Idiopathic Portal Hypertension Patients Research Articles

Performance of spleen stiffness measurement by 2D-shear wave elastography in evaluating the presence of high-risk varices: comparative analysis of idiopathic portal hypertension versus hepatitis B virus

BackgroundNoninvasive assessment of high-risk varices (HRV) in idiopathic portal hypertension (IPH) is rare. The purpose of this study was to investigate the performance of spleen stiffness (SS) for evaluating the presence of HRV in IPH patients as compared the measurements in patients with hepatitis B virus (HBV).MethodsA retrospective single-center study was performed to evaluate the performance of SS for assessing HRV in IPH and HBV-infected patients, in comparison with liver stiffness (LS), spleen stiffness-to-liver stiffness ratio (SS/LS), LS spleen-diameter-to-platelet-ratio score (LSPS), portal hypertension risk score (PH risk score) and varices risk score, by using upper gastrointestinal endoscopy (UGE) as the gold standard. Finally, 86 IPH and 102 HBV-infected patients were enrolled. UGE, two-dimensional shear wave elastography (2D-SWE) and laboratory data were collected, and noninvasive parameters were calculated. Analysis of receiver operating characteristic (ROC) curves was conducted to acquire the optimal area under the ROC curve (AUC) and cutoff value for predicting the presence of HRV.ResultsIn patients with HRV, the significantly different parameters between IPH (34.9%) and HBV-infected patients (46.1%) were as follows: spleen size (diameter 18.5 ± 3.9 cm vs. 20.8 ± 2.7 cm), SS (50.2 kPa vs. 42.9 kPa), LS (11.1 kPa vs. 18.3 kPa) and PT (prothrombin time 15.1 s vs. 16.7 s). No statistically significant differences were found in liver function, platelet counts, spleen thickness and flow volumes in the portal venous system (p > 0.05). The AUCs of SS were 0.98 and 0.96 for predicting the presence of HRV in IPH (44.0 kPa cutoff value; 0.93 sensitivity; 0.96 specificity) and HBV-infected patients (35.2 kPa cutoff value; 1.00 sensitivity; 0.82 specificity), respectively, which were significantly better than other parameters.ConclusionSS shows the optimal overall performance for predicting the presence of HRV in IPH and HBV-infected patients, in comparison with other noninvasive parameters.

Divergences in Macrophage Activation Markers Soluble CD163 and Mannose Receptor in Patients With Non-cirrhotic and Cirrhotic Portal Hypertension.

IntroductionMacrophages are involved in development and progression of chronic liver disease and portal hypertension. The macrophage activation markers soluble (s)CD163 and soluble mannose receptor (sMR), are associated with portal hypertension in patient with liver cirrhosis but never investigated in patients with non-cirrhotic portal hypertension. We hypothesized higher levels in cirrhotic patients with portal hypertension than patients with non-cirrhotic portal hypertension. We investigated sCD163 and sMR levels in patients with portal hypertension due to idiopathic portal hypertension (IPH) and portal vein thrombosis (PVT) in patients with and without cirrhosis.MethodsWe studied plasma sCD163 and sMR levels in patients with IPH (n = 26), non-cirrhotic PVT (n = 20), patients with cirrhosis without PVT (n = 31) and with PVT (n = 17), and healthy controls (n = 15).ResultsMedian sCD163 concentration was 1.51 (95% CI: 1.24–1.83) mg/L in healthy controls, 1.96 (95% CI: 1.49–2.56) in patients with non-cirrhotic PVT and 2.16 (95% CI: 1.75–2.66) in patients with IPH. There was no difference between non-cirrhotic PVT patients and healthy controls, whereas IPH patients had significantly higher levels than controls (P < 0.05). The median sCD163 was significantly higher in the cirrhotic groups compared to the other groups, with a median sCD163 of 6.31 (95% CI: 5.16–7.73) in cirrhotics without PVT and 5.19 (95% CI: 4.18–6.46) with PVT (P < 0.01, all). Similar differences were observed for sMR.ConclusionSoluble CD163 and sMR levels are elevated in patients with IPH and patients with cirrhosis, but normal in patients with non-cirrhotic PVT. This suggests that hepatic macrophage activation is more driven by the underlying liver disease with cirrhosis than portal hypertension.

Imaging and Pathological Features of Idiopathic Portal Hypertension and Differential Diagnosis from Liver Cirrhosis

Idiopathic portal hypertension (IPH) mimics liver cirrhosis in many aspects, and no efficient imaging method to differentiate the two diseases has been reported to date. In this study, the imaging and pathological characteristics were analysed for both IPH and cirrhosis. From January 2015 to March 2019, ultrasound, computed tomography (CT) and magnetic resonance imaging (MRI) images and pathological results from 16 IPH and 16 liver cirrhosis patients, as well as imaging results of 16 normal patients as a control group, were retrospectively reviewed. The age of the patients was 39 ± 20 years. There was a significant difference in the mean lumen diameter, wall thickness and ratio of thickness to diameter between the IPH and liver cirrhosis patients in the main and sagittal portal veins (P < 0.05), as well as in the lumen diameter and ratio of thickness to diameter between the IPH and liver cirrhosis patients in the Segment 3 (S3) portal vein (P < 0.05). In IPH patients, the main imaging changes were portal vein wall thickening, stenosis or occlusion, a low enhancement area along the portal vein in the delay phase in contrast-enhanced imaging, and a non-homogeneous change in T1WI. The corresponding pathological changes included interlobular vein thickening, stenosis, occlusion, portal area fibrosis, and atrophy or apoptosis of hepatocytes. The main imaging characteristic of liver cirrhosis was a nodular change in T1WI, and the related pathological change was pseudolobule formation. The imaging characteristics of IPH include thickening of the portal vein vascular wall, stenosis of the portal vein lumen and the absence of diffuse cirrhosis-like nodules. These imaging features have a definite pathological basis and could help make differential diagnoses between IPH and cirrhosis.

Japanese periodical nationwide epidemiologic survey of aberrant portal hemodynamics.

AimIdiopathic portal hypertension (IPH), extrahepatic portal obstruction (EHO), and Budd–Chiari syndrome (BCS) are characterized by aberrant portal hemodynamics of unknown etiology. The aim of this study was to explore trends in the descriptive epidemiology of these diseases through periodical nationwide surveys.MethodsNationwide epidemiologic surveys were undertaken in 1999, 2005, and 2015 using the same protocol. The survey targets were selected from all departments of gastrointestinal medicine, surgery, pediatrics, and pediatric surgery in Japan by stratified random sampling according to the number of beds. We asked each department to complete a mail‐back questionnaire on the annual numbers of patients with IPH, EHO, and BCS during the preceding year.ResultsThe estimated number of BCS patients increased from 280 (95% confidence interval, 200–360) in 1999 survey to 410 (300–530) in 2015 survey, whereas the number of IPH and EHO patients has remained largely unchanged during the 15 years (IPH was approximately 1000; EHO was approximately 770 in 2015 survey). The mean age at symptom onset was approximately 45 years for IPH, 30 years for EHO, and 40 years for BCS over the past 15 years. Those who described disease aggravation from the time of diagnosis accounted for approximately 10% of IPH, 15% of EHO, and 20% of BCS patients in each of the three surveys.ConclusionsIn Japan, the prevalence of BCS is increasing, while those of IPH and EHO appear to be stable. Clinical characteristics, including prognoses, have remained largely unchanged in the past 15 years.

Idiopathic portal hypertension: Natural history and long-term outcome

Idiopathic portal hypertension (IPH) is a rare cause of intrahepatic portal hypertension. Data on natural history and prognosis of IPH are limited. We sought to describe the complications and long-tem outcome of IPH by retrospectively studying 69 biopsy-proven cases of IPH. Mean duration of follow-up was 6.7 ± 4.6 years. All patients had evidence of portal hypertension (PH) at diagnosis, and 42% were symptomatic. Variceal bleeding (VB) was the most common manifestation. In those without bleeding at diagnosis, 74% had varices at first endoscopy. In those with large varices, the 1-year probability of first bleeding despite primary prophylaxis was 9%. The 1-year probability of rebleeding was 22%. Ascites and hepatic encephalopathy was documented in 26% and 7% of patients, respectively, at least once during the clinical course. The 1-year probability of developing portal vein thrombosis (PVT) was 9%, and 53% of patients receiving anticoagulation achieved recanalization. Human immunodeficiency virus (HIV) infection and VB at diagnosis were the independent predictors of PVT. Seven patients died (6 as a result of an IPH-related cause) and 2 were transplanted. Probability of liver transplantation-free survival was 82% at 10 years. Presence of a severe associated disorder and ascites as a presenting symptom were associated with poor survival. Variceal bleeding is a major complication of IPH. Using, in IPH patients, the same management approach for PH as in cirrhosis is safe and maintains a low incidence of first bleeding and rebleeding in IPH patients. PVT is a frequent complication, particularly in those with HIV infection. Despite several complications, overall survival of patients with IPH is considerably good.

Metabolomics Discloses Potential Biomarkers for the Noninvasive Diagnosis of Idiopathic Portal Hypertension

Idiopathic portal hypertension (IPH) is a rare cause of portal hypertension that lacks a specific diagnostic test. Requiring ruling-out other causes of portal hypertension it is frequently misdiagnosed. This study evaluates whether using high-throughput techniques there is a metabolomic profile allowing a noninvasive diagnosis of IPH. Thirty-three IPH patients were included. Matched patients with cirrhosis (CH) and healthy volunteers (HV) were included as controls. Metabolomic analysis of plasma samples was performed using UPLC-time-of-flight-mass spectrometry. We computed Student's P-values, corrected by multiple comparison and VIP score (Variable Importance in the Projection). The metabolites were selected with an adjusted Benjamini Hochberg P value <0.05. We use markers with a greater VIP score, to build partial least squares projection to latent structures regression with discriminant analysis (PLS-DA) representative models to discriminate IPH from CH and from HV. The performance of the PLS-DA model was evaluated using R(2) and Q(2) parameter. An additional internal cross-validation was done. PLS-DA analysis showed a clear separation of IPH from CH with a model involving 28 metabolites (Q(2)=0.67, area under the curve (AUC)=0.99) and a clear separation of IPH from healthy subjects with a model including 31 metabolites (Q(2)=0.75, AUC=0.98). After cross-validation, both models showed high rates of sensitivity (94.8 and 97.5), specificity (89.1 and 89.7), and AUC (0.98 and 0.98), reinforcing the strength of our findings. A metabolomic profile clearly differentiating patients with IPH from CH and healthy subjects has been identified using subsets of 28 and 31 metabolites, respectively. Therefore, metabolomic analysis appears to be a valuable tool for the noninvasive diagnosis of IPH.

Noninvasive diagnostic method for idiopathic portal hypertension based on measurements of liver and spleen stiffness by ARFI elastography

Acoustic radiation force impulse (ARFI) elastography is an ultrasound technique that is capable of measuring tissue stiffness noninvasively. It is difficult to differentiate idiopathic portal hypertension (IPH) from liver cirrhosis (LC) or chronic hepatitis (CH), and liver biopsy is essential. We investigated whether it would be possible to noninvasively diagnose IPH by measuring the stiffness of the liver and spleen by ARFI. The subjects were 17 IPH patients, 25 LC patients, 20 CH patients, and 20 normal controls (NC). We measured liver stiffness, spleen stiffness, and the spleen/liver stiffness ratio, and plotted ROC curves. The median value of liver stiffness in the IPH group was lower than that in the LC group (p = 0.00077) and about the same as in the CH group (p = 0.79). The median value of spleen stiffness was highest in the IPH group (IPH vs. LC group, p = 0.003; IPH vs. CH group, p < 0.00001). The spleen/liver stiffness ratio was lower in the LC group and in the CH group, and higher in the IPH group (p < 0.001, respectively). When an ROC curve of spleen/liver stiffness ratios was plotted to differentiate between the IPH group and the combined group of patients with other liver diseases (LC + CH group), when a cutoff value of 1.71 was used, the AUROC was 0.933 sensitivity 0.941, specificity 0.800, and accuracy 0.839. Measuring the spleen/liver stiffness ratio by ARFI made it possible to noninvasively, specifically, and accurately diagnose IPH.

Role of hepatic vein catheterisation and transient elastography in the diagnosis of idiopathic portal hypertension

BackgroundIdiopathic portal hypertension is a rare cause of portal hypertension, frequently misdiagnosed as cryptogenic cirrhosis. This study evaluates specific findings at hepatic vein catheterisation or liver stiffness in idiopathic portal hypertension. Methods39 cases of idiopathic portal hypertension patients were retrospectively reviewed. Hepatic vein catheterisation and liver stiffness measurements were compared to matched patients with cirrhosis and portal hypertension, and non-cirrhotic portal vein thrombosis, included as controls. ResultsHepatic vein-to-vein communications were found in 49% idiopathic portal hypertension patients precluding adequate hepatic venous pressure gradient measurements in 12. In the remaining 27 patients, mean hepatic venous pressure gradient (HVPG) was 7.1±3.1mmHg. Only 5 patients had HVPG≥10mmHg. HVPG was markedly lower than in cirrhosis (17±3mmHg, p<0.001). Mean liver stiffness in idiopathic portal hypertension was 8.4±3.3kPa; significantly higher than in non-cirrhotic portal vein thrombosis (6.4±2.2kPa, p=0.009), but lower than in cirrhosis (40.9±20.5kPa, p=0.005). Only 2 idiopathic portal hypertension patients had liver stiffness >13.6kPa. ConclusionsPatients with idiopathic portal hypertension frequently have hepatic vein-to-vein communications and, despite unequivocal signs of portal hypertension, HVPG and liver stiffness values much lower than the cut-off for clinical significant portal hypertension in cirrhosis. These findings oblige to formally rule-out idiopathic portal hypertension in the presence of signs of portal hypertension.

Induction of elastin expression in vascular endothelial cells relates to hepatoportal sclerosis in idiopathic portal hypertension: possible link to serum anti-endothelial cell antibodies

Hepatoportal sclerosis accompanied by dense elastic fibre deposition is generally regarded as the primary lesion in the development of idiopathic portal hypertension (IPH). This study was performed to clarify the mechanism of elastic fibre deposition in the peripheral portal tracts of IPH liver in relation to serum anti-endothelial cell antibodies (AECA). In-vitro experiments were performed using human dermal microvascular endothelial cells (HMVEC) and patients' sera. The presence of serum AECA was assayed by a cell-based enzyme-linked immunosorbent assay (ELISA) using HMVEC. Immunohistochemical analysis of elastin was performed using liver tissue sections of IPH patients. IPH sera contained one or more AECA that could bind to the vascular endothelial cells of the peripheral portal tracts of the liver. When the value of AECA greater than the mean ± 2 standard deviations of healthy controls was regarded as positive, the positive detection rate of either immunoglobulin (Ig)G, IgA or IgM AECA in IPH sera was 30% (10 of 33 cases). IPH sera induced the expression of elastin in HMVEC, which appeared to be associated with the presence of AECA. Apoptosis was also induced in HMVEC by the stimulation with IPH sera. In vivo, elastin expression was observed in the endothelial cells of the peripheral portal tracts of IPH livers in a proportion of cases. The disease pathogenesis of IPH seems to be heterogeneous, and this study elucidated a possible contribution of the induction of elastin expression in the portal vessels to hepatoportal sclerosis of IPH, which might be linked to serum AECA as a causative factor.

Implications of portal vein thrombosis after splenectomy for patients with idiopathic portal hypertension

Idiopathic portal hypertension (IPH) is considered to be closely related to portal vein thrombosis (PVT). The aim of this study was to clarify the incidence, clinical characteristics, and outcomes of PVT in patients with IPH after splenectomy. We investigated the rates, clinical characteristics, and outcomes of PVT in 18 patients who underwent splenectomy for IPH, during a mean follow-up period of 152 ± 83 months. Seven of the 18 patients (39%) experienced gastrointestinal bleeding, which was from the varices in 4. Eight patients (44%) had PVT, and the mean interval until its detection after splenectomy was 22 ± 41 months. The cumulative gastrointestinal bleeding rates 5, 10, and 15 years after surgery were 24%, 31%, and 41%, respectively. The cumulative survival rates 5, 10, and 15 years after surgery were 94%, 74%, and 65%, respectively. There were no significant differences in the cumulative gastrointestinal bleeding and survival rates between patients with and those without PVT. Despite the high incidence of PVT in IPH patients postsplenectomy, it may not be related to their gastrointestinal bleeding or prognosis.

Anabolic Steroid-Induced Hepatitis and Portal Gastropathy in a Young Bodybuilder

[Introduction] Virtual Touch Tissue Quantification (VTTQ) is an ultrasound technique to quantify tissue stiffness based on measurement of the propagation velocity of elastic shearwaves (Vs) generated by acoustic radiation force impulses that cause tissue displacements. [Objective] To explore the usefulness of liver and spleen stiffness measurements by VTTQ for diagnostic differentiation between idiopathic portal hypertension (IPH) and portal hypertension caused by liver cirrhosis (LC). [Subjects] Thirteen patients with histologically diagnosed IPH and 18 patients with histologically diagnosed LC were recruited for this study. Eight normal subjects (NC) and 7 patients with chronic hepatitis (CH) were also included. [Methods] With the region of interest (ROI) set at a 3-cm depth from the body surface, the mean of 5 successful Vs measurements of the liver and spleen in each patient was determined. The percentage of peripheral blood CD4+ CD25+ T cells (Tregs) in the LC cases and IPH cases was analyzed by FACS, and the size of the spleen (SI) was also measured. [Results] The measured stiffness of the liver (NC: CH: LC: IPH = 1.14: 1.40: 2.50: 1.56 m/s) was greater in the LC patients (p < 0.001), and that of the spleen (2.03: 2.30: 3.12: 3.90) was greater in the patients with IPH (p < 0.001). Making each ROC curve, we set the cut-off values of liver stiffness by VTTQ as follows (CH: LC: IPH = 1.14: 1.54: 1.23 m/s). The sensitivities were (89.5: 94.7: 89.5%) and the specificities were (62.5: 100.0: 75.0%). Meanwhile, setting the cut-off values of spleen stiffness as follows (CH: LC: IPH = 2.44: 2.61: 2.88 m/s), the sensitivities were (66.7: 90.5: 90.5%) and the specificities were (87.5: 100.0: 100.0%). The stiffness measurements of both liver and spleen were proved to be useful in diagnosis. Furthermore, a lower peripheral blood Tregs frequency [(LC: IPH) = (19.0: 11.6%)] (p < 0.001) and a larger SI (22.5: 44.5) (p < 0.001) were recorded in the IPH patients. [Discussion] The IPH patient group showed a lower liver stiffness relative to the LC group and comparable liver stiffness to that in the CH group. Stiffness of the spleen, nevertheless, was markedly higher in the IPH group; thus, stiffness measurements of both the liver and spleen allowed ready diagnostic differentiation between portal hypertension associated with LC and IPH. The increased splenic stiffness with splenomegaly in IPH was considered to be attributable to a state of enhanced immune functions when viewed with reference to the reduced percentage of peripheral blood Tregs.

Elucidation of Idiopathic Portal Hypertension Based on Liver and Spleen Stiffness Measurements by Virtual Touch Tissue Quantification and Peripheral Blood CD4+ CD25+ T Cytometry

[Introduction] Virtual Touch Tissue Quantification (VTTQ) is an ultrasound technique to quantify tissue stiffness based on measurement of the propagation velocity of elastic shearwaves (Vs) generated by acoustic radiation force impulses that cause tissue displacements. [Objective] To explore the usefulness of liver and spleen stiffness measurements by VTTQ for diagnostic differentiation between idiopathic portal hypertension (IPH) and portal hypertension caused by liver cirrhosis (LC). [Subjects] Thirteen patients with histologically diagnosed IPH and 18 patients with histologically diagnosed LC were recruited for this study. Eight normal subjects (NC) and 7 patients with chronic hepatitis (CH) were also included. [Methods] With the region of interest (ROI) set at a 3-cm depth from the body surface, the mean of 5 successful Vs measurements of the liver and spleen in each patient was determined. The percentage of peripheral blood CD4+ CD25+ T cells (Tregs) in the LC cases and IPH cases was analyzed by FACS, and the size of the spleen (SI) was also measured. [Results] The measured stiffness of the liver (NC: CH: LC: IPH = 1.14: 1.40: 2.50: 1.56 m/s) was greater in the LC patients (p < 0.001), and that of the spleen (2.03: 2.30: 3.12: 3.90) was greater in the patients with IPH (p < 0.001). Making each ROC curve, we set the cut-off values of liver stiffness by VTTQ as follows (CH: LC: IPH = 1.14: 1.54: 1.23 m/s). The sensitivities were (89.5: 94.7: 89.5%) and the specificities were (62.5: 100.0: 75.0%). Meanwhile, setting the cut-off values of spleen stiffness as follows (CH: LC: IPH = 2.44: 2.61: 2.88 m/s), the sensitivities were (66.7: 90.5: 90.5%) and the specificities were (87.5: 100.0: 100.0%). The stiffness measurements of both liver and spleen were proved to be useful in diagnosis. Furthermore, a lower peripheral blood Tregs frequency [(LC: IPH) = (19.0: 11.6%)] (p < 0.001) and a larger SI (22.5: 44.5) (p < 0.001) were recorded in the IPH patients. [Discussion] The IPH patient group showed a lower liver stiffness relative to the LC group and comparable liver stiffness to that in the CH group. Stiffness of the spleen, nevertheless, was markedly higher in the IPH group; thus, stiffness measurements of both the liver and spleen allowed ready diagnostic differentiation between portal hypertension associated with LC and IPH. The increased splenic stiffness with splenomegaly in IPH was considered to be attributable to a state of enhanced immune functions when viewed with reference to the reduced percentage of peripheral blood Tregs.

Effect of Signal Intensity from the Accumulated Microbubbles in the Liver for Differentiation of Idiopathic Portal Hypertension from Liver Cirrhosis

To examine the possibility of using contrast material-enhanced ultrasonography (US) to differentiate idiopathic portal hypertension (IPH) from cirrhosis. This was an institutional review board-approved prospective study with written informed consent. The study consisted of 23 patients (mean age, 60 years +/- 11; range, 37-85 years) with biopsy-proved cirrhosis, 10 patients (mean age, 65 years +/- 8; range, 51-78 years) with IPH, and 27 control subjects (mean age, 46 years +/- 17; range, 26-82 years) without any focal hepatic lesions or portal vein thrombosis. The patients underwent contrast-enhanced US for the observation of the right liver lobe. The time of the onset of contrast enhancement in the right hepatic artery and right portal vein was examined at vascular phase under continuous low-power emission, and signal intensity differences (in decibels) by using instantaneous high-power emission in the liver parenchyma were analyzed at late phase (15 minutes). Interobserver variability was quantified as coefficients of variation. Onset time of contrast enhancement in the right portal vein was significantly longer for both IPH (22 sec +/- 3.9, P = .0035) and cirrhosis (19.3 sec +/- 4.7, P = .04) patients than for control subjects (17 sec +/- 3.3), with no significant difference in the onset time in the right hepatic artery. Images obtained in both IPH patients (21.2 dB +/- 1.4) and control subjects (22.1 dB +/- 2.2) had significantly higher signal intensity differences than those obtained in cirrhosis patients (13.8 dB +/- 2.8, P < .0001), with no significant difference between images of IPH patients and control subjects. Signal intensity differences of more than 18 dB had 100% sensitivity and specificity for the diagnosis in IPH patients and control subjects. Interobserver variability for signal intensity differences was 8.7%. Contrast-enhanced US may offer the possibility for a simple, easy, and noninvasive diagnosis of IPH.

Analysis of inherited thrombophilic mutations and natural anticoagulant deficiency in patients with idiopathic portal hypertension

Idiopathic portal hypertension (IPH) is characterized by non-cirrhotic presinusoidal intrahepatic portal hypertension. The etiopathogenesis of the disease is poorly understood. Obliteration with microthrombosis of the small portal vein branches may lead to lesions underlying portal hypertension. We aimed to put forward a comprehensive thrombophilic mutation profile in IPH and its probable contribution to pathogenesis. Eleven patients and 12 controls were included. We used the CVD-StripAssay which is based on the reverse-hybridization principle to identify a total of 12 thrombophilic gene mutations: Factor V R506Q, Factor V H1299R, prothrombin G20210A, Factor XIII V34L, beta-Fibrinogen -455 G-A, PAI-1 4G/5G, platelet GPIIIa L33P, MTHFR C677T, MTHFR A1298C, ACE I/D, Apo B R3500Q and Apo E2/E3/E4, respectively. We also evaluated some blood parameters and protein C, protein S, AT-III levels using commercially available assays. IPH patients and controls were similar in respect to gender distribution (P = 1.000). Mean age was 31.2 in patients and 29.1 in controls (P = 0.622). Pica history was present in 54.5% of the patients. Mean protein C and AT-III levels were lower in patients than that of controls (P = 0.002 and 0.001, respectively). Factor XIII V34L, PAI-1, GPIIIa L33P, MTHFR C677T and MTHFR A1298C frequencies of genetic polymorphisms were found to be significantly higher among patients than that of controls. Apolipoprotein E2/E3/E4 analysis showed an inverse relationship with IPH when E2 plus E4 compared with E3. A higher frequency of Beta-Fibrinogen -455G-A mutation was observed in patients, but this difference did not reach a statistical significance. Our data represent the most comprehensive study to date with respect to thrombophilic gene polymorphisms in IPH. The data support a possible pathogenetic role in IPH, at least by some of the prothrombotic mutations. In order to confirm or refuse this proposal, a larger cohort of patients is needed.

Study of portal vein thrombosis in patients with idiopathic portal hypertension in Japan

The aim of this study was to elucidate the incidence and clinical manifestations of portal vein thrombosis (PVT) in patients with idiopathic portal hypertension (IPH) in Japan during long-term follow-up. Twenty-two patients with IPH were examined for PVT by sonography during a follow-up of 12+/-6 years. Clinical manifestations and patient outcome related to PVT were studied. Seventy patients with liver cirrhosis were examined by sonography as an incidence control of thrombosis. Nine IPH patients had portal thrombosis (9/22, 41%), a higher incidence than in liver cirrhosis patients (7/70, 10%). Those with thrombosis showed ascites, marked hypersplenism, and low serum albumin. Four patients with thrombosis died. Patients without thrombosis showed less clinical problems after long-term follow-up. Plasma antithrombin III and protein C activity decreased in almost half of the patients. However, there were no differences in these parameters between patients with and without thrombosis. In Japan, IPH patients had a high incidence of portal thrombosis, a significant factor for poor prognosis. Whether the management of PVT contributes to an improvement of a clinical course of IPH or not should be clarified in further study.

Predominant T helper 1 cells in patients with idiopathic portal hypertension

The pathologic mechanism of idiopathic portal hypertension (IPH) is unknown. Because cytokines and the balance of T helper (h) 1 and Th2 CD4+ T cells have been reported to be important for regulating the immune response, in the present study we investigated the role of cytokines and the distribution of cytokine-producing cells in IPH patients. Serum levels of tumor necrosis factor (TNF)-alpha, soluble TNF receptor-I, -II, interferon (IFN)-gamma and interleukin (IL)-4 were measured in IPH patients, fatty liver patients, chronic hepatitis patients and control subjects. The percentages of Th0, Th1 and Th2 CD4+ T cells were examined in peripheral and spleen lymphocytes in IPH patients by intracellular staining. Serum levels of TNF-alpha, soluble TNF receptor-I, interferon-gamma and IL-4 of IPH patients were not increased in comparison with control subjects. Only the mean value of soluble TNF receptor-II was significantly higher than that of control subjects and fatty liver patients. The ratios of Th1 and Th2 in both peripheral and spleen lymphocytes of IPH patients were significantly increased compared with the ratios found in peripheral lymphocytes of control subjects. The increase in the ratios was due to a decrease in the percentage of Th2 CD4+ T cells. These results suggest that the imbalance of Th1 and Th2 CD4+ T cells and TNF may be associated with the pathogenesis of IPH.

Analysis of adhesion molecules in patients with idiopathic portal hypertension.

The aetiology of idiopathic portal hypertension (IPH) is unknown. However, some evidence of immunological abnormalities in IPH patients has been reported. As adhesion molecules are important in the interaction between lymphocytes and accessory and target cells, the expression and release of the soluble form of vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule (ICAM-1) were examined in this study. In IPH patients, the serum level of soluble VCAM-1 was found to be increased, compared with that of healthy subjects, fatty liver patients and chronic hepatitis patients. The level of soluble ICAM-1 of IPH patients was found to be slightly increased, compared with that of healthy subjects; however, it was not different from the level in patients with other diseases. The expression of VCAM-1 was observed in the sinusoidal lining cells and endothelial cells around the liver vessels of several IPH patients. In contrast, ICAM-1 was weakly expressed in sinusoidal lining cells and hepatocytes in the liver tissue of only one of four IPH patients. This differential pattern of VCAM-1 and ICAM-1 was found in IPH patients and it was suggested that VCAM-1 might be an important molecule in the occurrence of IPH.

Long-term results after nonshunt operations for esophageal varices in children

The clinical results of nonshunt operations for esophageal varices in 15 children were evaluated. The varices were caused by congenital extrahepatic portal obstruction (EHPO) in 10, liver cirrhosis or fibrosis (C/F) in 3, and idiopathic portal hypertension (IPH) in 2. The operative procedures were transthoracic esophageal transection with paraesophageal devascularization (TR) for 2 EHPO patients under 5 years of age, TR combined with splenectomy and paragastric devascularization (Sugiura procedure) for 11 (8 EHPO, 3 C/F), and splenectomy with devascularization (SP) or splenectomy for the 2 IPH patients. In the EHPO patient under 5 years of age, TR is associated with a likelihood of gastric or esophageal hemorrhage resulting from hypersplenism, gastric congestion, or persistent distal esophageal varices, which can be treated with partial splanic arterial embolization (PSE), endosclerotherapy, or an additional abdominal procedure. The Sugiura procedure has provided satisfactory long-term results, without rebleeding from esophageal varices, in patients with EHPO and C/F for 1 to 20 years. But EHPO patients who undergo the Sugiura procedure before age 6 can have gastric hemorrhage, because of mucosal congestion, for more than 10 years after the procedure, and selective gastric arterial embolization (GAE) might be necessary. In some EHPO patients, especially young ones who have variceal bleeding, a significant increase in hepatopetal portal flow may not develop, but hepatofugal natural shunts may progress. Therefore we recommend direct operative procedures, ie, TR for patients ≤6 years of age and a one- or two-stage Sugiura procedure for those over 7 years old. Nonoperative treatment such as PSE, GAE, and sclerotherapy were effective as adjunct therapeutic measures for managing postoperative bleeding problems. The function of the lower esophageal sphincter deteriorated transiently during the early postoperative period, but recovered to the preoperative level 6 months after the TR or Sugiura procedure.

Comparison between portal vein pressure and wedged hepatic vein pressure in hepatitis B-related cirrhosis

Portal vein pressure and wedged hepatic vein pressure were measured simultaneously in 21 patients with hepatitis B-related cirrhosis of the liver and were compared to pressure measured in six patients with idiopathic portal hypertension. No significant difference in the portal venous pressure gradient was found between patients with cirrhosis and those with idiopathic portal hypertension (17.3 ± 4.3 mmHg (mean ± S.D.) vs. 19.7 ± 3.1 mmHg, P > 0.05). However, the difference between the portal and the hepatic venous pressure gradient was significantly smaller in patients with cirrhosis than in idiopathic portal hypertension patients (1.3 ± 1.7 vs. 10.8 ± 2.1 mmHg, P < 0.001). An excellent correlation was found between portal vein pressure and wedged hepatic vein pressure in hepatitis B-related cirrhosis ( r = 0.94, P < 0.001). There was no linear relationship between the portal venous pressure gradient and varix size or bleeding episodes. We concluded that a close agreement existed between portal vein pressure and wedged hepatic vein pressure in hepatitis B-related liver cirrhosis. Therefore, measurement of wedged hepatic vein pressure reliably reflects portal vein pressure in these patients.

Pathology of the Liver in “Idiopathic Portal Hypertension” Associated with Autoimmune Disease

The histopathology of the liver in idiopathic portal hypertension (IPH) associated with autoimmune disease (15 cases), was examined and compared with that of IPH without autoimmune disease (31 cases). It was found that hepatic histopathology was heterogeneous in the cases with autoimmune disease. That is, the hepatic histopathology in 7 cases was similar to that of classic IPH without autoimmune disease, and the remaining 8 cases disclosed unusual lesions such as focal non-suppurative cholangitis, nodular parenchymal hyperplasia, moderate portal inflammation, and intrahepatic ductopenia. These unusual lesions, which frequently coexisted in the same case, were not typical ones for making other diagnoses such as primary biliary cirrhosis or nodular regenerative hyperplasia of the liver. These findings suggest that unusual histologic lesions in the livers of IPH patients with autoimmune disease may represent an accentuated immunologic reaction inherent in IPH, or that such cases may be an abortive or incomplete form of primary biliary cirrhosis or nodular regenerative hyperplasia of the liver.