Antithrombin III for portal vein thrombosis in patients with liver disease: A randomized, double-blind, controlled trial.

AIM: Portal vein thrombosis (PVT) is one of the most critical disorders in liver disease patients. These patients have the imbalance of coagulation and coagulation inhibition resulting from decreased levels of coagulation inhibitory factors, such as protein C, protein S, and antithrombin III (AT-III). We designed this randomized, double-blind, placebo-controlled trial comparing the safety and efficacy of AT-III for PVT in liver disease patients with those who received no treatment. METHODS: Eligible patients were diagnosed with the association of thrombus, without tumor thrombus, and thrombus in more than 50% of the cross-sectional lumen of the portal vein. Patients with 70% or less serum level of AT-III were included. The study drug was given up to three times in a 5-day consecutive infusion interval if the thrombus decreased in size. Efficacy was evaluated by contrast enhanced computed tomography using a five-grade scale (complete response, partial response, slight response, no response, and progression). From October 2014 through to March 2016, 36 patients were randomly assigned to the AT-III group and 37 patients to the placebo group. RESULTS: The proportion of patients with complete response or partial response of PVT was significantly higher in the AT-III group (55.6%; 20/36 patients; 95% confidence interval, 38.1-72.1) than in the placebo group (19.4%; 7/36 patients, 95% confidence interval, 8.2-36.0) (P = 0.003). The overall incidence of adverse events and adverse drug reactions did not differ significantly between the two groups. CONCLUSION: Antithrombin III is one of the essential therapies for patients with PVT in cases with lower concentration levels of AT-III.

Current status of portal vein thrombosis in Japan: Results of a questionnaire survey by the Japan Society for Portal Hypertension.

AIM: To investigate the current status of portal vein thrombosis (PVT) in Japan, the Clinical Research Committee of the Japan Society of Portal Hypertension undertook a questionnaire survey. METHODS: A questionnaire survey of 539 cases of PVT over the previous 10 years was carried out at institutions affiliated with the Board of Trustees of the Japan Society of Portal Hypertension. RESULTS: The most frequent underlying etiology of PVT was liver cirrhosis in 75.3% of patients. Other causes included inflammatory diseases of the hepatobiliary system and the pancreas, malignant tumors, and hematologic diseases. The most frequent site was the main trunk of the portal vein (MPV) in 70.5%, and complete obstruction of the MPV was present in 11.5%. Among the medications for PVT, danaparoid was given to 45.8%, warfarin to 26.2%, heparin to 17.3%, and anti-thrombin III to 16.9%. Observation of the course was practiced in 22.4%. Factors contributing to therapeutic efficacy were implementation of various medications, thrombi localized to either the right or left portal vein only, non-complete obstruction of the MPV and Child-Pugh class A liver function. A survival analysis showed that the prognosis was favorable with PVT disappearance regardless of treatment. CONCLUSION: The questionnaire survey showed the current status of PVT in Japan. Any appropriate medication should be given to a patient with PVT when PVT is recognized. It is necessary to compile a large amount of information and reach a consensus on safe and highly effective management of PVT.

To-and-fro waveforms in the left gastric vein in portal hypertension.

Unusual to-and-fro waveforms were demonstrated in the left gastric vein on Doppler sonograms in four patients with liver cirrhosis. The patterns of the to-and-fro waveforms were diverse in each of the patients: both hepatopetal and hepatofugal flow occurred in a single waveform in case 1, changes in the flow direction with flow interruption were noted in case 2, and changes in flow direction without observation of flow interruption and changes after meals were noted in cases 3 and 4, respectively. These waveforms may represent a transitional phase during the development of a portal systemic shunt in patients with portal hypertension.

Portal vein thrombosis associated with ischemic colitis.

We report the case of a 52-year-old male who was admitted for sudden abdominal pain and hematochezia. Colonoscopy showed erosion and edema in the mucosa of the descending colon, leading to a diagnosis of ischemic colitis. Blood tests revealed hepatic dysfunctions. Using abdominal ultrasonography (US), thrombus was observed in the left branch of the portal vein and a part of the right branch. Although the Doppler method detected blood flow in the right branch, no blood flow signal was observed in the left branch. Since coagulation examinations were almost normal, and there was no past history of liver cirrhosis or malignancy, it was diagnosed to be portal vein thrombosis (PVT) associated with ischemic colitis. Anticoagulation therapy was initiated for PVT. According to the results of the US and abdominal computed tomography performed 3 months after starting the treatment, thrombus in the right branch had diminished but remained in the umbilical region of the left branch. Due to atrophy of the lateral segment of the liver, we terminated the treatment. Ischemic colitis is not a rare disease; however, when accompanying hepatic dysfunction, it is necessary to take the complications associated with PVT into consideration.

Portal hemodynamics and clinical outcomes of patients with gastric varices after balloon-occluded retrograde transvenous obliteration.

BACKGROUND: Long-term hemodynamic effects and clinical outcomes after balloon-occluded retrograde transvenous obliteration (B-RTO) remain unclear. The purpose of this study was to evaluate long-term clinical results and effects on portal hemodynamics after B-RTO for the treatment of gastric varices with spontaneous gastrorenal shunt. METHODS: A total of 21 patients with cirrhosis and gastric varices treated by B-RTO were evaluated. The cumulative survival rate was calculated, portal blood flow was measured by Doppler ultrasonography, and liver function was estimated on the basis of Child-Pugh classification before and 1 year after B-RTO. RESULTS: Gastric varices disappeared or decreased markedly in size in all patients. Overall cumulative survival rates at 1, 3 and 5 years were 90.48, 71.11 and 53.71%, respectively. Portal blood flow increased significantly from 681.9 +/- 294.9 to 837.0 +/- 279.1 ml/min (P = 0.0125) after B-RTO. Child-Pugh score was not significantly changed (P = 0.755) after obliteration, but serum albumin was elevated significantly from 3.49 +/- 0.49 to 3.75 +/- 0.53 g/dl (P = 0.0459). The ascites score was significantly increased (P = 0.0455) after B-RTO, but all cases of ascites could be controlled with medication. CONCLUSIONS: Balloon-occluded retrograde transvenous obliteration is a safe and effective treatment for gastric varices with gastrorenal shunt. Portal blood flow and serum albumin parameters are increased, and liver function is unchanged after B-RTO.

Blood flow parameters in the short gastric vein and splenic vein on Doppler ultrasound reflect gastric variceal bleeding.

PURPOSE: Hemodynamic features associated with the bleeding from gastric fundal varices (FV) have not been fully examined. The purpose of this study was to elucidate hemodynamics in the short gastric vein (SGV) which is a major inflow route for FV and flow direction of the splenic vein (SV) in relation to bleeding FV. MATERIALS AND METHODS: The subject of this retrospective study was 54 cirrhotic patients who had medium- or large-sized FV (20 bleeders, 34 non-bleeders) on endoscopy with SGV on both angiogram and sonogram. Diameter, flow velocity, flow volume of SGV and flow direction in the SV were evaluated by Doppler ultrasound. RESULTS: Diameter, flow velocity and flow volume of SGV were significantly greater in bleeders (9.6+/-3.1 mm, 11.4+/-5.2 cm/s, 499+/-250.1 ml/min) than non-bleeders (6.5+/-2.2 mm, p=0.0141; 7.9+/-3.3 cm/s, p=0.022; 205+/-129.1 ml/min, p=0.0031). SV showed forward flow in 37 (68.5%), to and fro in 3 (5.6%) and reversed flow in 14 patients (25.9%). The frequency of FV bleeding was significantly higher in case with reversed or "to and fro" SV flow (11/17) than forward SV flow (9/37, p=0.0043). The cumulative bleeding rate at 3 and 5 years was significantly higher in patients without forward SV flow (38.8% at 3 years, 59.2% at 5 years) than in patients with forward SV flow (18.7% at 3 years, 32.2% at 5 years, p=0.0199). CONCLUSION: Advanced SGV blood flow and reversed SV flow direction may be a hemodynamic features closely related to the FV bleeding.

Long-term effect of endoscopic injection therapy with combined cyanoacrylate and ethanol for gastric fundal varices in relation to portal hemodynamics.

BACKGROUND: The understanding on the long-term effect of endoscopic therapy for gastric fundal varices (FV) is still insufficient. The aim of this study was to evaluate the relationship between the long-term effect of the endoscopic injection therapy with combined cyanoacrylate (CA) and absolute ethanol (ET) for FV, and the portal hemodynamics. METHODS: The subjects of this retrospective study were ten consecutive cirrhotic patients with bleeding FV treated by endoscopic injection therapy with combined CA and ET. Percutaneous transhepatic portography was done after the completion of endoscopic treatment to assess portal hemodynamics. RESULTS: All the patients showed hemostasis by CA injection and complete obturation of FV by combined therapy of 5.6 +/- 2.1 (3-9) times without any severe complications except for gastric ulcer in one case. Five patients had recurrence (50%), and three of them showed rebleeding (30%). The other five patients had no recurrence during a mean observation period of 5.58 years (1190-2735 days). Although recurrence did not correlate with portal venous pressure, it was significantly frequent in patients without advanced portosystemic collateral vessels (5/7, P = 0.0384) compared to patients with them (0/3). CONCLUSIONS: Endoscopic injection therapy combining CA and ET may be effective for FV. Significant development of portosystemic collateral vessels would support long-term therapeutic effect after this treatment.

Portal hypertension in primary biliary cirrhosis (PBC): A reversible condition? Yes, but not in all UDCA treated patients.

Portal hypertension is not a rare complication of PBC, but there are no useful clinical predictors of its severity. In fact, in PBC patients, the evaluation of portal hypertension needs a direct access to the portal vein in order to measure the real porto-hepatic gradient (PHG), mainly because of a possible pre-sinusoidal component. The severity of portal hypertension, as measured by the PHG using a thin needle, correlated significantly with the long-term survival of PBC patients, but the initial Mayo score remained the best predictor of survival. In addition to the well-known effects on biological parameters, ursodeoxycholic acid (UDCA) treatment has been associated with a stabilization or improvement of portal hypertension but this effect was not observed in all patients: "responders" and "non-responders" to the UDCA could be identified according to changes in PHG and aspartate aminotransferase (AST) levels observed 2 years after UDCA therapy and had significantly different long-term survivals. This notion of "responders" and "non-responders" is new and may well explain the conflicting data found in the literature concerning the effects of UDCA in PBC patients as reported in various clinical trials. These findings are of interest when considering the emerging non-invasive methods aimed at evaluating liver fibrosis, particularly elastography that may prove useful in the indirect assessment of portal hypertension in the near future, therefore avoiding the need for the invasive measurement of the PHG.

Contrast-enhanced US with Levovist for the diagnosis of hepatic hemangioma: time-related changes of enhancement appearance and the hemodynamic background.

BACKGROUNDS/AIMS: To elucidate the diagnostic confidence of contrast-enhanced ultrasound (CEUS) with Levovist for hepatic hemangioma. METHODOLOGY: The subjects were 34 patients with 38 hemangiomas and 12 patients with 15 hypervascular hepatocellular carcinomas. The early-phase (15-60 second) and liver-specific phase (after 5 min) were observed by the first injection. The 2nd injection was done for solo-phase method to observe liver-specific phase images without taking early-phase sonograms. The 3rd injection was done for changing posture method to observe liver-specific sonograms under left lateral ducubitus position. RESULTS: In the early-phase of hemangioma, nodular enhancement (NE) was found transiently in 13 lesions (34%) and continuously in 25 lesions (66%), while hepatocellular carcinoma (HCC, n = 15) did not show this pattern. Intratumoral arterioportal shunt was closely related to the short duration of NE. Two enhancement patterns were observed in the liver-specific phase of hemangioma, diffuse in 12 lesions (31%) and partial in 26 lesions (69%), which were dependent on the early-phase enhancement. Liver-specific findings were also affected by taking early-phase sonograms or changing the posture of the patient. This method provided sensitivity of 79% and specificity of 100% for the diagnosis of hemangioma. CONCLUSIONS: CEUS with Levovist may be promising method for the diagnosis of hepatic hemangioma.

How to characterize non-hypervascular hepatic nodules on contrast-enhanced computed tomography in chronic liver disease: feasibility of contrast-enhanced ultrasound with a microbubble contrast agent.

BACKGROUND AND AIM: Although hypervascular appearance is characteristic in hepatocellular carcinoma (HCC), hepatic nodules without hypervascular appearance are sometimes found in patients with chronic liver disease (CLD). The aim of the present study was to clarify the efficacy of contrast-enhanced ultrasound (CEUS) with Levovist to characterize small, non-hypervascular hepatic nodules on contrast-enhanced computed tomography (CECT) in patients with CLD. METHODS: The subject was 41 hepatic nodules (<30 mm, 18.5 +/- 5.6 mm) which showed non-hypervascular appearance on CECT in 35 patients with CLD; their histological results were 31 HCC (15 well, 14 moderate, and two poor) and 10 regenerative nodules (RN). CEUS with Levovist was performed under intermittent scanning (1-s interval) using APLIO at the early phase and the liver-specific phase, and the contrast enhancement of the nodule was assessed in comparison to that of the surrounding liver parenchyma. The contrast-enhanced findings with the time-intensity analysis were compared with the histological results. RESULTS: Twelve nodules with weak enhancement in the liver-specific phase were HCC, regardless of their early-phase appearances. The other 29 nodules with equivalent or weak enhancement in the early phase and equivalent enhancement in the liver-specific phase were 19 HCC and 10 RN. Among them, the maximum-intensity ratio of tumor to non-tumor in the early phase was significantly higher in HCC than in RN (P < 0.01, n = 16), and the receiver-operating characteristic analysis showed a sensitivity of 1.0 and a specificity of 0.83 for their characterization. CONCLUSION: CEUS with Levovist may be an alternative to biopsy to characterize small, non-hypervascular hepatic nodules on CECT in patients with CLD.

Microbubble disappearance-time is the appropriate timing for liver-specific imaging after injection of Levovist.

Contrast enhancement in the portal vein was repeatedly observed at 1 min intervals with wide-band Doppler ultrasonography in 152 consecutive patients (132 with liver cirrhosis and HCC, 20 controls), 5 min after the injection of Levovist. The duration time of contrast enhancement in the portal vein (microbubble disappearance-time; MD-T) was measured in all patients and contrast-enhanced appearances were compared between the 5 min phase and MD-T phase in 68 HCC nodules. MD-T in patients with liver cirrhosis (572.4 +/- 117.9 s) was significantly longer than in controls (481.6 +/- 89.3 s, p < 0.05). MD-T was prolonged in patients with Child B and C compared with Child A (p < 0.05). The contrast-enhanced appearances between the two phases were different in 30 of 68 HCC nodules (44.1%), showing positive enhancement in the 5 min phase and negative enhancement in the MD-T phase. The proposed MD-T may become an essential factor for the evaluation of liver-specific sonograms.

Ring-shaped appearance in liver-specific image with Levovist: a characteristic enhancement pattern for hypervascular benign nodule in the liver of heavy drinkers.

BACKGROUND/AIMS: The aim was to clarify the features of contrast-enhanced ultrasound (CEUS) with Levovist for diagnosis of hypervascular benign nodules in the liver of heavy drinkers. PATIENTS AND METHODS: Seven heavy drinkers with hypervascular nodules in the liver were studied. Findings of CEUS with Levovist (wide-band Doppler, 7/7), contrast-enhanced computed tomography (CECT, 7/7) and magnetic resonance imaging (MRI, 5/7) were compared for one nodule in each patient. RESULTS: Diagnosis of all seven nodules on CECT was HCC, whereas pathological results were HCC for four nodules and benign lesion for three nodules. The former four showed compatible findings for HCC on CEUS (4/4) and MRI (2/4). However, the latter three showed characteristic liver-specific sonograms with a ring-shaped appearance--peripheral enhancement with a central non-enhanced area. Two of the three nodules showed decreased signal-intensity in the periphery on SPIO-enhanced MRI. CONCLUSIONS: The ring-shaped appearance on liver-specific sonograms with Levovist may be a useful sign for the differential diagnosis of hypervascular benign nodule from HCC in heavy drinkers.

Magnetic resonance images of the globus pallidus in patients with idiopathic portal hypertension: a quantitative analysis of the relationship between signal intensity and the grade of portosystemic shunt.

BACKGROUND AND AIM: To elucidate a quantitative relationship between hyperintensity of the globus pallidus on T1-weighted magnetic resonance images (MRI) and portosystemic shunt (PSS) in portal hypertension. METHODS: Fifteen patients with idiopathic portal hypertension (IPH) and 44 patients with liver cirrhosis (LC) underwent brain MRI to asses signal intensity at the globus pallidus and Doppler sonography to examine the blood flow volume of PSS. Blood manganese (Mn) levels were examined in 36 patients and neuropsychological tests were performed in 15 patients without overt hepatic encephalopathy. RESULTS: Pallidal hyperintensity on MRI was more prominent in patients with IPH than in patients with LC. There was no correlation between MRI pallidal hyperintensity and the severity of liver dysfunction or hepatic encephalopathy. The grade of hyperintensity correlated well with the grade of PSS. The correlation was stronger in patients with IPH than in patients with LC. The plasma ammonia level and whole blood Mn level significantly correlated with MRI pallidal hyperintensity, but blood Mn level showed a stronger correlation than plasma ammonia. CONCLUSION: Hyperintensity of the globus pallidus on T1-weighted MRI correlated with the development of PSS independent of liver cell function. This brain image should be an index of the grade of PSS rather than a landmark of chronic liver failure.

Study of hemodynamic changes in portal systemic shunts and their relation to variceal relapse after endoscopic variceal ligation combined with ethanol sclerotherapy.

BACKGROUND: Among the factors influencing variceal relapse after endoscopic treatment, portal hemodynamic changes, especially in portal systemic shunts, could be the most important factor because hemodynamics are directly related to the development of esophageal varices. We aimed to clarify the influence of endoscopic treatment for esophageal varices on portal systemic shunts as well as its predictive value for variceal relapse. METHODS: Fifty patients who underwent combined endoscopic variceal ligation and injection sclerotherapy were examined with sonography and portography. RESULTS: Decrease of diameter, hepatopetal flow direction in the left gastric vein, or the presence of non-varices portal systemic shunt were sonographic findings related to a low incidence of variceal relapse. The presence of blood flow in and around the esophagus on venograms was highly predictive for variceal relapse. In patients with such venograms, non-varices portal systemic shunts did not develop. CONCLUSIONS: Sonographic assessment of hemodynamic changes in portal systemic shunt could be useful for estimating the results of endoscopic treatment for esophageal varices.

Large regenerative nodule perfused by the portal vein.

In a 42-year-old Japanese woman with esophageal varices, abdominal ultrasound (US) demonstrated a hyperechoic lesion 3 cm in diameter in segment 4 (S4). This nodular lesion had high intensity on T1-weighted magnetic resonance imaging (MRI), low intensity on T2, and very high intensity on superparamagnetic iron oxide (SPIO) enhanced MRI. Angiography showed sparse distribution of arterial branches and dense distribution of portal branches in S4. Meandering, thin arteries were seen in the peripheral area of the right lobe. The second branches of the portal vein were hardly visualized anywhere in the liver. Computed tomography arterioportography (CTAP) revealed portal blood flow dominance in this nodular lesion. There was no evidence of ischemic liver damage, such as thromboembolic episodes, laboratory data of liver damage, coagulation abnormalities etc. Therefore this abnormality was more likely to be caused by anomalous changes than thrombotic changes. Needle biopsy revealed no atypical cells. Two years later, the nodule size was reduced to 1.9 cm, showing its benign nature. Based on these findings, this lesion was classified as a new type of large regenerative nodule (LRN) associated with anomalies in the portal veins and arteries. This is the first report of an LRN of this size in which portal vein perfusion was dominant. Moreover, this lesion was difficult to differentiate from hepatocellular carcinoma (HCC) by imaging. Analysis of the images and pathological features of this case would contribute to a better understanding of the pathogenesis of nodular lesions of the liver.