Stabilization of vulnerable carotid plaques with proprotein convertase subtilisin/kexin type 9 inhibitor alirocumab.

Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, a novel class of monoclonal antibodies, reduce low-density lipoprotein cholesterol levels and improve outcomes of myocardial infarction and stroke. However, the effects of PCSK9 inhibitors on carotid plaques remain unclear. We describe three patients treated with PCSK9 inhibitor alirocumab for progressive carotid stenosis despite lipid-lowering statin therapy. All three patients had vulnerable plaques on magnetic resonance (MR) plaque imaging. After alirocumab treatment initiation, no patients suffered stroke or adverse events, and the stabilization of the carotid plaques was observed on MR plaque imaging.

Long term results of balloon-occluded retrograde transvenous obliteration for portosystemic shunt encephalopathy in patients with liver cirrhosis and portal hypertension.

This study examined 19 patients with portosystemic shunt encephalopathy caused by a splenorenal shunt (SRS), which was treated with balloon-occluded retrograde transvenous obliteration (B-RTO). Long-term treatment outcomes were evaluated based on hepatic functional reserve and vital prognosis. Encephalopathy improved in all patients after shunt embolization and closure. Albumin, serum ammonia, and the Child-Pugh score, a measure of liver function, were significantly improved 3 years after B-RTO, and exacerbation of damage to liver function was avoided (p<0.01). During the follow-up period, three patients died from liver failure and two patients from hepatocellular carcinoma. Patients had a poor prognosis if their albumin levels were less than 2.8 mg / dL before B-RTO (p<0.05). Encephalopathy patients had complete response to B-RTO, but long-term prognosis was affected by hepatic functional reserve before B-RTO and by concurrent hepatocellular carcinoma. The results of this study suggest that in patients with SRS, it is important to perform B-RTO at an early stage when the hepatic functional reserve is still satisfactory.

Balloon-occluded retrograde transvenous obliteration versus endoscopic injection sclerotherapy for isolated gastric varices: a comparative study.

Isolated gastric varices (IGV) have a lower risk of bleeding than esophageal varices, however IGV bleeding is associated with a higher mortality than bleeding of esophageal varices. In recent years, two widely used treatments for IGV have been balloon-occluded retrograde transvenous obliteration (B-RTO) and endoscopic injection sclerotherapy (EIS) using cyanoacrylate or ethanolamine oleate (EO). This study compared these two treatment methods for IGV. The subjects were 112 patients who were treated at our hospital for IGV bleeding between October 1990 and December 2003. Forty-nine (49) patients were treated with B-RTO and 63 patients with EIS. These two patient groups were compared as regards content of treatment, post-treatment incidence of variceal bleeding, incidence of IGV rebleeding, survival rate, cause of death, and complications. Multivariate analysis was performed on post-treatment variceal bleeding and survival. Although EO was used in higher amounts in the B-RTO group than in the EIS group, the B-RTO group had a significantly lower number of treatment sessions and a significantly shorter treatment period (p<0.05). The EIS group had significantly more patients with IGV rebleeding after treatment than the B-RTO group. Treatment method was the only independent prognostic factor of IGV bleeding after treatment (p=0.024). The two groups did not differ significantly in the percentage of patients with aggravated esophageal varices after treatment. Bleeding from ectopic varices was not observed in any patient. There was no significant difference in survival by treatment method. The presence of hepatocellular carcinoma was the only independent prognostic factor for survival (p=0.003). It is concluded that B-RTO was more effective than EIS in the eradication of IGV and prevention of IGV recurrence and rebleeding.

CD34(+) cell therapy is safe and effective in slowing the decline of hepatic reserve function in patients with decompensated liver cirrhosis.

BACKGROUND AND AIM: Preclinical studies in rodent models of chronic liver fibrosis have shown that transplantation of peripheral blood (PB) CD34(+) cells leads to hepatic regeneration and a reduction of liver fibrosis by suppressing hepatic stellate cell activity and increasing matrix metalloproteinase activity. The aim of this study was to examine the safety and clinical efficacy of intrahepatic transplantation of autologous granulocyte colony-stimulating factor (G-CSF)-mobilized PB-CD34(+) cells in patients with decompensated liver cirrhosis. METHODS: PB-CD34(+) cells were isolated from G-CSF-mobilized apheresis products. Ten patients were treated with G-CSF-mobilized PB-CD34(+) cells (treatment group) and seven patients were treated with standard medical therapy. For mobilization, patients in the treatment group received subcutaneous injections of 10 µg G-CSF/kg/day for 5 days. The cells were then injected at three different doses (5 × 10(5) , 1 × 10(6) and 2 × 10(6) cells/kg) through the hepatic artery. Thereafter, all patients were followed up for 24 months. RESULTS: G-CSF treatment and leukapheresis were well tolerated, and no serious adverse events were observed. Patients in the treatment group had a significant but transient splenomegaly. After 24 weeks, serum albumin was significantly increased in patients who had received middle or high doses of CD34(+) cells compared with baseline. Doppler ultrasound showed a significant increase in hepatic blood flow velocity and blood flow volume after CD34(+) cell therapy. The hepatic vein pressure gradient decreased in two patients who received high-dose CD34(+) cells at week 16. CONCLUSIONS: CD34(+) cell therapy is feasible, safe and effective in slowing the decline of hepatic reserve function.

Contrast-enhanced ultrasonograpic studies on pancreatic carcinoma with special reference to staining and muscular arterial vessels.

Comparative study of contrast-enhanced ultrasonography (CE-US) and histopathology of surgically resected specimens in 13 patients with pancreatic carcinoma. A time intensity curve was used to determine the percentage brightness increase in cancerous and normal regions and the patients were divided into two groups, hyperperfusion, with a percentage brightness increase over 80% (n=6) and hypoperfusion, with an increase of less than 80% (n=7) on CE-US. The hyperperfusion group included well-differentiated tubular adenocarcinoma, adenosquamous cell carcinoma and acinar cell carcinoma, while all 7 patients in the hypoperfusion group had moderately differentiated tubular adenocarcinoma. Immunological staining (α-SMA and anti-CD34) of the resected specimens showed significantly higher microartery count (MAC) in the hyperperfusion group (p<0.005) than in the hypoperfusion group or normal pancreas. In the normal pancreas, the mean vessel diameter was significantly higher (over 100 µm) than in the hyperperfusion group (30 µm; p<0.005). It was concluded that a muscular arterial vessel density of less than 30 µm is an important factor in determining staining degree and carcinoma progression by CE-US in pancreatic carcinoma.

Effect of Helicobacter pylori infection on esophagogastric variceal bleeding in patients with liver cirrhosis and portal hypertension.

BACKGROUND AND AIMS: Bleeding from esophageal and gastric varices is a fatal event in patients with liver cirrhosis and portal hypertension. However, the effects of Helicobacter pylori (H. pylori) infection on esophagogastric variceal bleeding are not known. The present study was aimed to elucidate the role of H. pylori infection in esophagogastric variceal bleeding. METHODS: The subjects were 196 cirrhotic patients who were admitted to the Kurume University Hospital to treat their esophagogastric varices consisted of 95 with acute bleeding and 101 with nonbleeding but high risk of bleeding. For the diagnosis of H. pylori infection, a (13) C-urea breath test was used, and serum pepsinogen (PG) I and II levels and the PG I/II ratio were also measured. RESULTS: Esophagogastric variceal bleeding was seen in 34.9% (n = 30) of the H. pylori-infected patients (n = 86) and in 59.1% (n = 65) of the noninfected patients (n = 110) (P < 0.0007). There was no significant difference in the infection rate between the bleeding sites of the esophagus and the stomach. The serum PG I and II levels and the PG I/II ratio were 65.6 ng/dL, 14.7 ng/dL, and 4.4, respectively, for the bleeding patients (n = 95), and 43.7 ng/dL, 17.7 ng/dL, and 3.1 for the nonbleeding patients (n = 101). Thus, the nonbleeding patients had significantly higher rate of H. pylori infection and lower acid secretion than bleeding patients (0.001). In addition, multivariate logistic regression analysis showed a significant negative association between H. pylori infection and esophagogastric variceal bleeding. CONCLUSIONS: These results suggest that H. pylori infection has a protective effect against esophagogastric variceal bleeding through the induction of gastric mucosal atrophy and concomitant hypoacidity.

Long-term results of balloon-occluded retrograde transvenous obliteration for gastric fundal varices: hepatic deterioration links to portosystemic shunt syndrome.

BACKGROUND AND AIMS: It is well known that a large portosystemic shunt develops during portal hypertension. In this study, we studied the long-term effects of a large splenorenal shunt (SRS) on liver function and survival. METHODS: The subjects were divided into three groups: an SRS (-) group consisting of cirrhotic patients without SRS; an SRS (+) group consisting of patients with gastric fundal varices and SRS; and a balloon-occluded retrograde transvenous obliteration (B-RTO) group with a completely obliterated SRS by B-RTO. We compared the following among these groups: the total bilirubin levels, serum albumin levels, prothrombin times, changes in Child-Pugh scores, and survival rates. RESULTS: After a 3-year follow-up period the Child-Pugh scores showed significant differences among the SRS (+), SRS (-), and B-RTO groups. The score worsened for the SRS (+) group. The cumulative survival rates were significantly different between the SRS (+) and SRS (-) groups and between the SRS (+) and B-RTO groups. The vital prognosis worsened for the SRS (+) group. CONCLUSIONS: The presence of a large splenorenal shunt (portosystemic shunt) was indicated to lower liver function and vital prognosis. B-RTO, which completely obliterates large splenorenal shunts, inhibited the lowering of hepatic functional reserve and the worsening of vital prognosis, indicating a protective role. Liver pathology and the presence of a large portosystemic shunt each separately result in progressive liver dysfunction and worsen the survival rate. We found that such a pathological condition had occurred due to a large portosystemic shunt, and it should be called 'portosystemic shunt syndrome.'

Current status of ectopic varices in Japan: Results of a survey by the Japan Society for Portal Hypertension.

AIM: The Clinical Research Committee of the Japan Society for Portal Hypertension has conducted a nationwide questionnaire survey to clarify the current status of ectopic varices in Japan. METHODS: A total of 173 cases of ectopic varices were collected. RESULTS: Duodenal varices were found in 57 cases, and most of them were located in the descending to transverse parts. There were 11 cases of small intestinal varices and 6 cases of colonic varices, whereas 77 patients had rectal varices, accounting for the greatest proportion (44.5%). Other sites of varices were the biliary tract, anastomotic sites, the stoma, and the diaphragm. Liver cirrhosis was the most frequent diseases (80.3%) underlying ectopic varices. It was noted that patients with rectal varices frequently had a history of esophageal varices (94.8%) and received endoscopic treatment (87.0%). The treatments for ectopic varices were as an emergency in 46.5%, elective in 35.4% and prophylactic in 18.2%. In emergency cases, endoscopic therapy was most frequent (67.4%), followed by interventional radiology (IVR; 15.2%), and endoscopy-IVR combination (6.5%). Elective treatment was performed by endoscopy in 34.3%, IVR in 28.6%, combined endoscopy-IVR in 5.7%, and surgical operation in 25.7%. The prophylactic treatment was endoscopic in 50.0%, IVR in 33.3%, combined treatments in 11.1%, and prophylactic surgery in none. The change of ectopic varices after treatment was disappearance in 54.9%, remnant in 35.4% and recurrence in 9.7%. The rate of disappearance was significantly lower in rectal varices (40.8%) than in duodenal varices (73.4%). The patient outcome did not differ among the various sites of the lesion. Conslusions: Current status of ectopic varices in Japan has been clarified by a nationwide questionnaire survey. The authors expect that the pathophysiology of ectopic varices will be further elucidated, and that improved diagnostic modalities and treatment methods are established in the future.

General rules for recording endoscopic findings of esophagogastric varices (2nd edition).

General rules for recording endoscopic findings of esophageal varices were initially proposed in 1980 and revised in 1991. These rules have widely been used in Japan and other countries. Recently, portal hypertensive gastropathy has been recognized as a distinct histological and functional entity. Endoscopic ultrasonography can clearly depict vascular structures around the esophageal wall in patients with portal hypertension. Owing to progress in medicine, we have updated and slightly modified the former rules. The revised rules are simpler and more straightforward than the former rules and include newly recognized findings of portal hypertensive gastropathy and a new classification for endoscopic ultrasonographic findings.

Lamivudine treatment-related morphological changes of esophageal varices in patients with liver cirrhosis.

AIM: Many studies have reported the therapeutic effects of lamivudine on cirrhotic patients with hepatitis B; however, no study has investigated the morphological changes of esophageal varices after lamivudine treatment. METHOD: The morphological changes of esophageal varices in patients with cirrhosis were retrospectively compared between 12 patients treated with lamivudine and six historical untreated patients. RESULTS: In the treated group, the HBV DNA and hyaluronic acid (HA) levels in the serum were significantly lower than those in the untreated group (P = 0.013 and P = 0.009, respectively) at the end of follow-up, with a significant improvement in the Child-Pugh-Turcotte score (P = 0.022). In the treated group, the disappearance or reduction of esophageal varices was observed in six (50%) of the 12 patients. In three (25%) of the 12 patients, esophageal varices worsened. In the remaining three patients (25%), there were no changes in esophageal varices. In the untreated group, all patients showed the worsening of esophageal varices during the follow-up period, with a significant difference between this group and the treated group (P = 0.009). The serum HA level decreased in the nine treated patients without worsening of esophageal varices. However, in the three patients with worsening, the HA level significantly increased. CONCLUSION: Lamivudine treatment for patients with cirrhosis improves not only liver function but also esophageal varices.

Postmarketing surveillance of rabeprazole in upper gastrointestinal peptic lesions in Japanese patients with coexisting hepatic disorders.

BACKGROUND: Many Japanese patients with hepatic disorders confirmed on diagnostic imaging and coexisting upper gastrointestinal (GI) peptic lesions receive treatment with proton pump inhibitors. Some pharmacotherapies used to treat peptic ulcers have been associated with adverse drug reactions (ADRs), including elevated liver enzyme levels. OBJECTIVE: The aim of this study was to determine the tolerability and effectiveness of rabeprazole sodium in treating peptic lesions in patients with coexisting hepatic disorders. METHODS: This open-label, practice-based, postmarketing surveillance investigation was conducted at 15 centers across Japan. Male and female patients aged ≥18 years with peptic lesions confirmed on upper GI endoscopy and with underlying hepatic disease were enrolled. Patients were randomly assigned to receive rabeprazole 10 or 20 mg PO (tablet) QD after a meal for up to 8 weeks. Tolerability was assessed using monitoring of the incidence of ADRs determined by direct patient questioning, spontaneous reporting, and laboratory assessment. All patients who received at least 1 dose of study drug were included in the tolerability assessment. Effectiveness was assessed at baseline and study end using the rates of achievement of improvement on endoscopy, relief of subjective/objective symptoms (rates of improvement in epigastric pain and heartburn), and global improvement. The effectiveness analysis included all patients with complete data before and after treatment. Subanalyses were conducted to determine the effectiveness of drug by identification of the proportion of patients with coexisting hepatic disorders (cirrhosis, chronic hepatitis, and other hepatic diseases [eg, alcoholic hepatitis, fatty liver]) and by peptic lesion (gastric ulcer, duodenal ulcer, stomal ulcer, and reflux esophagitis) who achieved improvement. RESULTS: A total of 114 patients were enrolled; 108 patients were included in the tolerability analysis (81 men, 27 women; mean age, 59.9 years; 10-mg dose, 90 patients; 20-mg dose, 18 patients) and 98 patients were included in the analysis of effectiveness. Twenty-one ADRs occurred in 11 (10.2%) patients. Serious ADRs occurred in 2 patients (elevated bilirubin level and hepatic encephalopathy, 1 patient each). Administration of rabeprazole was discontinued in 5 patients due to the occurrence of the following ADRs: constipation (1 patient); epigastric pain (1); dyslalia, disorientation, tremor, sleep disorder, and hepatic encephalopathy (1); diarrhea (1); and elevated alkaline phosphatase and y-glutamyl transpeptidase levels (1). On endoscopy, the proportion of patients achieving improvement with either dose was 30/33 (90.9%). The relief rates assessed using subjective symptoms were 47/55 (85.5%) and 47/56 (83.9%) for epigastric pain and heartburn, respectively. The proportion of patients achieving global improvement with either dose was 80/98 (81.6%) patients (49/62 [79.0%] for cirrhosis, 11/16 [68.8%] for chronic hepatitis, and 20/20 [100.0%] for other hepatic diseases [alcoholic hepatitis, fatty liver]). CONCLUSION: In this study in Japanese patients with hepatic disorders, rabeprazole was well tolerated and appeared effective for the treatment of upper GI peptic lesions.

Balloon-occluded retrograde transvenous obliteration improves liver function in patients with cirrhosis and portal hypertension.

BACKGROUND AND AIM: Balloon-occluded retrograde transvenous obliteration (B-RTO) is a novel therapeutic method for the treatment of large gastric fundal varices with spontaneous splenorenal shunt (SRS). However, the effects of B-RTO on liver function remain unknown. METHODS: Fourteen patients with portal hypertension and gastric varices with SRS were studied, consisting of four patients with acute bleeding, five with high-risk varices, and five with refractory portosystemic encephalopathy. Hepatic venous catheterization was performed to evaluate hepatic blood flow and liver function using the continuous indocyanine green (ICG) infusion method. To assess the metabolic activity of the hepatocyte, the intrinsic clearance of ICG was calculated. In all patients, endoscopic study was performed before and 1 week and 1 month after the B-RTO, and followed every 6 months thereafter. After baseline measurements, B-RTO was performed. Four weeks after the B-RTO, the same catheter measurements were repeated. RESULTS: The B-RTO was successful in all patients. Contrast-enhanced computed tomography showed complete obliteration of the SRS prior to the follow-up measurements. Endoscopic eradication of the fundal varices was obtained 6 months after B-RTO in all patients and encephalopathy was improved within 1 week after B-RTO. Following the B-RTO, hepatic blood flow (441 +/- 214 vs 668 +/- 299 mL/min, P < 0.0001) and the intrinsic clearance of ICG (233 +/- 123 vs 285 +/- 148 mL/min, P < 0.05) were significantly increased. Furthermore, intrahepatic resistance decreased after the B-RTO (P < 0.005). CONCLUSION: From short-term assessment, B-RTO increases hepatic blood flow and improves the metabolic activity of the liver in patients with portal hypertension.

Propranolol ameliorates thrombocytopenia in patients with cirrhosis.

BACKGROUND: Propranolol causes splanchnic arterial vasoconstriction owing to the unopposed alpha vasoconstriction resulting from the blockade of beta-2 adrenoceptors. It is therefore hypothesized that this drug may cause vasoconstriction in the splenic arterial circulation and, thus, modify the manifestations of hypersplenism, such as thrombocytopenia. The aim of the present study was to test this hypothesis. METHODS: Nineteen patients with cirrhosis and thrombocytopenia (fewer than thrombocytes 7 x 10(4)/mm3) were include. The subjects of the study. All of them were studied in the morning after an overnight fast. To evaluate splenic arterial hemodynamics, the pulsatility index was measured by Doppler ultrasonography. Platelet counts and platelet-associated immunoglobulin G levels were also recorded. The subjects were then randomized to receive propranolol (n = 10) or placebo (n = 9). The measurements were repeated after 1 week of propranolol or placebo administration. The dose of propranolol was determined so that a 20% to 25% reduction in heart rate was achieved. RESULTS: Placebo administration caused no significant changes in splenic artery hemodynamics. In contrast, propranolol administration significantly increased the intra splenic artery pulsatility index (from 1.10+/-0.06 to 1.24+/-0.08; P < 0.01). Placebo administration caused no significant changes in the platelet count. In contrast, propranolol administration significantly increased the platelet count (from 4.5+/-0.3 to 6.1+/-0.73 x 10(4)/mm3; P < 0.05). Furthermore, the change in platelet count was significantly correlated with either the change in extrasplenic artery pulsatility index (r = 0.78, P < 0.05) or the change in intrasplenic artery pulsatility index (r = 0.78, P < 0.01). Platelet-associated immunoglobulin G levels were not modified in either of the two groups. CONCLUSIONS: Propranolol ameliorates thrombocytopenia in patients with cirrhosis. This effect may be caused mainly by hemodynamic changes in the spleen, rather than being caused by immunological mechanisms.