 3 weeks after the dosage was increased to 0.6 mg. Serum T 4 also increased, but serum T 3 and the calculated free T 3 index remained in a subnormal range. The low T 3 was due to decreased conversion of T 4 to T 3 , which was caused by cirrhosis (5) and bypass-induced fasting state (6, 7). After bypass surgery, the absorption of labelled thyroid hormones was markedly diminished, and the serum concentration of T 3 after oral ingestion of L-T3 peaked at a level far below that of the cirrhotic patients and that of normal subjects (8). Therefore, it appears that malabsorption of thyroid hormones in our patient was not caused by cirrhosis.
9 4 2
Free T 3 Index
Daily Dose of Thyroxine
June 1979 • Annals of Internal Medicine • Volume 90 • Number 6
Downloaded from https://annals.org by Tulane University user on 01/16/2019
Free T 4 Index
Total T 3
Serum TSH
nU/mL
ng/dL
>50 1.8
36 8.9 2.5 2.0
1.6 < 1.2-5.0
Our finding that an intestinal bypass may result in significant malabsorption of T 4 and T 3 is in accord with findings from a previous report of impaired absorption of thyroid hormone in malabsorption and small intestinal disease (9). Patients with hypothyroidism who undergo this type of surgery should have periodic assessments of their thyroid hormone status. The exact intestinal site of absorption of thyroid hormones is not known. In-vitro studies have shown that in rats all three parts of the small intestine absorb labelled thyroxine; the absorption is least complete in the duodenum and most complete in the ileum (10). Present studies support the theory that thyroid hormones are absorbed throughout the small intestine, a large area of which is needed for complete absorption. This study was supported by grant 5S10RR 05587-07, General Research Support, National Institutes of Health, Bethesda, . Maryland. REFERENCES
1. D E W I N D LT, PAYNE JH: Intestinal bypass surgery for morbid obesity. Long-term results. JAMA 236:2298-2301, 1976 2. S A W I N CT, C H O P R A D, A L B A N O J, A Z I Z I F: The free triiodothyronine
(T,) index. Ann Intern Med 88:474-477, 1978 3. O D E L L W D , W I L B E R J F , U T I G E R R D : Studies of thyrotropin physiolo-
gy by means of radioimmunoassay. Recent Prog Horm Res 23:47-85, 1967 4. JOHANSSON EDB, K R A I JG: Oral contraceptives after intestinal bypass operations (letter). JAMA 236:2847, 1976 5. C H O P R A IJ, SOLOMON DH, C H O P R A U, Y O U N G RT, C H U A T E C O G N :
Alterations in circulating thyroid hormones and thyrotropin in hepatic cirrhosis: evidence for euthyroidism despite subnormal serum triiodothyronine. J Clin Endocrinol Metab 39:501-511, 1974 6. PORTNAY G I , O ' B R I A N JT, BUSH J, VAGENAKIS AG, A Z I Z I F, A R K Y RA, INGBAR SH, B R A V E R M A N LE: The effect of starvation on the con-
centration and binding of thyroxine and triiodothyronine in serum and on the response to TRH. J Clin Endocrinol Metab 39:191-194, 1974 7. AZIZI F: The effect of dietary composition on fasting induced changes in serum thyroid hormones and thyrotropin. Metabolism 27:935-942, 1978 8. LIEBLICH J, U T I G E R R D : Triiodothyronine radioimmunoassay. J Clin
Invest 51:157-166, 1972 9. HAYS MT, K A T Z L: Thyroxine (T4) absorption in small intestinal disease (abstract). J Nucl Med 14:406-407, 1973 10. C H U N G SJ, V A N M I D D L E S W O R T H L: Absorption of thyroxine from the
small intestine of rats. Endocrinology 74:694-700, 1964 © 1 9 7 9 American College of Physicians
