Altered thyroid status modulates portal pressure in normal rats.

BACKGROUND & AIMS: Disturbances in thyroid function in humans and experimental animal models have been associated with alterations in liver function and portal circulation. We have previously shown that hypothyroidism can significantly reduce portal pressure in portal vein ligated rats as well as inhibit the development of cirrhosis and fulminant hepatic failure following toxic liver injury. The aim of this study was to determine the effects of increased and decreased thyroid function on portal pressure in rats with normal liver histology and portal circulation. METHODS: Three groups of 12 Wistar rats each were studied over a 30 day period: euthyroid (Group 1), hyperthyroid (Group 2) and hypothyroid (Group 3). Hyperthyroidism was induced by subcutaneous injection of triiodothyronine (400 microg/100g body weight) every ten days during the study period. Hypothyroidism was induced by methimazole (0.04% in drinking water) from 2 weeks prior to and throughout the 30 day study. Serum triiodothyronine (T3) and thyroid stimulating hormone (TSH) levels were determined to confirm the induction of hyper- and hypothyroidism. Portal pressure was assessed by direct catheterization of the portal vein prior to sacrifice. Indirect confirmation of changes in portal circulation was obtained by determining splenic weight at the time of sacrificing the animals. Animals were sacrificed at 10 day intervals throughout the 30 day study. RESULTS: Triiodothyronine treated rats were hyperthyroid compared to controls, with an elevation in serum T3 levels (3.8+/-0.9 mmol/L vs 1.3+/-0.4 mmol/L, p<0.05). In rats treated with methimazole, hypothyroidism was confirmed by a 7-fold increase in serum TSH compared to controls (1.8+/-0.4 vs 0.24+/-0.04 mmol/L, p<0.01). Portal pressure was significantly higher in the triiodothyronine treated rats compared to controls (12.8+/-1.7 and 9.6+/-0.75 cm H2O, p<0.001). Splenic weights in hyperthyroid rats were significantly higher than in controls (579+/-44 vs 478+/-46 mg, p<0.01). Portal pressure was significantly lower in the methimazole treated group compared to the control group (8.13+/-0.68 vs 9.6+/-0.75 cm H2O, p<0.01) as were splenic weights (400+/-33 vs 478+/-46 mg, p<0.01). CONCLUSION: These studies demonstrate that disturbed thyroid function exerts significant hemodynamic effects on the portal circulation in normal rats and complements results from previous similar studies in cirrhotic animals.     

Hemodynamic effects of hypothyroidism induced by methimazole in normal and portal hypertensive rats

Portal hypertension is accompanied by a hyperdynamic circulatory state that shares some similarities with thyrotoxicosis. This study was conducted in order to investigate the hemodynamic effects of hypothyroidism in a rat model with portal hypertension induced by partial portal vein ligation (PVL). Four groups of 10 rats each were studied: normal control and hypothyroid rats, and PVL control and hypothyroid rats. Hypothyroidism was induced by methimazole 0.04% in drinking water. Hemodynamic measurements were performed using the radioactive microsphere technique. Induction of hypothyroidism was confirmed by elevated TSH levels. In the PVL groups, hypothyroidism ameliorated the hyperdynamic circulation. Portal venous inflow and portal pressure dropped significantly: 7.1±0.2 vs 4.8±0.3 ml/min/100 g body wt (P<0.01) and 13.4±0.9 vs 10.9±0.8 mm Hg; (P<0.01), respectively. In normal rats, hypothyroidism was manifested by a hypodynamic circulatory state. These results demonstrate that hypothyroidism induced by methimazole is followed by amelioration of the hyperdynamic circulation, normalization of portal venous inflow, and reduction of portal pressure.     

Plasma catecholamine concentrations in hyperthyroidism and hypothyroidism

Using a modification of the fluorometric method of Anton and Sayre,⁴ we have measured the plasma epinephrine (E) and norepinephrine (NE) concentrations in patients with thyroid dysfunction. There was no significant difference in plasma E in hyperthyroid or hypothyroid subjects, the values being similar to those observed in normal subjects. There was a striking relationship between age and plasma NE in the euthyroid individuals (r = 0.685, p < 0.001, n = 41). Observed plasma NE concentrations were similar in control subjects (21.05 ± 1.6 ng/100 ml; mean ± SEM) and hyperthyroid patients (22.33 ± 2.0 ng/100 ml). However, plasma NE was significantly increased in hypothyroidism (35.46 ± 3.9 ng/100 ml; p < 0.01) and remained statistically different when the age factor was excluded (31.31 ± 2.67 ng/100 ml; p < 0.025). There was no correlation between plasma NE and serum thyroxine (T₄), free thyroxine (FT₄), or triiodothyronine (T₃), in any of the three groups studied. These data indicate that hyperthyrodism is accompanied by normal plasma NE concentrations and that hypothyroidism is associated with significantly increased plasma NE concentrations, possibly in an attempt to compensate for the lack of thyroid hormones.     

Systemic and splanchnic hemodynamic changes in patients with hepatic schistosomiasis

Abstract: Although hepatic schistosomiasis is a common cause of portal hypertension, only a few hemodynamic studies, in humans, have been published on this subject. The aim of this study was to determine the systemic and splanchnic hemodynamic changes in hepatic schistosomiasis and to evaluate the influence of liver fibrosis on these changes. A retrospective analysis of a series of 13 patients with hepatic schistosomiasis who had undergone hemodynamic studies was performed. Portal or perisinusoidal fibrosis was present at liver biopsy in 8 patients. The control group included 22 patients with chronic hepatitis and normal hepatic venous pressure gradients. Patients with schistosomiasis exhibited high cardiac index (4.11±1.15 1 · min^-1 · m^-2 vs 2.99±0.85 1 · min^-1 · m^-2; p<0.05) and low systemic vascular resistance (1039±316 dyn · s · cm^-5 vs 1334±336 dyn · cm^-5; p<0.05). The hepatic venous pressure gradient and hepatic blood flow were normal. Azygos blood flow was markedly increased (0.90±0.66 1 · min^-1 vs 0.13±0.04 1 · min^-1; p<0.05). Hemodynamic values were not significantly different between patients with liver fibrosis and those without fibrosis at liver biopsy. In conclusion, patients with hepatic schistosomiasis had a hyperkinetic systemic and splanchnic circulation. In patients with esophageal varices, a normal hepatic venous pressure gradient confirmed presinusoidal portal hypertension. The presence of portal or perisinusoidal fibrosis did not influence hyperdynamic splanchnic state.     

Follow up of patients with postpartum thyroiditis: a population-based study

In this survey we studied the prevalence of permanent hypothyroidism and prognostic factors for its occurrence 3–5 yr after postpartum thyroiditis (PPT); 54 of 120 women with PPT and 50 of 920 healthy women from among 1040 women followed 4–5 yr earlier for PPT were recalled. Demographic information, signs, and symptoms of thyroid disorders and results of physical exams were documented. Serum T₃, T₄, RT₃U, TSH, and antithyroperoxidase (antiTPO ab) and antithyrogluboline (antiTg ab) antibodies were measured. Twenty-two percent of the cases and four percent of the control group had permanent hypothyroidism, p<0.01. Based on the TSH level we divided the case group into two subgroups: PPT-Hypothyroidism (PPT-Hypo) and PPT-Eutyhroidism (PPT-EU); PPT-Hypo had greater titer of antiTPO ab than PPT-Eu (437±283 vs 126±221 IU/mL, p<0.001). Comparison of mean peak serum TSH level and antiTPO ab during the postpartum thyroiditis phase between PPT-Hypo and PPT-Eu in the case group was significant (56±24 vs 23±28 mU/L, p<0.001, and 1960±1270 vs 640±959 IU/L, p<0.001, respectively). Results of this survery show a high prevalence of permanent hypothyroidism following PPT in Tehran. High titers of antiTPOAb and TSH levels at postpartum period are prognostic factors for occurrence of permanent hypothyroidism.     

Inhibition of concanavalin A-induced acute T cell dependent hepatic damage in mice by hypothyroidism

Abstract: Aims/Background: Concanavalin A (Con A) activates T lymphocytes and causes acute T-cell-mediated hepatic injury in mice. Decreased thyroid hormonal production is associated with a variety of immunological manifestations, including inactivation of macrophages with reduced TNF production and reduced soluble IL-2 receptors in the serum. We have recently shown that hypothyroidism prevents the development of cirrhosis and also minimizes hepatic damage in rats with fulminant hepatic failure. In the present study we examined the effects of hypothyroidism on a mouse model of Con A induced T cell-mediated acute hepatitis. Methods: Hypothyroidism was induced both medically (MMI, PTU) and surgically. Eight groups of 10 mice each were studied: euthyroid controls (2 groups: water, Con A) and hypothyroid (6 groups: MMI, PTU, Surgical, MMI-Con A, PTU-Con A, Surgical-Con A). Results: Hepatic inflammation was significantly decreased in each of the Con A treated hypothyroid groups of mice. The serum transaminases, TNF-α and IL-6 levels were significantly elevated in the Con A treated group while near normal levels were found in the hypothyroid Con A treated groups (mean±SE AST: 1499±18 vs 78±10 IU/1, p<0.001; TNF: 2500±250 vs 135± 15 pg/ml. p<0.001, IL-6: 12,200±300 vs 1260±140 pg/ml, p<0.001, respectively). Conclusions: Hypothyroidism, independent of the mode of induction, can effectively inhibit the development of acute T cell-mediated liver damage in mice. These results suggest that some decrease in thyroid function might have a role in the prevention of immune mediated liver diseases.     

Prolactin and thyroid hormones in patients with systemic sclerosis: correlations with disease manifestations and activity

Summary. Objective: To determine serum levels of prolactin (PRL) and thyroid hormones and to investigate the correlation between these hormones and different disease manifestations in patients with systemic sclerosis (SSc). Methods: Twenty four patients with SSc (23 women, mean age 37.7±12.7) were subjected to thyroid hormones assessment. Prolactin (PRL) was assessed in 23female patients. The patients were evaluated regarding different disease manifestations. Fifteen normal female volunteers were involved as controls. Results: Serum levels of PRL in all patients was significantly higher than controls (16.75±9.06 for patients vs. 11.6±4.5 for controls with p<0.001). Eight patients out of 23 (34.8%) showed hyperprolactinemia. In patients with diffuse SSc (dSSc), PRL levels showed significant correlation with the rate of skin tethering (r=+0.72, p<0.01) and abnormal left ventricular filling pattern (↓E/A ratio), i.e., occurrence of diastolic dysfunction (r=+0.65, p<0.05). Hyperprolactinemia in all patients correlated significantly with disease duration (r=–0.42, p<0.05).     Mean serum levels of free thyroxin (FT4) in all patients were significantly lower than the control group(7.46±2.7 for patients vs 10.47±2.5 with p<0.001). Eight out of all 24 patients (33.3%) showed hypothyroidism. In groupA (duration<3years); FT4 levels correlated significantly with Dlco% (r=+0.90, p<0.01). While in groupB (duration>3years), T4 hypothyroidism correlated significantly with hand joint restriction of motion (r=+0.66, p<0.01).    Serum levels of triiodothironine (FT3) in all patients were nonsignificantly lower than the control group (4.8±2.3 for patients vs 5.3±1.9 for controls, P=NS). Three patients out of 24 (12.5%) showed T3 thyrotoxicosis. Serum levels of T3 correlated significantly with liver enzyme elevations (r=+0.46, p<0.05) and ESR (r=+0.41, p<0.05). Conclusion: This study demonstrates the close association between PRL or thyroid hormones and some organ involvement in SSc. Correspondence to Amira A. Shahin     

Portal venous blood flow while breath-holding after inspiration or expiration and during normal respiration in controls and cirrhotics

In this study, we used magnetic resonance (MR) imaging to measure portal blood flow in 12 healthy controls and 17 cirrhotics while they were breath-holding after inspiration and after expiration. We then compared the results with measurements made during normal respiration in the healthy controls and cirrhotics. Blood flow in the main portal vein under basal fasting conditions was quantitated using the cine phase-contrast MR velocity mapping method. Three measurements were made on one occasion, as follows: (1) throughout the cardiac cycle during normal respiration, (2) with the subject breath-holding after maximal inspiration, and (3) with the subject breath-holding after maximal expiration. During normal respiration, portal blood flow was 1.3 ± 0.2 l/min in controls vs 1.0 ± 0.1 l/min in cirrhotics (P < 0.0001); while subjects were breath-holding after inspiration, portal blood flow was 1.0 ± 0.2 l/min in controls vs 0.9 ± 0.1 l/min in cirrhotics; and while subjects were breath-holding after expiration, portal blood flow was 1.5 ± 0.2 l/min in controls vs 1.1 ± 0.2 l/min in cirrhotics (P < 0.0001). The differences were primarily due to changes in flow velocity. When the magnitude of these hemodynamic changes in the three respiratory conditions was compared in controls and cirrhotics, analysis of variance (ANOVA) showed a significant difference (P < 0.0001). In controls, portal blood flow decreased during maximal inspiration relative to flow during normal respiration (−24.6 ± 8.3%). Changes in portal blood flow in controls were greater than in cirrhotics (−13.5 ± 4.5%) (P < 0.0001); however, the difference in blood flow increase associated with maximal expiration between the two groups (+11.8 ± 9.4% vs +5.9 ± 11.5%) was not significant. We found that the respiration-induced hemodynamic variation in portal blood flow was less in cirrhotics than in the healthy controls. Portal blood flow measurements made during normal respiration using MR imaging closely reflect nearly physiologic conditions. Received: November 19, 1998 / Accepted: March 26, 1999     

Hepatic dysfunction in patients with extrahepatic portal venous obstruction

Background: Extrahepatic portal venous obstruction (EHPVO) developing due to thrombotic occlusion of the portal vein in children is generally considered a benign disease. Whether hepatic dysfunction develops in these patients in the absence of a gastrointestinal bleed has not been well studied. Materials and methods: Forty‐three patients with EHPVO who had not bled in the last 3 months were studied. Patients were divided into those with (group I) or without ascites (group II). Matched cirrhotic patients with ascites (group III) served as controls. Clinical, biochemical, ultrasonographic, and histopathological evaluation was carried out. Portal biliopathy was assessed in five patients in group I and in 12 patients in group II by cholangiography. Results: Of 43 EHPVO patients, ascites was seen in nine (21%) patients (group I). Thirty‐four patients had no ascites (group II). Serum ALT (54±24 vs. 34±10 IU/l, P<0.01), albumin (3.2±0.3 vs. 3.7±0.4 g/dl, P<0.01), and prothrombin time difference (9.0±4.5 vs. 2.4±1.9 s, P<0.05) were deranged in patients in group I compared with group II. Patients in group I were 4 years older, and the duration of portal hypertension was longer than in group II (11.5 vs. 5.6 year, P<0.05). Portal biliopathy changes were significantly more severe in group I than in group II patients. Ascites was high gradient in all the patients in group I and the serum‐ascitic albumin gradient was comparable between groups I and III. None of the EHPVO patients, but four cirrhotic patients, developed spontaneous bacterial peritonitis during a follow‐up of 11±4 months. Conclusions: Hepatic dysfunction in the form of ascites and deranged liver functions is not uncommon in patients with EHPVO, more so in patients with prolonged portal hypertension. Based on our data it would be worthwhile to study whether prolonged portal vein thrombosis in EHPVO patients could lead to progressive liver disease.     

Effect of Metoclopramide on Portal Blood Flow in Patients with Liver Cirrhosis,Measured by the Pulsed Doppler System

The effect of metoclopramide on portal blood flow, the maximal diameter of the portal vein, and some cardiovascular haemortynamic variables was studied in 10 patients with cirrhosis of the liver and portal hypertension. Portal vein haemo-dynamics were studied by the pulsed Doppler system. Within 15 min of intravenous administration of 20 mg metoclopramide, portal blood velocity and portal blood flow decreased significantly, from 11.2 ± 1.1 to 10.8 ± 1.2 cm/sec and from 769.0 ± 87.7 to 707.9 ± 84.2 ml/min, respectively (p < 0.001). Within about 30 min portal blood velocity and portal blood flow returned to basal values (p >0.05). The maximal diameter of the portal vein, systolic and diastolic blood pressure, and heart rate remained unchanged. These results support the hypothesis that metoclopramide, which raises lower oesophageal sphincter pressure and reduces intravariceal blood flow, significantly decreases the portal blood flow in cirrhotic patients with portal hypertension.     

Hemodynamic characterization in experimental liver cirrhosis induced by thioacetamide administration

Systemic and splanchnic hemodynamics in experimental liver cirrhosis in rats induced by thioacetamide were evaluated by the radioactive microsphere method. Cardiac output and regional blood flow were measured in conscious and anesthetized control and cirrhotic rats. The conscious thioacetamide-treatment rats had hyperdynamic circulation with an increased cardiac index (300±10 vs 258±3 ml/min/kg body weight,P<0.001) and increased portal venous inflow compared with the controls (64.60±2.4 vs 48.39±0.88 ml/min/kg body weight,P<0.001). Under pentobarbital anesthesia, the hyperdynamic circulation of the cirrhotic rats was maintained, with an increased cardiac index (276±7 vs 229±5 ml/min/kg body weight,P<0.001) and increased portal venous inflow compared with the controls (72.47±3.0 vs 54.08±1.2 ml/min/kg body weight,P<0.001). Portal pressure, portal venous resistance, and portal systemic shunting increased significantly while splanchnic arterial resistance decreased significantly in cirrhotic rats. Thioacetamide-induced cirrhosis is a useful model for the hemodynamic study of portal hypertension and remains useful in hemodynamic studies in the basal state under pentobarbital anesthesia.     

Total parenteral nutrition modulates hormone release by stimulating expression and activity of inducible nitric oxide synthase in rat pancreatic islets

The expression and activities of constitutive nitric oxide synthase (cNOS) and inducible nitric oxide synthase (iNOS) in relation to insulin and glucagon secretory mechanisms were investigated in islets isolated from rats subjected to total parenteral nutrition (TPN) for 10 d. TPN is known to result in significantly increased levels of plasma lipids during the infusion time. In comparison with islets from freely fed control rats, islets taken from TPN rats at d 10 displayed a marked decrease in glucose-stimulated insulin release (4.65±0.45 ng/[islet·h] vs 10.25±0.65 for controls) (p<0.001) accompanied by a strong iNOS activity (18.3±1.1 pmol of NO/[min·mg of protein]) and a modestly reduced cNOS activity (11.3±3.2 pmol of NO/[min.mg of protein] vs 17.7±1.7 for controls) (p<0.01). Similarly, Western blots showed the expression of iNOS protein as well as a significant reduction in cNOS protein in islets from TPN-treated rats. The enhanced NO production, which is known to inhibit glucose-stimulated insulin release, was manifested as a strong increase in the cyclic guanosine 5′-monophosphate content in the islets of TPN-treated rats (1586±40 amol/islet vs 695±64 [p<0.001] for controls). Moreover, the content of cyclic adenosine monophosphate (cAMP) was greatly increased in the TPN islets (80.4±2.1 fmol/islet vs 42.6±2.6 [p<0.001] for controls). The decrease in glucose-stimulated insulin release was associated with an increase in the activity of the secretory pathway regulated by the cAMP system in the islets of TPN-treated rats, since the release of insulin stimulated by the phosphodiesterase inhibitor isobutylmethylxanthine was greatly increased both in vivo after iv injection and after in vitro incubation of isolated islets. By contrast, the release of glucagon was clearly reduced in islets taken from TPN-treated rats (33.5±1.5 pg/[islet·h] vs 45.5±2.2 for controls) (p<0.01) when islets were incubated at low glucose (1.0 mmol/L). The data show that long-term TPN treatment in rats brings about impairment of glucose-stimulated insulin release, that might be explained by iNOS expression and a marked iNOS-derived NO production in the β-cells. The release of glucagon, on the other hand, is probably decreased by a direct “nutrient effect” of the enhanced plasma lipids. The results also suggest that the islets of TPN-treated rats have developed compensatory insulin secretory mechanisms by increasing the activity of their β-cell cAMP system.     

Thyroid hormones and thyroid-stimulating hormone in Egyptian patients with systemic lupus erythematosus: correlation between secondary hypothyroidism and neuropsychiatric systemic lupus erythematosus syndromes

 The purpose of this study was to determine the serum levels of thyroid hormones and thyroid-stimulating hormone (TSH), in addition to antithyroglobulin and antimicrosomal antibodies and to investigate the correlation between these hormones and various disease manifestations among Egyptian patients with systemic lupus erythematosus (SLE). A group of 45 patients with SLE (43 women and 2 men with a mean age of 27.57 ± 9.89 years) underment assessment of their thyroid hormones. Antithyroglobulin and antimicrosomal antibodies were assessed in 27 patients. Various disease manifestations were evaluated. A group of 20 normal female volunteers were involved as controls. The mean serum free triiodothyronine (FT₃) levels in all patients were significantly lower than in controls (1.89 ± 1.14 vs. 3.15 ± 0.93 pg/ml; P < 0.05). Patients with a history of intravenous pulsed cyclophosphamide therapy showed significantly decreased levels of FT₃ compared to those in other patients (1.17 ± 0.5 vs. 2.05 ± 0.95 pg/ml; P = 0.04). The mean serum free thyroxine (FT₄) levels in all patients were significantly less than in the control group (1.24 ± 1.22 vs. 1.4 ± 0.3 mg/dl; P < 0.001). Of the 45 patients, 2 (4.4%) were considered to have primary hypothyroidism. Five of six patients (83.3%) with decreased FT₄ levels developed fibromyalgia compared to 7 of 39 (17.9%) patients with normal T₄ (P = 0.003). The mean serum TSH levels in all patients were significantly higher than in the controls (4.82 ± 22.2 vs. 2.65 ± 1.18 μIU/ml; P < 0.001). Six patients with decreased TSH levels were considered to have secondary hypothyroidism (13.3%); one of them showed decreased T₃ and T₄, two had decreased T₄ only, and the other three were euthyroid. Comparing patients with and without secondary hypothyroidism, showed acute confusion in four (66.7%) in the former group versus four (10.3%) in the latter group (P = 0.006), anxiety in four (66.7%) in the former group versus six (15.4%) in the latter group (P = 0.016), and cognitive disorders in five (83.3%) in the former group versus nine (23.1%) in the latter group (P = 0.008). This study demonstrated evidence of secondary as well as primary hypothyroidism in SLE patients and revealed a close association between thyroid hormones or TSH and some organ involvement in SLE. Received: August 7, 2001 / Accepted: May 8, 2002 Present address: 453 Al-Ahram Street, Al-Ahram, Giza, Egypt Tel./Fax +202-5870668 e-mail: rughe@rusys.eg.net Correspondence to:A.A. Shahin     

Role of sympathetic cardiovascular tone in control of arterial pressure in rats with cirrhosis

Abstract: Although an increase in sympathetic nervous activity has been recognized in cirrhosis, the contribution of this overactivity to the regulation of arterial pressure is unknown. The arterial pressure response to increasing doses of hexamethonium (0.05 to 3.2 mg · kg^-1 · min^-1), a ganglionic blocker that decreases sympathetic cardiovascular tone, was explored in normal rats and in two models of portal hypertension, i.e., rats with cirrhosis and rats with portal vein stenosis. Changes in plasma norepinephrine concentrations were greater in rats with cirrhosis (356±50 vs 166±30 pg/ml, p=0.04) than in normal rats (186±23 vs 86±31 pg/ml, p=0.06) and rats with portal vein stenosis (103±37 vs 93±5 pg/ml, p=0.10). The maximum decrease in arterial pressure was obtained at a dose of 1.6 mg · kg^-1 · min^-1 in each group. However, the decrease in arterial pressure was significantly greater in rats with cirrhosis (-25±2%) than in normal rats (-11±1%) and in rats with portal vein stenosis (-13±2%) (p=0.04). In conclusion, the results of this study suggest that the sympathetic cardiovascular tone is more important for the maintenance of arterial pressure in rats with cirrhosis than in normal rats and in rats with portal vein stenosis.     

A non-invasive method for evaluating cirrhotic portal hypertension by administration of 99mTc-MIBI per rectum

Abstract A study was performed to evaluate radio-isotopic imaging using technetium-99m hexakis 2-meth-oxyisobutyl isonitrile administered per rectum to assess portal collateral circulation. The heart-liver ratios (H/L; mean ± standard deviation) in 15 controls, 13 cases of histologically confirmed viral hepatitis and 57 cirrhosis patients were 0.27 ± 0.11, 0.43 ± 0.14 and 1.00 ± 0.28, respectively (P < 0.001). Among the cirrhosis patients those with the Child-Pugh classification A, B and C had H/L of 0.56 ± 0.14, 1.00 ± 0.20 and 1.19 ± 0.26, respectively (P < 0.001). A high value of H/L was associated with a high risk of hepatic encephalopathy (1.25 ± 0.17, P < 0.01) and oesophageal varices (1.02 ± 0.20, P < 0.01). There were associations between H/L and serum bilirubin (P < 0.01), albumin (P < 0.05) and prothrombin time (P < 0.05). The results also showed a good correlation between H/L and portal vein pressure measured during operation in 13 patients (P < 0.001, r= 0.87). The regression equation: y= 6.77 + 32.5 H/L, allowed portal vein pressure to be estimated. The prognostic value of the test was supported by the fact that good correlations were observed between the H/L ratio and widely accepted prognostic classification (Child-Pugh). It is suggested that this new method could be a reliable non-invasive way to give an indication of the degree of portasystemic shunting to evaluate the prognosis and to follow up the effects of medications for reducing portal hypertension in patients with cirrhotic portal hypertension.     

An endothelin receptor antagonist TAK-044 ameliorates carbon tetrachloride-induced acute liver injury and portal hypertension in rats

ABSTRACT— Hepatic levels of a powerful vasoconstrictor endothelin-1 (ET-1) and its receptors increase in human and carbon tetrachloride (CCl₄)-induced liver cirrhosis. The aim of this study was to determine whether antagonism of hepatic ET-1 receptors ameliorates CCl₄-induced hepatic injury and portal hypertension in rats. Acute liver injury was induced by a single intraperitoneal injection of CCl₄ (0.3 ml/kg), whereas cirrhosis and portal hypertension were induced by CCl₄ treatment (0.15 ml/kg twice a week) for 8 weeks. Hepatic morphology, ET-1 and its receptors, and portal venous pressures were determined. Increases in ET-1 and its receptors occurred within 24 h of CCl₄ administration, and progressively thereafter during the development of cirrhosis. The acute CCl₄-induced hepatic injury was characterized by significant increases in portal pressure (from 8.7 ± 1.8 to 17.6 ± 3.3 mmHg; p<0.01) and serum levels of liver enzymes, as well as massive hepatocellular necrosis (62±8%). Intravenous administration of an ET-1 receptor antagonist TAK-044 reduced portal pressure to 13.6±2.8 mmHg (p<0.05), and ameliorated hepatocellular necrosis by about 35% (p<0.001). TAK-044 treatment also produced significant reduction in serum levels of liver enzymes. In cirrhotic rats, portal venous infusion of TAK-044 reduced portal hypertension by about 40% (p<0.05). In conclusion, these results indicate involvement of ET-1 in acute liver injury as well as portal hypertension associated with hepatic cirrhosis, and a potential for ET-1 receptor antagonists in the treatment of these pathologic conditions.     

Possible implications of leptin, adiponectin and ghrelin in the regulation of energy homeostasis by thyroid hormone

Thyroid hormone plays a critical role in energy homeostasis through mechanisms, which are not fully understood. In the present study, we investigated possible alterations of important energy regulators such as leptin, adiponectin, and ghrelin in relation to changes in thyroid hormones. Thyroid hormone (250 μg/kg) was administered in male Wistar rats for 2 weeks (THYR), while hypothyroidism (HYPO) was induced by propylthiouracil administration (0.05% in drinking water) for 3 weeks. Untreated animals served as controls (NORM). Leptin and adiponectin were measured in plasma by ELISA, while total ghrelin was measured with RIA. Body weight was significantly reduced both in THYR and HYPO rats, while food intake was significantly increased in THYR and decreased in HYPO. This response was associated with various changes in leptin, adiponectin, and ghrelin in plasma. In fact, in THYR rats, leptin levels (mean ± SEM) were 240 ± 55 pg/ml as compared to 819 ± 70 pg/ml in untreated rats (P < 0.05), while no changes were observed in ghrelin and adiponectin. In HYPO rats, leptin levels were 1400 ± 200 pg/ml vs. 819 ± 70 pg/ml in untreated rats (P < 0.05), while ghrelin and adiponectin were significantly increased in HYPO rats as compared to untreated rats (P < 0.05). Furthermore, T₃ and T₄ levels were inversely correlated to leptin (P = 0.014), while ghrelin and adiponectin were inversely correlated to weight changes (P = 0.05 and P = 0.03, respectively). In conclusion, leptin seems mainly to be involved in the thyroid hormone effects on energy homeostasis. Ghrelin and adiponectin may serve a compensatory physiological role in hypothyroidism.     

Non‐alcoholic steatohepatitis induces non‐fibrosis‐related portal hypertension associated with splanchnic vasodilation and signs of a hyperdynamic circulation in vitro and in vivo in a rat model

Introduction: Steatosis, without fibrosis, may lead to changes in liver blood flow, which are poorly understood, and to date have not been correlated to portal pressure and related haemodynamics. Aims: To study the temporal relation between progressive steatosis, portal pressure, systemic haemodynamics, vascular responsiveness, mesenteric and portal blood flow in methionine–choline‐deficient diet (MCDD)‐fed rats. Methods: Male Wistar rats fed the MCDD were examined at week (w) 0‐1‐2‐3‐4‐5‐6‐7‐8, respectively, including systemic haemodynamics and portal pressure. At w0‐4‐8, in vivo blood flow was measured in the portal vein and the superior mesenteric artery. Dose–response curves to phenylephrine (PE) were established in abdominal aortic rings. Results: Histology showed 100% steatosis from w3 on. Fibrosis was absent. Significant inflammation was nearly absent upon w4. Portal pressure slightly increased at w2, reached a maximum at w4 [9.4 ± 0.3 vs 2.9 ± 0.6 mmHg at w0 (P=0.003)] and remained stable upon w8. Mean arterial blood pressure (MABP) decreased from w2 on [98.7 ± 5.7 mmHg on w4 compared with 123.8 ± 1.8 on w0 (P=0.002)]. Portal flow increased from 1.85 ± 0.11 to 3.07 ± 0.44 ml/min/100 g on w0 and w8 respectively (P=0.039). Mesenteric artery flow increased from 3.40 ± 0.26 to 4.56 ± 0.30 ml/min/100 g on w0 and w8 respectively (P=0.043). Vascular responsiveness to PE gradually decreased from 138 ± 3% on w0 to 110 ± 5% on w4 (P=0.013). Conclusion: Steatohepatitis induces significant portal hypertension (PHT) in the absence of fibrosis, associated with an increase in mesenteric arterial and portal venous flow, arterial hyporesponsiveness to vasoconstrictors and a decrease in MABP, indicating the presence of splanchnic vasodilation and hyperdynamic circulation. These alterations resemble those seen in cirrhotic PHT.     

Menstrual Irregularities are more Common in Adolescents with Type 1 Diabetes: Association with Poor Glycaemic Control and Weight Gain

Ovarian function in post-menarchal girls with Type 1 diabetes was evaluated. Menstrual histories from 24 adolescents with Type 1 diabetes were compared with those from 24 age and sex matched controls. A fasting blood sample was obtained from subjects with Type 1 diabetes for the measurement of ovarian and adrenal sex hormones, LH and FSH, glucose and insulin, insulin-like growth factor-l (IGF-I), and insulin-like growth factor binding protein-1 (IGFBP-1); and an ovarian ultrasound scan was performed. Menstrual irregularity was more prevalent in patients with Type 1 diabetes than controls (54% vs 21%, p < 0.01) and their mean body mass index (BMI) was greater (22.3 ± 0.5 (± SEM) vs 20.7 ± 0.6 kg m^?2, p < 0.05). Subjects with Type 1 diabetes with irregular menses (when compared with diabetic subjects with a regular cycle) had a significantly higher HbA_***1 (12.8 ± 0.4 vs 10.5 ± 0.5%, p < 0.01) and BMI (23.2 ± 0.6 vs 21.4 ± 0.6 kg m^?2, p < 0.05) associated with a lower sex hormone binding globulin (SHBG) (37.2 ± 4.0 vs 52.6 ± 4.0 nmol I^?1, p < 0.025) and IGF-I (1.4 ± 0.2 vs 2.2 ± 0.2 ***mUI^?1, p < 0.025) and a higher LH:FSH ratio (2.6 ± 0.5 vs 1.4 ± 0.2, p < 0.05). Polycystic ovarian changes were identified in 10/13 (77%) of these patients with an irregular cycle. Menstrual irregularity is common in post-menarchal girls with Type 1 diabetes and is associated with poor glycaemic control and weight gain. The apparent high incidence of polycystic ovarian change requires further investigation.     

Intra-uterine environment influences glomerular number and the acute renal adaptation to experimental diabetes

Aims/hypothesis. We sought to test the hypothesis of whether low birth weight rats would have reduced glomerular number, higher systolic blood pressure and an altered acute response to streptozotocin diabetes compared to normal birth weight rats. Methods. Female offspring of Wistar rats fed an isocaloric diet containing either 6 % casein (LPD) or 18 % casein (NPD) in utero were studied. Birth weight, body weight, systolic blood pressure and urine albumin excretion were measured before and after streptozotocin diabetes. Glomerular number and volume were estimated after one week of diabetes. Results. The LPD rats were of low birth weight (5.4 ± 0.5 g vs 6.4 ± 0.8 g, p < 0.0001) with higher systolic blood pressure (137 ± 9 mmHg vs 120 ± 7 mmHg, p < 0.0001) and reduced glomerular number (17 435 ± 2074 vs 24 846 ± 1864, p < 0.0001). The LPD rats had smaller kidneys (0.925 ± 0.009 g vs 1.200 ± 0.173 g, p = 0.041) but similar glomerular volume to NPD control rats (1.11 ± 0.15 · 10⁶μm³ vs 1.08 ± 0.17 · 10⁶μm³). After 1 week of diabetes LPD rats had a greater proportional increase in renal size (diabetes 50 ± 12 % vs control 20 ± 4 %, p = 0.003). Insulin suppressed renal hypertrophy in both LPD and NPD rats but failed to suppress glomerular hypertrophy in LPD rats (1.48 ± 0.21 · 10⁶μm³ vs 1.03 ± 0.23 · 10⁶μm³ p = 0.015). Conclusion/interpretation. Abnormal intra-uterine environment reduces both renal size and glomerular number and influences the acute renal adaptation to experimental diabetes. [Diabetologia (2001) 44: 721–728] Received: 25 September 2000 and in revised form: 26 February 2001