Splanchnic vasodilatation and vascular hyporesponsiveness to vasopressors are characteristic features of patients with cirrhosis. Although the vascular response to different vasopressors has been shown to be attenuated in cirrhosis, alterations on the receptor level are discussed controversially. Thus, impaired postreceptor signaling has been postulated. However, so far this has not been studied in human splanchnic vessels. Therefore, we assessed the vascular response of human hepatic arteries after activating the G-protein-dependent signal transduction pathway by stimulation with angiotensin II, the thromboxane A 2 analog U46619, or by G-protein activation with NaF/AlCl 3 . After endothelium denudation, cumulative isometric concentration contraction curves were obtained for hepatic arteries from 32 cirrhotic patients undergoing liver transplantation and from 40 organ donors after stimulation with either angiotensin II (10 ؊11 -10 ؊5 mol/L), U46619 (10 ؊10 -10 ؊6 mol/L) or AlCl 3 (30 mol/L)/NaF (10 ؊4 -3 ؋ 10 ؊2 mol/L). Hepatic arteries from cirrhotic patients were markedly less responsive to angiotensin II (P < .0001) than those from organ donors. Both stimulation of the G-protein phospholipase C pathway via the thromboxane A 2 receptor and receptor-independent Gprotein stimulation with AlCl 3 /NaF, induced an intact contractile response. In conclusion, the G-protein-dependent signal transduction system itself is unaltered in cirrhosis. Hence, the cause of the hyporesponsiveness to some vasoconstrictors in cirrhosis appears to be a receptor-specific phenomenon localized upstream from the G-protein level. (HEPATOLOGY 2001;34:884-888.)Peripheral and splanchnic vasodilatation leading to hyperdynamic circulation are characteristic hemodynamic features in patients with cirrhosis and in animal models with portal hypertension. 1-3 Supposedly, this is caused by an impaired vascular response to different vasoconstrictors as found in animal models with cirrhosis. [4][5][6][7][8][9][10] Recently, hyporesponsiveness of human hepatic arteries from patients with cirrhosis to vasoconstrictors such as the ␣ 1 -agonist methoxamine, 11 vasopressin, 12 or 5-hydroxytryptamine 12 has also been found. However, the exact pathophysiologic basis of the vascular hyporesponsiveness in cirrhosis has so far not been elucidated. Because vascular hyporesponsiveness has been shown to persist after inhibition of nitric oxide synthesis and endothelium removal 11,13 it cannot be solely explained by increased formation of nitric oxide in cirrhosis.Vascular hyporeactivity in cirrhosis involves different Gprotein-linked transmembrane receptors including the ␣ 1 -adrenoceptor, 6,10,11 the angiotensin II type 1 (AT 1 ) receptor, 5,14-16 and the vasopressin receptor. 12 Stimulation of these receptors predominantly induces smooth muscle contraction by G-protein (␣-subunit)-dependent activation of phospholipase C (PLC). This catalyzes formation of inositol 1,4,5-triphosphate (IP 3 ) and 1,2-diacylglycerol, which induces Ca 2ϩ mobilization and protein ki...

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In 27 families with familial non-autoimmune hyperthyroidism (FNAH) reported up to date, the onset of hyperthyroidism varies from 18 months to 60 years. Also the manifestation of goitres is variable in these families. A 74-year-old woman first presented at the age of 69 years with tachyarrhythmia and hypertension. After initial treatment of her hypertension and oral anticoagulation for her intermittent atrial fibrillation, a thyroid workup revealed a suppressed TSH and normal fT3 and fT4. TPO, TSH receptor (TSHR), and thyroglobulin antibodies were negative. Thyroid ultrasound revealed a thyroid volume of 102 ml with several nodules with diameters of up to 2.6 cm right and up to 1.8 cm left. Scintigraphy showed a homogeneous Technetium-99 m ((99 m)Tc) uptake of 1.27%. She was subsequently treated with 1 GBq radioiodine ((131)I). At the age of 74, her thyroid function was normal and her thyroid volume decreased to 90 ml. Because of the diffuse (99 m)Tc uptake and the negative TPO, TSHR, and thyroglobulin antibodies, genetic analysis of her TSHR gene was performed, in spite of her negative family history for hyperthyroidism. Sequencing revealed a N670S TSHR germline mutation. Previous in vitro characterisation of this TSHR mutation suggests a weak constitutive activity, yet the experimental data are ambiguous. This case illustrates the necessity to analyse patients with hyperthyroidism accompanied by diffuse (99 m)Tc uptake and negative TPO, TSHR, and thyroglobulin antibodies for TSHR germline mutations. Moreover, it demonstrates that TSHR germline mutations may first lead to longstanding nodular goitrogenesis before the late manifestation of subclinical hyperthyroidism.

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