1B). Kidney size and weight were significantly reduced in CBDL mice (Fig. 1C), whereas kidney/body weight ratio (not shown) did not differ significantly, compared to sham-operated controls. These structural changes were associated with increased serum urea levels (Fig. 1C) and an increased urinary volume indicative of polyuric renal failure in 8-week CBDL mice (5.2 ± 2.0 versus 1.3 ± 0.7 mL/24 hours in controls; P = 0.009). Kidneys of 8-week CBDL mice showed dilated tubuli and renal tubulointersititial

nephritis and pronounced fibrosis on H&E-stained sections (Fig. 1E). Cytologic urinalysis revealed characteristic findings for tubular injury in CBDL mice, reflected by a significantly increased number of tubular cell cylinders and urinary casts (Fig. 1F). In contrast, the urine of 8-week sham-operated controls was almost free of cells and debris. Consequently, the characteristic kidney phenotype of cholemic nephropathy in long-term CBDL mice called Protein Tyrosine Kinase inhibitor for more-detailed mechanistic time-course studies. Already after 3 day CBDL, kidneys showed tubular epithelial injury at the border region between the outer and the inner strip and in the inner medulla, with small foci of coagulation necrosis and tubular casts detectable only on PAS-stained sections at Opaganib that early time point (Fig. 2B). From day 7, we observed dilated tubules and an increasing number of protein and cell casts occasionally

in distal tubules and most prominent in collecting ducts in the inner medulla (Fig. 2C). In addition, kidneys frequently showed progressive partial occlusion and dilatation of distal tubules and collecting ducts in 3-, 6-, and 8-week CBDL mice (Fig. 1D-F). Concomitantly, we observed an increasing number of atrophic glomeruli over time with a dilated Bowman’s space. Additional support for the conclusion that the predominant injury in response to 3-day see more CBDL was to collecting ducts was achieved by IHC and IF staining of AQP2 (specifically expressed in the apical plasma membrane and apical vesicles of collecting duct cells[25,

26]), showing a partial lack of AQP2 positivity and parallel loss of nuclear staining in necrotic collecting duct epithelial cells (Fig. 3A-D). In addition, serial sections convincingly showed that injured tubuli observed on PAS-stained sections corresponded nicely to AQP2-positive collecting ducts (Fig. 3D-F), whereas NKCC2-positive cells of the thick ascending limb of Henle appeared normal (Supporting Fig. 1). We found no evidence that the observed reduced AQP2 staining of collecting ducts observed in CBDL mice was the result of an increased relative number of intercalated cells,[27] as demonstrated by double IF staining for AQP2 and AE1 for type A intercalated cells or pendrin for non-type-A intercalated cells[21, 22] (Fig. 3C and Supporting Fig. 2). Together, these findings were indicative of a loss of epithelial barrier continuity of collecting ducts in 3-day CBDL mice (Fig. 3A,C,D).

1B). Kidney size and weight were significantly reduced in CBDL mice (Fig. 1C), whereas kidney/body weight ratio (not shown) did not differ significantly, compared to sham-operated controls. These structural changes were associated with increased serum urea levels (Fig. 1C) and an increased urinary volume indicative of polyuric renal failure in 8-week CBDL mice (5.2 ± 2.0 versus 1.3 ± 0.7 mL/24 hours in controls; P = 0.009). Kidneys of 8-week CBDL mice showed dilated tubuli and renal tubulointersititial

nephritis and pronounced fibrosis on H&E-stained sections (Fig. 1E). Cytologic urinalysis revealed characteristic findings for tubular injury in CBDL mice, reflected by a significantly increased number of tubular cell cylinders and urinary casts (Fig. 1F). In contrast, the urine of 8-week sham-operated controls was almost free of cells and debris. Consequently, the characteristic kidney phenotype of cholemic nephropathy in long-term CBDL mice called Galunisertib chemical structure for more-detailed mechanistic time-course studies. Already after 3 day CBDL, kidneys showed tubular epithelial injury at the border region between the outer and the inner strip and in the inner medulla, with small foci of coagulation necrosis and tubular casts detectable only on PAS-stained sections at MG-132 in vivo that early time point (Fig. 2B). From day 7, we observed dilated tubules and an increasing number of protein and cell casts occasionally

in distal tubules and most prominent in collecting ducts in the inner medulla (Fig. 2C). In addition, kidneys frequently showed progressive partial occlusion and dilatation of distal tubules and collecting ducts in 3-, 6-, and 8-week CBDL mice (Fig. 1D-F). Concomitantly, we observed an increasing number of atrophic glomeruli over time with a dilated Bowman’s space. Additional support for the conclusion that the predominant injury in response to 3-day selleck screening library CBDL was to collecting ducts was achieved by IHC and IF staining of AQP2 (specifically expressed in the apical plasma membrane and apical vesicles of collecting duct cells[25,

26]), showing a partial lack of AQP2 positivity and parallel loss of nuclear staining in necrotic collecting duct epithelial cells (Fig. 3A-D). In addition, serial sections convincingly showed that injured tubuli observed on PAS-stained sections corresponded nicely to AQP2-positive collecting ducts (Fig. 3D-F), whereas NKCC2-positive cells of the thick ascending limb of Henle appeared normal (Supporting Fig. 1). We found no evidence that the observed reduced AQP2 staining of collecting ducts observed in CBDL mice was the result of an increased relative number of intercalated cells,[27] as demonstrated by double IF staining for AQP2 and AE1 for type A intercalated cells or pendrin for non-type-A intercalated cells[21, 22] (Fig. 3C and Supporting Fig. 2). Together, these findings were indicative of a loss of epithelial barrier continuity of collecting ducts in 3-day CBDL mice (Fig. 3A,C,D).

24 The vessel area was calculated as follows: All experiments were performed in Napabucasin nmr triplicate. Samples of 8 × 106 HCCLM3, shRNA-CD151-HCCLM3, shRNA-MMP9-HCCLM3, HCCLM3-mock, and Hep3B cells were used for spontaneous metastasis assays, as described

previously.25 Lung metastases of shRNA-CD151-HCCLM3, shRNA-MMP9-HCCLM3, and HCCLM3-mock were visualized with fluorescence stereomicroscopy (Leica Microsystems Imaging Solutions, Ltd., Cambridge, United Kingdom). Serial sections were made for every tissue block from the lung, and the total number of lung metastases was counted under the microscope as described previously.6 There were five animals in each group. Immunohistochemical analysis of subcutaneous xenografts was performed as described elsewhere.6 Antibodies used in this study are listed in the Supporting Information. The construction of tissue microarrays was described in detail in our earlier study.6 Immunohistochemical Selleck Forskolin double staining was performed as described elsewhere.26 Mouse anti-human CD151 antibodies (1:100; 11G5a, Serotec, NK), rat anti-human MMP9 antibodies (1:50; Cell Signal Tec, United States), mouse anti-human CD34 antibodies (1:100; DakoCytomation, Denmark), and rabbit polyclonal VEGF antibodies

(1:100; Neomarkers, Fremont, CA) were used to detect the expression of CD151, MMP9, MVD, and VEGF. The density of positive staining click here of CD151, MMP9, and VEGF was measured as described previously.6 The MVD was evaluated as described elsewhere.27 Statistical analysis was performed with SPSS12.0 software (SPSS, Chicago, IL). Values are expressed as means and standard deviations. The Student t test and one-way analysis of variance were used for comparisons between groups. Correlation analysis was performed. Overall survival (OS) and time to recurrence were defined as described previously.28 OS and the cumulative recurrence rates were calculated by the Kaplan-Meier method and the log-rank test. Cox’s proportional hazards regression model was used to analyze the independent prognostic factors. P < 0.05 was set

as the level of statistical significance. In an earlier study,6 we demonstrated that the bioactivity of MMP9 in the supernatant from HCCLM3 cells with a high level of expression of CD151 was much stronger than that in shRNA-CD151-HCCLM3 cells and HepG2 cells with low CD151 expression by gelatin zymography. We now explore the relationship between the expression of CD151 and MMP9 in HCC cell lines (HCCLM3, MHCC97-L, PLC/PRF/5, Hep3B, and HepG2) with different metastatic potentials by qRT-PCR and immunoblotting. Highly metastatic HCCLM3 cells with CD151high expression showed the highest expression of MMP9 at both the mRNA and protein levels, whereas low-metastatic HCC cell lines (MHCC97-L, PLC/PRF/5, Hep3B, and HepG2) showed low levels of expression of CD151 and MMP9 (Fig. 1A,B).

24 The vessel area was calculated as follows: All experiments were performed in Rapamycin clinical trial triplicate. Samples of 8 × 106 HCCLM3, shRNA-CD151-HCCLM3, shRNA-MMP9-HCCLM3, HCCLM3-mock, and Hep3B cells were used for spontaneous metastasis assays, as described

previously.25 Lung metastases of shRNA-CD151-HCCLM3, shRNA-MMP9-HCCLM3, and HCCLM3-mock were visualized with fluorescence stereomicroscopy (Leica Microsystems Imaging Solutions, Ltd., Cambridge, United Kingdom). Serial sections were made for every tissue block from the lung, and the total number of lung metastases was counted under the microscope as described previously.6 There were five animals in each group. Immunohistochemical analysis of subcutaneous xenografts was performed as described elsewhere.6 Antibodies used in this study are listed in the Supporting Information. The construction of tissue microarrays was described in detail in our earlier study.6 Immunohistochemical selleck compound double staining was performed as described elsewhere.26 Mouse anti-human CD151 antibodies (1:100; 11G5a, Serotec, NK), rat anti-human MMP9 antibodies (1:50; Cell Signal Tec, United States), mouse anti-human CD34 antibodies (1:100; DakoCytomation, Denmark), and rabbit polyclonal VEGF antibodies

(1:100; Neomarkers, Fremont, CA) were used to detect the expression of CD151, MMP9, MVD, and VEGF. The density of positive staining selleck kinase inhibitor of CD151, MMP9, and VEGF was measured as described previously.6 The MVD was evaluated as described elsewhere.27 Statistical analysis was performed with SPSS12.0 software (SPSS, Chicago, IL). Values are expressed as means and standard deviations. The Student t test and one-way analysis of variance were used for comparisons between groups. Correlation analysis was performed. Overall survival (OS) and time to recurrence were defined as described previously.28 OS and the cumulative recurrence rates were calculated by the Kaplan-Meier method and the log-rank test. Cox’s proportional hazards regression model was used to analyze the independent prognostic factors. P < 0.05 was set

as the level of statistical significance. In an earlier study,6 we demonstrated that the bioactivity of MMP9 in the supernatant from HCCLM3 cells with a high level of expression of CD151 was much stronger than that in shRNA-CD151-HCCLM3 cells and HepG2 cells with low CD151 expression by gelatin zymography. We now explore the relationship between the expression of CD151 and MMP9 in HCC cell lines (HCCLM3, MHCC97-L, PLC/PRF/5, Hep3B, and HepG2) with different metastatic potentials by qRT-PCR and immunoblotting. Highly metastatic HCCLM3 cells with CD151high expression showed the highest expression of MMP9 at both the mRNA and protein levels, whereas low-metastatic HCC cell lines (MHCC97-L, PLC/PRF/5, Hep3B, and HepG2) showed low levels of expression of CD151 and MMP9 (Fig. 1A,B).

Thus, the recent Baveno V consensus conference on PH VX-765 nmr recommended to investigate and identify further noninvasive markers for PH.3 Hepatic decompensation is the most important predictor of prognosis and mortality in patients with liver cirrhosis, with several precipitating factors contributing to the first event of decompensation.5 Endothelial dysfunction is considered as an important determinant of the increased

intrahepatic vascular resistance in cirrhotic livers.6, 7 von Willebrand factor antigen (vWF-Ag) is released by activated endothelial cells (ECs) and therefore represents an indicator of EC activation8 and plays a crucial role in high shear stress, depending on primary hemostasis. Furthermore, in patients with liver cirrhosis, elevated levels of vWF-Ag are frequently observed.9 vWF-Ag levels were also shown to be an independent risk factor of myocardial infarction and mortality in patients with angina pectoris.10, 11 Although it is established that VWF-Ag is increased in patients with cirrhosis, no data on the association of vWF-Ag and portal pressure exist. One recent study describes a correlation

between vWF-Ag and HVPG in patients with CSPH, but patients without PH were not included, and thus the diagnostic power of vWF-Ag for CSPH could not be evaluated.12 Because vWF-Ag plays a phosphatase inhibitor library crucial role in primary hemostasis and is an indicator of endothelial selleck activation and development of thrombotic vascular obliteration, which are all discussed as possible mechanisms leading to PH,13 we hypothesized that patients with CSPH have increased vWF-Ag levels, compared to patients without CSPH. Thus, the aims of our study were (1) to evaluate the diagnostic performance of vWF-Ag to detect clinically significant PH defined by HVPG, compared to TE in patients with compensated liver cirrhosis (i.e., when CSPH is not clinically evident), and (2) to evaluate vWF-Ag levels in the prediction of mortality

and decompensation in patients with liver cirrhosis. Ag, antigen; AUC, area under the curve; CI, confidence interval; CPS, Child Pugh score; CSPH, clinically significant portal hypertension; ECs, endothelial cells; HCC, hepatocellular carcinoma; HR, hazard ratio; HVPG, hepatic venous pressure gradient; IFN, interferon; IQR, interquartile range; ITD, intention to diagnose; LT, liver transplantation; MELD, Model for End-Stage Liver Disease; NPV, negative predictive value; OR, odds ratio; PH, portal hypertension; PPV, positive predictive value; ROC, receiver operator characteristic TE, transient elastography; TIPS, transjugular intrahepatic portosystemic shunt; vWF, von Willebrand factor. Patients referred to the hepatic hemodynamic laboratory at the Department of Internal Medicine III, Division of Gastroenterology, Medical University of Vienna (Vienna, Austria) were included between September 2006 and December 2009.

Thus, the recent Baveno V consensus conference on PH Selleck Ceritinib recommended to investigate and identify further noninvasive markers for PH.3 Hepatic decompensation is the most important predictor of prognosis and mortality in patients with liver cirrhosis, with several precipitating factors contributing to the first event of decompensation.5 Endothelial dysfunction is considered as an important determinant of the increased

intrahepatic vascular resistance in cirrhotic livers.6, 7 von Willebrand factor antigen (vWF-Ag) is released by activated endothelial cells (ECs) and therefore represents an indicator of EC activation8 and plays a crucial role in high shear stress, depending on primary hemostasis. Furthermore, in patients with liver cirrhosis, elevated levels of vWF-Ag are frequently observed.9 vWF-Ag levels were also shown to be an independent risk factor of myocardial infarction and mortality in patients with angina pectoris.10, 11 Although it is established that VWF-Ag is increased in patients with cirrhosis, no data on the association of vWF-Ag and portal pressure exist. One recent study describes a correlation

between vWF-Ag and HVPG in patients with CSPH, but patients without PH were not included, and thus the diagnostic power of vWF-Ag for CSPH could not be evaluated.12 Because vWF-Ag plays a selleck products crucial role in primary hemostasis and is an indicator of endothelial selleck chemicals activation and development of thrombotic vascular obliteration, which are all discussed as possible mechanisms leading to PH,13 we hypothesized that patients with CSPH have increased vWF-Ag levels, compared to patients without CSPH. Thus, the aims of our study were (1) to evaluate the diagnostic performance of vWF-Ag to detect clinically significant PH defined by HVPG, compared to TE in patients with compensated liver cirrhosis (i.e., when CSPH is not clinically evident), and (2) to evaluate vWF-Ag levels in the prediction of mortality

and decompensation in patients with liver cirrhosis. Ag, antigen; AUC, area under the curve; CI, confidence interval; CPS, Child Pugh score; CSPH, clinically significant portal hypertension; ECs, endothelial cells; HCC, hepatocellular carcinoma; HR, hazard ratio; HVPG, hepatic venous pressure gradient; IFN, interferon; IQR, interquartile range; ITD, intention to diagnose; LT, liver transplantation; MELD, Model for End-Stage Liver Disease; NPV, negative predictive value; OR, odds ratio; PH, portal hypertension; PPV, positive predictive value; ROC, receiver operator characteristic TE, transient elastography; TIPS, transjugular intrahepatic portosystemic shunt; vWF, von Willebrand factor. Patients referred to the hepatic hemodynamic laboratory at the Department of Internal Medicine III, Division of Gastroenterology, Medical University of Vienna (Vienna, Austria) were included between September 2006 and December 2009.

Although a unified criteria for combined HCC-CC is still not available, it is generally accepted that a firm diagnosis of combined HCC-CC requires evidence of HCC differentiation (Fig. 2a), such as trabecular growth

pattern, bile production, or bile canaliculi as well as clear evidence of CC (Fig. 2b), such as true glandular structures formed by biliary-type epithelium, mucin production or prominent desmoplastic stoma.4,14 In addition, ideally, an interface of these two components showing they intermingle intimately with each other should also be appreciated (Fig. 3). Practically, a definitive diagnosis always requires the use of immunohistochemical and special stains to demonstrate Midostaurin both hepatocytic and biliary phenotypes. Commonly used stains include Hep Par 1 (Fig. 4a), polyclonal CCI-779 mw carcinoembryonic antigen (Fig. 4b), or CD10 for the hepatocytic differentiation, and mucin (Fig. 4c), CK7, and CK19 (Fig. 4d) stains for the biliary differentiation. Combined HCC-CC often expresses both biliary cytokeratins and markers of HCC, and is an important diagnosis to consider when there is an apparently conflicting or overlapping immunophenotype.15 While fibrolamellar carcinoma, a variant of HCC, very rarely occurs in association with CC, a single case of combined fibrolamellar HCC-CC has been reported previously.16 Studies with a series of combined fibrolamellar HCC-CC

are needed to further characterize this rare neoplasm. Glypican-3 (GPC3) is a novel serological and immunohistochemical marker of hepatocellular carcinoma.17–19 A recent study to examine GPC3 immunoreactivity find more in combined HCC-CC shows the expression is sensitive and specific to the HCC component of combined HCC-CC but few cases also show weak immunoreactivity in the cholangiocarcinoma component of combined HCC-CC.20 While the positivity of GPC3 in the cholangiocarcinoma component may be a drawback, this antibody may offer as an additional immunohistochemical stain in diagnosing combined HCC-CC, if used along with

other antibodies and in careful correlation with morphology. The cell of origin of combined HCC-CC has been a matter of dispute. Overall three possibilities may be postulated regarding its cell of origin: (i) collision (double) tumor of HCC and CC that incidentally coexist in the same liver; (ii) subsequent differentiation of HCC or CC into the other component; and (iii) the cancer derives from the hepatic progenitor cells (Fig. 5). The fact that the HCC and CC elements intermingle with each other in a transitional area in most combined HCC-CC makes the first hypothesis less likely. Depending on various investigations, patients with combined HCC-CC share similar clinical and pathological features with patients with HCC4,21 or CC12,15,22 or the tumors are clinicopathologically different from those of CC11 or HCC.

Although a unified criteria for combined HCC-CC is still not available, it is generally accepted that a firm diagnosis of combined HCC-CC requires evidence of HCC differentiation (Fig. 2a), such as trabecular growth

pattern, bile production, or bile canaliculi as well as clear evidence of CC (Fig. 2b), such as true glandular structures formed by biliary-type epithelium, mucin production or prominent desmoplastic stoma.4,14 In addition, ideally, an interface of these two components showing they intermingle intimately with each other should also be appreciated (Fig. 3). Practically, a definitive diagnosis always requires the use of immunohistochemical and special stains to demonstrate Proteasome inhibitor both hepatocytic and biliary phenotypes. Commonly used stains include Hep Par 1 (Fig. 4a), polyclonal NVP-AUY922 nmr carcinoembryonic antigen (Fig. 4b), or CD10 for the hepatocytic differentiation, and mucin (Fig. 4c), CK7, and CK19 (Fig. 4d) stains for the biliary differentiation. Combined HCC-CC often expresses both biliary cytokeratins and markers of HCC, and is an important diagnosis to consider when there is an apparently conflicting or overlapping immunophenotype.15 While fibrolamellar carcinoma, a variant of HCC, very rarely occurs in association with CC, a single case of combined fibrolamellar HCC-CC has been reported previously.16 Studies with a series of combined fibrolamellar HCC-CC

are needed to further characterize this rare neoplasm. Glypican-3 (GPC3) is a novel serological and immunohistochemical marker of hepatocellular carcinoma.17–19 A recent study to examine GPC3 immunoreactivity selleck chemicals in combined HCC-CC shows the expression is sensitive and specific to the HCC component of combined HCC-CC but few cases also show weak immunoreactivity in the cholangiocarcinoma component of combined HCC-CC.20 While the positivity of GPC3 in the cholangiocarcinoma component may be a drawback, this antibody may offer as an additional immunohistochemical stain in diagnosing combined HCC-CC, if used along with

other antibodies and in careful correlation with morphology. The cell of origin of combined HCC-CC has been a matter of dispute. Overall three possibilities may be postulated regarding its cell of origin: (i) collision (double) tumor of HCC and CC that incidentally coexist in the same liver; (ii) subsequent differentiation of HCC or CC into the other component; and (iii) the cancer derives from the hepatic progenitor cells (Fig. 5). The fact that the HCC and CC elements intermingle with each other in a transitional area in most combined HCC-CC makes the first hypothesis less likely. Depending on various investigations, patients with combined HCC-CC share similar clinical and pathological features with patients with HCC4,21 or CC12,15,22 or the tumors are clinicopathologically different from those of CC11 or HCC.

Although a unified criteria for combined HCC-CC is still not available, it is generally accepted that a firm diagnosis of combined HCC-CC requires evidence of HCC differentiation (Fig. 2a), such as trabecular growth

pattern, bile production, or bile canaliculi as well as clear evidence of CC (Fig. 2b), such as true glandular structures formed by biliary-type epithelium, mucin production or prominent desmoplastic stoma.4,14 In addition, ideally, an interface of these two components showing they intermingle intimately with each other should also be appreciated (Fig. 3). Practically, a definitive diagnosis always requires the use of immunohistochemical and special stains to demonstrate JQ1 both hepatocytic and biliary phenotypes. Commonly used stains include Hep Par 1 (Fig. 4a), polyclonal hypoxia-inducible factor pathway carcinoembryonic antigen (Fig. 4b), or CD10 for the hepatocytic differentiation, and mucin (Fig. 4c), CK7, and CK19 (Fig. 4d) stains for the biliary differentiation. Combined HCC-CC often expresses both biliary cytokeratins and markers of HCC, and is an important diagnosis to consider when there is an apparently conflicting or overlapping immunophenotype.15 While fibrolamellar carcinoma, a variant of HCC, very rarely occurs in association with CC, a single case of combined fibrolamellar HCC-CC has been reported previously.16 Studies with a series of combined fibrolamellar HCC-CC

are needed to further characterize this rare neoplasm. Glypican-3 (GPC3) is a novel serological and immunohistochemical marker of hepatocellular carcinoma.17–19 A recent study to examine GPC3 immunoreactivity this website in combined HCC-CC shows the expression is sensitive and specific to the HCC component of combined HCC-CC but few cases also show weak immunoreactivity in the cholangiocarcinoma component of combined HCC-CC.20 While the positivity of GPC3 in the cholangiocarcinoma component may be a drawback, this antibody may offer as an additional immunohistochemical stain in diagnosing combined HCC-CC, if used along with

other antibodies and in careful correlation with morphology. The cell of origin of combined HCC-CC has been a matter of dispute. Overall three possibilities may be postulated regarding its cell of origin: (i) collision (double) tumor of HCC and CC that incidentally coexist in the same liver; (ii) subsequent differentiation of HCC or CC into the other component; and (iii) the cancer derives from the hepatic progenitor cells (Fig. 5). The fact that the HCC and CC elements intermingle with each other in a transitional area in most combined HCC-CC makes the first hypothesis less likely. Depending on various investigations, patients with combined HCC-CC share similar clinical and pathological features with patients with HCC4,21 or CC12,15,22 or the tumors are clinicopathologically different from those of CC11 or HCC.

In the daily course RAD001 order of clinical work, the group felt that a global physician impression usually prevails. Clinicians rely on an empiric global scale based on the parameters articulated by the above statement. On the other hand, formal indexes are usually employed in clinical trial settings. Ulcerative colitis is usually characterized by relapsing

and remitting idiopathic inflammation of the colon and may affect extra intestinal sites. Level of agreement: a-94%, b-6%, c-0%, d-0%, e-0% Quality of evidence: II-2 Classification of recommendation: B All the studies from Asia-Pacific reflect the relapsing remitting nature of UC.57,59–63,73,74 An elegant study from South Korea documented high rates of cumulative relapse after 1, 5, and 10 years Tyrosine Kinase Inhibitor Library at 30%, 72%, and 88%, respectively.57 Extra intestinal sites of involvement

were noted to be within 6–20% in Asia Pacific.60–63,73,74 The group recognized that older retrospective studies may have under-reported these manifestations. The incidence of UC is rising in the Asia-Pacific region, with some exceptions. Level of agreement: a-73%, b-14%, c-13%, d-0%, e-0% Quality of evidence: II-2 Classification of recommendation: B From the available data, UC is increasing in many parts of the Asia Pacific region.58,75–77 Exceptions include Australia and New Zealand where the disease pattern follows the other Caucasian predominant populations in Europe and America.78 There are few epidemiological regional studies and true population based registries are only available in Japan and Korea.58,75,76 The rising trend seen clearly in the Far East may not apply to all Asian countries and all ethnicities. It is also difficult to establish whether any rise in incidence is a true increase and not due to increased awareness and diagnosis. The reason for this apparent increase has not been established but is almost certainly due to environmental factors. The most likely cause is thought to be associated with the

improved economic prosperity in the region and ‘Westernization’ of Asian countries leading to an increase in diseases that are common in the West but previously relatively rare see more in Asia.79–81 The incidence and prevalence of UC is lower in the Asia-Pacific region compared to the West, with some exceptions. Level of agreement: a-87%, b-13%, c-0%, d-0%, e-0% Quality of evidence: II-2 Classification of recommendation: B Available data suggest that overall, the incidence of UC in Asian countries ranges from 0.4 to 2.1 per 100 000 population.58,63,75,77,82 This is in contrast to the incidence rates of 6–15.6 and 10–20.3 per 100 000 in North America and North Europe, respectively.83 Similarly, the prevalence rates appear to be lower in Asia with rates ranging from 6 to 30 per 100 000 population58,63,75,77,82,84,85 compared to 37.5–229 and 21.4–243 per 100 000 population in North America and Europe, respectively.