Intracystic hemorrhage required no treatment from one of multiple hepatic cysts.

We describe a patient with intracystic hemorrhage from one of multiple hepatic cysts. A 66-year-old woman was admitted to Nippon Medical School Hospital because of pain in the right upper quadrant of the abdomen. The medical history included multiple hepatic cysts and angina pectoris, which had been treated with aspirin. Three weeks before presentation, pain occurred in the right upper quadrant of the abdomen but resolved spontaneously. Ultrasonography revealed multiple hepatic cysts. One of the cysts in segment 8 had a hypoechoic structure and contained fluid. Computed tomography showed an area of homogenous density (diameter, 6 cm) which was slightly greater than that of the other hepatic cysts in segment 8. There was calcification of the cyst wall. On magnetic resonance imaging, this cyst showed heterogeneous hyperintensity on T1- and T2- weighted sequences which was greater than that of the other hepatic cysts. Intracystic hemorrhage of one of the multiple hepatic cysts was diagnosed. The pain gradually resolved without drainage, embolization, or operation, and the patient was discharged. After discharge, the upper abdominal pain did not recur. On magnetic resonance imaging 14 months later, the cyst showed heterogeneous hyperintensity on T1- and T2- weighted sequences which was less than that on the previous scan.

Inhibition of nitric oxide synthase in hyperdynamic circulation of rats with early or late cirrhosis secondary to common bile duct ligation.

BACKGROUND/AIMS: Preventing internal hemorrhage extends the lifespan of rats with chronic bile duct ligation (CBDL), a common animal model of portal hypertension. We investigated hemodynamics during the early and late stages of cirrhosis caused by CBDL. We also evaluated the hemodynamic influence of NO, which is the chief vasodilator in hyperdynamic syndrome, by administration of an NO synthase inhibitor (N(G)-nitro-L-arginine methyl ester: L-NAME; 10 mg/kg). ANIMALS/METHODS: In 24 Sprague-Dawley rats (9 sham rats and 15 CBDL rats), hemodynamics were assessed under conscious and unrestrained conditions 4 and 8 weeks after surgery. Before and 30 minutes after L-NAME administration, the cardiac index (CI) and regional blood flow were measured with the reference sample method using (141)Ce- and (113)Sn-microspheres (15 µm in diameter). RESULTS: A hyperdynamic systemic circulation and splanchnic hyperemia were observed after CBDL, and these changes increased with the progression of cirrhosis. L-NAME significantly diminished the hyperdynamic circulation and also reduced splanchnic hyperemia. In 4-week CBDL rats, a low hemoglobin concentration made an important contribution to the hyperdynamic circulation, and the portal collateral system collapsed when inflow to the portal territory was reduced by L-NAME treatment. In 8-week CBDL rats, systemic hemodynamics were closely linked to both the splanchnic circulation and the renal circulation before and after L-NAME administration, apart from hepatic artery blood flow. CONCLUSION: The distinctive hemodynamic changes of portal hypertension were found in 8-week CBDL rats. Thus, 8-week CBDL rats may be a better animal model of human portal hypertension than 4-week CBDL rats.

Effect of chronic methylene blue administration on hypoxemia in rats with common bile duct ligation.

AIM: Acute administration of methylene blue (MB) can reverse hypoxemia in patients with hepatopulmonary syndrome (HPS). We evaluated the effect of chronic MB administration in common bile duct-ligated rats, which develop HPS by 5 weeks after surgery. METHODS: A total of 96 Sprague-Dawley rats were used, including 63 rats with common bile duct ligation (CBDL), 22 sham-operated rats and 11 normal control rats. MB (6 mg/kg) was injected s.c. once a day for 4 weeks. Evaluation of hemodynamics and intrapulmonary vascular dilatation (IPVD), as well as blood sampling for arterial blood gas analysis, were done under conscious and unrestrained conditions. Hemodynamics were assessed by the reference sample method using (141)Ce-microspheres (15 microm in diameter), and IPVD was also determined by i.v. injection of these microspheres. Histological examination of the lungs was done with hematoxylin-eosin staining and immunohistochemical staining for von Willebrand factor or vascular endothelial growth factor. RESULTS: Both the arterial oxygen tension and alveolar-arterial oxygen difference were significantly improved in MB-treated CBDL rats. The hyperdynamic circulation and splanchnic hyperemia seen in untreated CBDL rats were also alleviated by MB treatment. However, IPVD was not affected by MB. Histological examination of the lungs indicated that MB treatment reduced the proliferation of alveolar capillary vessels and angiogenesis, leading to improvement of arterial dysoxygenation. Hepatic synthetic and detoxification functions, as well as renal function, were not altered by MB treatment. CONCLUSION: Methylene blue may be a candidate treatment for HPS that does not cause deterioration of hepatic or renal function.

Successful transcatheter chemoembolization for acute jaundice in a patient with advanced hepatocellular carcinoma and portal vein tumor thrombosis: a case report.

A 54-year-old man with suspected cirrhosis and a hepatic tumor on positron emission tomography presented to our hospital for assessment and treatment in January 2007. Laboratory tests and diagnostic imaging revealed that the patient had cirrhosis due to hepatitis B virus infection and advanced hepatocellular carcinoma (HCC) along with portal vein tumor thrombosis (PVTT) (T4N1M0, Child's B). After hospitalization, the serum levels of total and direct bilirubin increased markedly within several days (26.0 and 20.0 mg/dL), and biliary obstruction by the tumor appeared to have caused this sudden jaundice. To treat the biliary obstruction, selective transcatheter chemoembolization (TACE) was performed via the feeding arteries of the tumor in the anterior segment of the right lobe. After TACE, total bilirubin decreased to 7.0 mg/dL, and the patient survived for 4 more months.

Characterization of a novel congenic strain of diabetic fatty (WBN/Kob-Lepr(fa)) rat.

The WBN/Kob-Lepr(fa) rat is a new congenic strain for the fa allele of the leptin receptor gene (Lepr). Homozygous (fa/fa) WBN/Kob-Lepr(fa) rats provide a model of non-insulin-dependent diabetes with obesity. Here, we describe the characteristics of this new animal model in detail. At 7 weeks of age, both male and female obese WBN/Kob rats showed inflammatory cell infiltration of the pancreas that suggested pan-pancreatitis and an abnormal OGTT. At 3 months of age, both male and female obese WBN/Kob rats developed overt diabetes mellitus associated with severe chronic pancreatitis. In contrast, lean female WBN/Kob rats do not develop pancreatitis or diabetes. In WBN/Kob rats, this mutation might promote the onset of severe pancreatitis, leading to the rapid development of diabetes mellitus.

Arterial hypoxemia and intrapulmonary vasodilatation in rat models of portal hypertension.

BACKGROUND: Rats with chronic bile duct ligation (CBDL) and portal vein ligation (PVL) are used as models of portal hypertension. CBDL rats show hypoxemia with intrapulmonary vasodilatation (IPVD), and are recognized as a model of hepatopulmonary syndrome (HPS), while PVL rats are normoxemic. We investigated the differences in arterial oxygenation between these models, and the key factors leading to HPS. METHODS: Forty-eight Sprague-Dawley rats were prepared as CBDL or PVL models, or as Sham rats. Arterial oxygenation, hemodynamics (reference sample method), and IPVD were simultaneously evaluated in conscious and unrestrained animals, using (141)Ce- or (113)Sn-labeled microspheres (15 microm in diameter), respectively. Endothelin-1 (ET-1) and nitrate/nitrite (end products of nitric oxide; NOx) production by the lung tissue (increment across the lungs) was also determined. RESULTS: The extent of IPVD was similar in both models, but hypoxemia was only observed in CBDL rats. The ET-1 level and the increment in NOx were significantly increased in CBDL rats, and the increment was directly correlated with impairment of oxygenation. Blood flow through the bronchial arteries (anatomical shunting) was increased in CBDL rats, reaching more than three times the level in PVL rats or Sham rats. CONCLUSIONS: These results support the hypothesis that NO derived from the lung tissues contributes to hypoxemia, and IPVD appears to be a prerequisite for impaired oxygenation. The considerable increase of anatomical shunting may potentially contribute to impaired oxygenation in CBDL rats.

Hemodynamic features of advanced cirrhosis due to chronic bile duct ligation.

AIM: The aim of the present study was to compare the hemodynamic features of portal hypertension in rats with early cirrhosis with those of rats with advanced cirrhosis following common bile duct ligation (CBDL). METHODS: A total of 53 male Sprague-Dawley rats were used. Hemodynamics were evaluated under conscious and unrestrained conditions 4 weeks and 8 weeks after CBDL, and 4 weeks after a sham operation. Arterial pressure and portal pressure were measured directly via catheters placed in the right femoral artery and main portal vein, respectively. The cardiac index and organ (splanchninc organs, brain, kidneys and lungs) blood flow were determined by the reference sample method using (141)Ce-labeled microspheres (15 mum in diameter). Arterial levels of endothelin-1 and nitrate/nitrite, as well as liver function variables, were also determined. RESULTS: Portal pressure was significantly higher 8 weeks after CBDL (15.8+/-2.1, n=8) than 4 weeks after CBDL (13.9+/-2.1 mmHg, n=12, p<0.05), and the hyperdynamic circulation of the early period was attenuated (p<0.05). Although hepatic artery blood flow 4 and 8 weeks after CBDL was higher than that after sham operation (p<0.05), portal territory blood flow was not increased. There was a significant positive correlation between portal pressure and portal territory blood flow 8 weeks after CBDL (r=0.822, n=8, p=0.012). In rats with anemia 4 weeks after CBDL, the hemoglobin concentration was negatively correlated with portal territory blood flow (r=-0.597, n=12, p=0.040). CONCLUSION: Portal pressure was higher 8 weeks after CBDL than 4 weeks after CBDL and increased with portal territory blood flow, suggesting that portal hypertension is maintained by a mechanism consistent with the forward flow theory. Anemia might exacerbate the hyperdynamic systemic circulation 4 weeks after CBDL.

Association of limited scleroderma and pulmonary hypertension in a patient with primary biliary cirrhosis.

We report a male patient with primary biliary cirrhosis (PBC) who developed limited scleroderma (l-SSc) and pulmonary hypertension (PHT). He had noticed shortness of breath seven months earlier, which slowly progressed before admission. Sclerodactyly and telagiectasia of the fingers and chest wall were found. Chest X-ray and Doppler echocardiography suggested the presence of PHT. Histologic examination of the liver (needle biopsy) revealed stage two PBC, and histologic findings of the skin (obtained from the dorsum of right finger IV) were compatible with l-SSc. Direct measurement of pulmonary arterial pressure revealed PHT with normal capillary wedge pressure during right heart catheterization. A striking increment of plasma thromboxane B(2) across the lungs was found, which suggested that thromboxane A(2) (precursor of thromboxane B(2)) contributed considerably to a rise in pulmonary vascular resistance leading to PHT.

Hemodynamic features and impaired arterial oxygenation in patients with portopulmonary hypertension.

Portopulmonary hypertension (P-PHT) is sporadically found in cirrhosis patients who have portal hypertension. We retrospectively investigated the clinical features of six patients with P-PHT and compared their hemodynamics and arterial oxygenation with data from 60 cirrhosis patients without pulmonary hypertension (non-PHT cirrhosis) admitted to our department. The mean pulmonary artery pressure and pulmonary vascular resistance index of P-PHT patients ranged from 25 to 57mmHg and from 399 to 1405dynesscm(-5)m(-2), respectively, and their arterial oxygenation was impaired. The systemic vascular resistance and cardiac index of P-PHT patients were similar level to those of patients with non-PHT cirrhosis. We found 10 patients with non-PHT cirrhosis in whom pulmonary vascular resistance exceeded the critical level for pre-capillary pulmonary hypertension (120dynesscm(-5)). These patients showed a distinctive hemodynamic profile, including a decrease of cardiac output due to contraction of the plasma volume and resultant elevation of systemic vascular resistance. However, the decrease of cardiac output contributed little to the elevation of pulmonary vascular resistance. Our findings suggested that certain factor(s) were acting to raise pulmonary vascular tone in these patients, which might cause chronic damage to the pulmonary vascular bed, leading to the onset of pulmonary hypertension.

Viability and plasma vitamin K levels in the common bile duct-ligated rats.

The common bile duct-ligated (CBDL) rat, which is widely used as a model of human cirrhosis, rapidly develops secondary biliary cirrhosis (SBC) within 4 weeks. The CBDL rat shows poor viability, however, a detailed examination of the causes of its death has not been made. In this study, we investigated the outcome of bile duct ligation in detail and attempted to extend the life span of this model by feeding the animals a diet supplemented with nutrients. Survival rate, blood chemistry, blood cell counts, plasma levels of K vitamins and liver histology were compared among CBDL rats fed a standard diet and an enriched diet. Sham-operated rats were used as a control. Six out of 18 CBDL rats fed the standard diet died within 32 days of operation. The cause of death was massive internal hemorrhage in various organs or body cavities. All CBDL rats fed the enriched diet survived more than 31 days, but the viability of CBDL rats was not significant between those fed the standard diet and the enriched diet. The degree of anemia correlated significantly with the prolongation of prothrombin time. Plasma vitamin K1 levels in CBDL rats were significantly lower than those in sham-operated rats, but vitamin K2 levels were similar. We suggest that massive hemorrhage, which was the direct cause of death, is caused by the impairment of hemostasis resulting from vitamin K deficiency. The enriched diet with vitamin K nutritional supplements seemed to contribute to the prolongation of the life span of CBDL rats.

Pulmonary blood transit time and impaired arterial oxygenation in patients with chronic liver disease.

BACKGROUND: Contrast-enhanced echocardiography (CEE) using agitated saline can detect intrapulmonary vasodilatation (IPVD) in patients with hepatopulmonary syndrome (HPS). We estimated the pulmonary transit time of erythrocytes (PTT) by CEE, using microbubbles, and studied its relationship to arterial oxygenation in chronic liver disease. METHODS: Sixteen patients with chronic liver disease and seven healthy subjects were studied. PTT was defined as the time between opacification of the right atrium and left atrium on CEE, using human serum albumin-air microbubble complexes with a mean diameter of 4 microm (Albunex). IPVD was detected by CEE with agitated saline. Arterial blood gases were analyzed with patients in the supine position, and while they were seated. Cardiac output (CO) was determined by Doppler echocardiography. RESULTS: The mean PTT value for all of the patients was 4.0 +/- 1.4 s. One of the 3 patients who showed IPVD was normoxemic. Mild orthodeoxia was observed in the patients with abnormal alveolar-arterial oxygen difference (A-aDO2) values (>15 mmHg), but not in those with normal A-aDO2 values, or in the healthy subjects. PTT was correlated with PaO2 (r = 0.52; P < 0.05; n = 16) and A-aDO2 (r = -0.54; P < 0.05; n = 16) in the seated position. CO was significantly correlated with PTT (r = -0.62; P < 0.05; n = 15), but not with PaO2 and A-aDO2, in both positions. CONCLUSIONS: PTT may be a useful parameter for evaluating arterial oxygenation in patients with chronic liver disease with early HPS.

Increased chymase in livers with autoimmune disease: colocalization with fibrosis.

Chymase, one of the proteases contained in human mast cells, promotes myocardial and renal interstitial fibrosis by converting angiotensin I to II (AII). We previously established a method for measuring chymase in liver tissue and examined the relationship between chymase and fibrosis in chronic hepatitis. In the present study, chymase was determined in liver specimens affected by autoimmune hepatitis (AIH, n=10) or primary biliary cirrhosis (PBC, n=12). To investigate spatial relationships between hepatic fibrosis and human chymase, mast cell distribution in the specimens was determined immunohistochemically using anti-chymase antibody. The mean amounts of chymase in livers with AIH and PBC were 11.56+/-10.64 and 11.67+/-9.96 ng/mg respectively. Hepatic chymase in AIH and PBC was significantly more abundant than in acute hepatitis (AH, 2.72+/-2.23 ng/mg, n=10; p<0.05). When sections from patients with AIH and PBC were immunostained for chymase, immunoreactive mast cells were detected in portal areas and sinusoidal walls, coinciding with zones of fibrosis. Thus chymase appears to be involved in hepatic fibrosis in AIH and PBC.

Intrapulmonary vascular dilatation and nitric oxide in hypoxemic rats with chronic bile duct ligation.

BACKGROUND/AIMS: Nitric oxide (NO) has been suggested as the major cause of pulmonary vascular dilatation and hypoxemia in hepatopulmonary syndrome (HPS). The aim of this study was to assess the effect of NO on arterial oxygenation in rats with common bile duct ligation (CBDL rats), a model of HPS. METHODS: Arterial blood gases were measured in 44 CBDL rats and 44 Sham rats under unrestrained conditions. Intrapulmonary shunting was assessed with (141)Ce-labeled microspheres (15-mum diameter) and serum nitrate/nitrite levels were measured by HPLC. The effect of NOS inhibition on A-aDO(2) was studied using L-NAME. RESULTS: A decrease of PaO(2) below 82.7 mmHg (the mean value-2sigma in Sham rats) was seen in 43% of CBDL rats. Intrapulmonary shunting was greater in CBDL rats than in Sham rats (P<0.001). A correlation between the extent of shunting and A-aDO(2) was found in all animals studied (r=0.89, P<0.001, n=16). Serum levels of nitrate/nitrite increased significantly across the lungs, and the increase was significantly correlated with A-aDO(2) in the total population of animals studied. Administration of L-NAME to CBDL rats achieved a significant improvement of A-aDO(2). CONCLUSIONS: These results suggest that pulmonary vascular dilatation due to NO leads to hypoxemia in CBDL rats.

Hepatic chymase level in chronic hepatitis: co-localization of chymase with fibrosis.

Chymase, secreted by mast cells, is associated with angiotensin II production and fibrosis of myocardium and renal interstitium. Assuming that chymase also is involved in liver fibrosis, we previously established an enzyme-linked immunosorbent assay for chymase in human liver tissue. In the present study, we explored the localization of mast cells in the liver using antibodies against human chymase and also studied relationships between hepatic chymase level and histologic findings in 49 patients with chronic hepatitis. By the international classification, fibrosis was staged from F0 to F4 and activity was graded from A1 to A3. Cells immunoreactive for chymase were seen throughout portal areas and intralobular sinusoidal walls, largely colocalizing with inflammation and fibrosis. Hepatic chymase levels in F3 and F4 cases were greater than in F1 and F2 (F3+F4, 30.8+/-41.2 ng/mg vs. F1+F2, 5.7+/-6.6 ng/mg; P<0.01). Chymase in A3 casese (39.4+/-50.8 ng/mg) was more abundant than in A1 (3.7+/-4.3 ng/mg) or A2 (12.8+/-19.4 ng/mg); P<0.05 for each. Our findings suggest that hepatic chymase level is implicated in fibrosis and activity in human liver disease.

Establishment of an assay method for human mast cell chymase.

Chymase secreted by mast cells found in fibroblast-containing interstitial connective tissue has been implicated in collagen fiber formation and extracellular matrix production. We established a method for determination of human chymase activity, and applied this technique to measurements in serum and liver tissue. The mean chymase concentration in liver biopsy specimens from 26 patients with chronic hepatitis was 5.23+/-5.98 ng/mg (ranges 0.32-21.4). The serum chymase concentration was below the limit of detection, in both chronic hepatitis patients and healthy individuals. No significant relationship was seen between chymase activity in liver tissue and severity of liver fibrosis, but further investigation in larger numbers of patients is warranted.