Liver abscesses after peritoneal venous shunt.

A 70-year-old man was referred to our hospital for high-grade fever with chills. He has visited our hospital for alcoholic liver cirrhosis and diabetes mellitus for over 20 years. Nine months earlier, he had received a peritoneal venous shunt (Denver shunt®) because of refractory ascites. Laboratory examinations revealed elevated C-reactive protein and liver dysfunction. Ultrasonography and abdominal enhanced computed tomography showed multiple small abscesses in the right lobe of the liver. Blood culture test did not detect the pathogenic bacteria of liver abscesses. The patient was treated with antibiotics for more than 2 months and cured from the infection, but 3 months later, he developed high-grade fever again. He had a recurrence of multiple small liver abscesses involving both lobes of the liver. He was treated with antibiotics, and the abscesses disappeared within a month. After the antibiotic treatment, he had selective intestinal decontamination with kanamycin. He has had no recurrence of liver abscess for over a year. To our knowledge, this is the first report of liver abscess in a cirrhotic patient with Denver shunt. Clinicians should bear liver abscess in mind when treating patients with high-grade fever and liver dysfunction following Denver shunt implantation.

Large cell neuroendocrine carcinoma presenting with neck swelling in the submandibular gland: a case report.

INTRODUCTION: Large cell neuroendocrine carcinoma in the salivary glands is rare. We report a second case of large cell neuroendocrine carcinoma of the submandibular gland diagnosed at autopsy, and a review of the literature. CASE PRESENTATION: A 68-year-old Japanese man was referred to our hospital for thorough investigation of swelling on the right side of his neck. Fine-needle aspiration cytology of the cervical mass suggested poorly differentiated metastatic carcinoma. The primary tumor could not be detected by several examinations. One month after admission, he died of cancer. An autopsy was performed, and it revealed a tumor of the right submandibular gland. The histopathological diagnosis was large cell neuroendocrine carcinoma of the submandibular gland. CONCLUSION: To the best of our knowledge, only eight cases of large cell neuroendocrine carcinoma in the salivary glands, including our case, have been reported. This report indicates total biopsy and immunohistochemistry are necessary for diagnosing large cell neuroendocrine carcinoma properly.

The effect of inflammatory cytokines in alcoholic liver disease.

Alcohol is the most common cause of liver disease in the world. Chronic alcohol consumption leads to hepatocellular injury and liver inflammation. Inflammatory cytokines, such as TNF-α and IFN-γ, induce liver injury in the rat model of alcoholic liver disease (ALD). Hepatoprotective cytokines, such as IL-6, and anti-inflammatory cytokines, such as IL-10, are also associated with ALD. IL-6 improves ALD via activation of the signal transducer and activator of transcription 3 (STAT3) and the subsequent induction of a variety of hepatoprotective genes in hepatocytes. IL-10 inhibits alcoholic liver inflammation via activation of STAT3 in Kupffer cells and the subsequent inhibition of liver inflammation. Alcohol consumption promotes liver inflammation by increasing translocation of gut-derived endotoxins to the portal circulation and activating Kupffer cells through the LPS/Toll-like receptor (TLR) 4 pathways. Oxidative stress and microflora products are also associated with ALD. Interactions between pro- and anti-inflammatory cytokines and other cytokines and chemokines are likely to play important roles in the development of ALD. The present study aims to conduct a systemic review of ALD from the aspect of inflammation.

Innate immune reactivity of the ileum-liver axis in nonalcoholic steatohepatitis.

BACKGROUND: Over-proliferation and bacterial translocation of Gram-negative bacilli within the intestinal flora, and increased portal venous levels of endotoxins, are involved in nonalcoholic steatohepatitis (NASH). AIM: To evaluate the innate immune response in the small intestine and liver using the rat NASH model. METHODS: We produced the NASH model by administering a choline-deficient amino acid-defined diet to F344 rats. We analyzed the serum and liver tissue to assess the effects of innate immune reactivity in this NASH model. RESULTS: Significant increases were detected in serum ALT levels and in the portal venous serum and whole-liver levels of TNF-α and IFN-γ in the NASH group. Strong Sirius red staining and TNF-α immune staining were seen in the NASH group, and real-time PCR revealed significantly increased expression of TNF-α and TLR4 mRNA in the NASH group. Higher TNF-α levels were detected in the Kupffer cells isolated culture supernatant in the NASH group than in the control group. Immune staining of the ileal tissue specimens resulted in greater staining of TNF-α, TLR4, and macrophage/dendritic cells, mainly in the submucosa, in the NASH group than in the control group. CONCLUSIONS: In the small intestine and liver of the rat NASH model, the possibility that enhancement of the innate immune response, mediated by the TLR4 signal, led to increased production of TNF-α was suggested. This interaction between the small intestine and liver may be involved in the onset and progression of NASH.

ADAMTS13 activity may predict the cumulative survival of patients with liver cirrhosis in comparison with the Child-Turcotte-Pugh score and the Model for End-Stage Liver Disease score.

AIM: Decreased plasma ADAMTS13 activity (ADAMTS13:AC) results in accumulation of unusually large von Willebrand factor multimers and platelet thrombi formation. Our aim was to evaluate whether ADAMTS13:AC is a prognostic marker in patients with liver cirrhosis. METHODS: Plasma ADAMTS13:AC and its related parameters were examined in 108 cirrhotic patients. RESULTS: ADAMTS13:AC decreased as the severity of liver disease increased (means: controls 100%, Child A-cirrhotics 79%, Child B-cirrhotics 63%, and Child C-cirrhotics 31%). ADAMTS13:AC markedly decreased in the cirrhotics with hepatorenal syndrome, refractory ascites and hepatic encephalopathy. The cumulative survival time was the shortest (median: 4.5 months) in the cirrhotics with severe to moderate ADAMTS13:AC deficiency (<3-25%), followed by those with mild ADAMTS13:AC deficiency (25-50%), and was the longest in those with normal activity (>50%). In contrast, based on the Child-Turcotte-Pugh (CTP) score, Child C-cirrhotics had the worst survival, but the survival probabilities did not differ between Child A and B cirrhotics. Based on the Model for End-Stage Liver Disease (MELD) score, the survival was the worst for the cirrhotics in the fourth quartile, but it was not different among cirrhotics in the first three quartiles. Cox proportional-hazards regression analysis showed that ADAMTS13:AC and serum albumin were independent factors affecting the survival. CONCLUSIONS: ADAMTS13:AC concomitantly decreases as the functional liver capacity decreases. This activity may be a useful prognostic marker that is equal or superior to the CTP score and the MELD score to predict not only the short-term prognosis but also the long-term survival of the cirrhotic patients.

A case of lobulated and pedunculated duodenal hyperplastic polyp treated with snare polypectomy.

We report herein the case of a lobulated and pedunculated hyperplastic polyp in the third portion of the duodenum causing anemia and occult blood in stools, which was detected by capsule endoscopy (CE) and treated with snare polypectomy. A 71-year-old man was referred to our hospital because of anemia and occult blood in stools. Three months earlier, he had been admitted to another hospital because of hemorrhage from gastric antral vascular ectasia (GAVE). Despite being treated for GAVE, hemoglobin decreased gradually. Esophagogastroduodenoscopy (EGD) and colonoscopy revealed no source of bleeding. However, CE revealed a polyp at the distal duodenum. Barium meal and EGD revealed a lobulated and pedunculated polyp in the third portion of the duodenum. The polyp was treated with snare polypectomy. Histopathological examination of the polyp revealed hyperplasia. After treatment of the polyp, the anemia improved gradually. To our knowledge, there are only 6 reported cases of a duodenal hyperplastic polyp, including our case. The polyp was pedunculated in only 2 cases and lobulated only in our case. Moreover, our case was diagnosed by CE. When a patient presents with anemia or obscure gastrointestinal bleeding undiagnosed by EGD and colonoscopy, CE is useful for detecting the bleeding lesion.

Combination treatment of angiotensin II type I receptor blocker and new oral iron chelator attenuates progression of nonalcoholic steatohepatitis in rats.

Angiotensin II type I receptor blocker and iron chelator reportedly exert suppressive effects on nonalcoholic steatohepatitis (NASH) progression, including liver fibrosis and hepatocarcinogenesis. The aim of this study was to elucidate the combined effect of losartan (LOS), an angiotensin II type I receptor blocker, and deferasirox (DSX), a newly developed oral iron chelator, on the progression of NASH in rats. To induce NASH, F344 rats were fed a choline-deficient l-amino acid-defined diet for 12 wk, and the effects of LOS and DSX at clinically comparable low doses were elucidated in conjunction with oxidative stress, neovascularization, and hepatic stellate cells (HSC) activation, all known to play important roles in the progression of NASH. Treatment with both LOS and DSX suppressed choline-deficient L-amino acid-defined diet-induced liver fibrosis development and hepatocarcinogenesis. This combination treatment exerted a stronger inhibitory effect compared with treatment with a single agent. These inhibitory effects occurred almost concurrently with the suppression of oxidative stress, neovascularization, and HSC activation. Our in vitro study demonstrated that LOS and DSX inhibited angiotensin II-induced proliferation, transforming growth factor-ß(1) expression of activated HSC, and in vitro angiogenesis. These results indicated that dual inhibition by combined treatment of LOS and DSX attenuated the progression of NASH. Since both agents are widely used in clinical practice, this combination therapy may represent a potential new strategy against NASH in the near future.

Therapeutic effects of cytokine modulator Y-40138 in the rat alcoholic liver disease model.

BACKGROUND AND AIM: Inflammatory cytokines, such as tumor necrosis factor-α (TNF-α) and interferon-gamma (IFN-γ), induce liver injury in the rat alcoholic liver disease (ALD) model. Y-40138 is known to suppress the pro-inflammatory cytokines and augment the anti-inflammatory cytokines. We investigated whether or not Y-40138 may be effective as a novel immunotherapy in the rat ALD model. METHODS: Male Wistar rats were fed Lieber-DeCarli ethanol liquid diet. The effects of Y-40138 treatment in the ALD models were assessed by analyzing the serum and the liver tissues. RESULTS: The serum levels of alanine aminotransferase (ALT), TNF-α, and IFN-γ, and the liver levels of TNF-α and IFN-γ were significantly higher in the ethanol-fed group than in the pair-fed group. The immunohistochemistry of the liver TNF-α and 4-hydroxynonenal (4HNE), and the expressions of TNF-α and IFN-γ mRNA were increased, too. The gene expressions of interleukin-10 (IL-10) in the ethanol-fed group were suppressed as compared with the pair-fed group. The serum triglyceride (TG) and liver TG were increased, and Oil Red O and α-smooth muscle actin (α-SMA) staining showed greater expression by ethanol-fed feeding. After administration of Y-40138, enzyme linked immunosorbent assay and real-time polymerase chain reaction of the liver showed that the increased TNF-α and IFN-γ were suppressed, and that IL-10 was augmented. Moreover, ethanol-induced lipid accumulation in the liver was suppressed by administering Y-40138. CONCLUSIONS: Y-40138 decreased the inflammation, fibrosis, oxidative stress, and lipid synthesis, and augmented the anti-inflammatory cytokines of the liver. These results indicate that the multiple cytokine production modulator, Y-40138, is a promising novel therapy for ALD.

Secondary aortoduodenal fistula identified by ultrasonography.

A 73-year-old man underwent coronary artery bypass grafting, abdominal aortic aneurysm resection, and prosthetic implantation as a single procedure in 2002. His progress was favorable until April 2008, when he was admitted to our hospital with melena. B-mode ultrasonography revealed a 5-mm defect in the abdominal aorta at the graft anastomosis, and an umbilicated lesion was seen projecting between the posterior wall of the third part of the duodenum and the abdominal aorta. A color signal was noticed at this site on color Doppler ultrasonography, leading to the diagnosis of a secondary aortoduodenal fistula (ADF). We resected the inflammatory mass comprising the graft and the third part of the duodenum, and performed prosthetic re-implantation, omentopexy, and duodenojejunostomy. We could not find any previous reports of successful identification of secondary ADF using ultrasonography. When a patient with gastrointestinal hemorrhage following reconstructive aortic surgery is encountered in the emergency department, ultrasonography may be considered to be a useful modality in the diagnosis of secondary ADF.

Soluble VEGF receptor-2 may be a predictive marker of anti-angiogenic therapy with clinically available safe agents.

The identification of biomarkers of anti-angiogenic therapy that predict clinical benefit is of vital importance. We previously reported that a combination treatment with clinically available safe agents, specifically angiotensin-converting enzyme inhibitor (ACE-I) and vitamin K (VK), inhibited the cumulative recurrence of hepatocellular carcinoma (HCC) via suppression of the vascular endothelial growth factor (VEGF). The present study aimed to identify non-invasive biological markers that predict the clinically beneficial effect of this combination regimen. A combination of ACE-I (perindopril; 4 mg/day) and VK (menatetrenone; 45 mg/day) was administered for 54 months following curative therapy for HCC. The cumulative recurrence and several indices, which are reportedly considered as biological markers of anti-angiogenic therapies, were analyzed. The combined treatment of ACE-I and VK markedly inhibited the cumulative recurrence of HCC during the 54-month follow-up. The serum VEGF and soluble VEGF receptor (sVEGFR)-2 were significantly suppressed with this combination regimen, whereas sVEGFR-1 was not. In HCC patients without recurrence, a significant suppression of VEGF and sVEGFR-2 was achieved within 6 and 3 months after treatment, respectively. In conclusion, the combination treatment of ACE-I and VK is a potentially novel anti-angiogenic strategy for secondary chemoprevention against HCC since the two agents are widely used in clinical practice without serious side effects. Furthermore, sVEGFR-2 may become a useful clinical predictive marker of this combination treatment.

Pseudomembranous colitis complicating ulcerative colitis.

Clostridium difficile toxin (CD toxin) causes antibiotic-associated colitis, or pseudomembranous colitis (PMC). Although CD toxin is sometimes found in the stools of patients with ulcerative colitis (UC), UC is rarely complicated by PMC. We report herein a case of PMC complicating UC, and present a review of the literature. A 71-year-old woman was diagnosed as having UC of the left colon, and treated with prednisolone and mesalazine. Later, however, lumbar spinal stenosis was also detected. After surgery for lumbar spinal stenosis, she suffered postoperative infection of the lumbar region. After 3-week treatment with antibiotics, she developed diarrhea, bloody stools, and abdominal pain. Colonoscopy revealed PMC of the cecum, ascending colon, sigmoid colon, and rectum. Stools were positive for CD toxin. As cefotiam hydrochloride, levofloxacin hydrate (LVFX), and prednisolone were suspected as the causative agents, she was treated with 1.5 g vancomycin (VCM) daily for 2 weeks without ceasing LVFX. Her symptoms improved, and colonoscopy confirmed resolution of PMC. The possibility of PMC should be considered in UC patients treated with antibiotics, immunosuppressive agents or corticosteroids who complain of gastrointestinal symptoms. These patients should be thoroughly investigated by several modalities, including colonoscopy and CD toxin testing.

The vascular endothelial growth factor (VEGF) receptor-2 is a major regulator of VEGF-mediated salvage effect in murine acute hepatic failure.

Although administration of the vascular endothelial growth factor (VEGF), a potent angiogenic factor, could improve the overall survival of destroyed sinusoidal endothelial cells (SEC) in chemically induced murine acute hepatic failure (AHF), the mechanistic roles of the VEGF receptors have not been elucidated yet. The respective roles of VEGF receptors; namely, Flt-1 (VEGFR-1: R1) and KDR/Flk-1 (VEGFR-2: R2), in the D-galactosamine (Gal-N) and lipopolysaccharide (LPS)-induced AHF were elucidated with specific neutralizing monoclonal antibody against R1 and R2 (R1-mAb and R2-mAb, respectively). The serum ALT elevation, with a peak at 24 h after Gal-N+LPS intoxication, was markedly augmented by means of the R1-mAb and R2-mAb. The aggregative effect of R2-mAb was more potent than that of R1-mAb, and the survival rate was 70% in the R2-mAb-treated group and 100% in the other groups. The results of SEC destruction were almost parallel to those of the ALT changes. Our in-vitro study showed that R1-mAb and R2-mAb significantly worsened the Gal-N+LPS-induced cytotoxicity and apoptosis of SEC mediated by caspase-3, which were almost of similar magnitude to those in the in-vivo study. In conclusion, these results indicated that R2 is a major regulator of the salvage effect of VEGF on the maintenance of SEC architecture and the anti-apoptotic effects against chemically-induced murine AHF.

Pneumatosis cystoides intestinalis induced by the α-glucosidase inhibitor miglitol.

Pneumatosis cystoides intestinalis (PCI) is a rare condition in which pneumocysts develop in the submucosa or subserosa of the colon. We report herein a case of PCI induced by the alpha-glucosidase inhibitor (alphaGI) miglitol. There have been 9 recorded cases of PCI induced by other alphaGIs, but this is the first report of miglitol causing PCI. The PCI lesions in our case were smaller than those induced by voglibose or acarbose. The possibility of PCI should be considered in diabetic patients on alphaGI therapy who complain of gastrointestinal symptoms, and the gastrointestinal tract should be thoroughly investigated in these patients.

Selective aldosterone blocker ameliorates the progression of non-alcoholic steatohepatitis in rats.

Although non-alcoholic steatohepatitis (NASH) may progress to cirrhosis and hepatocellular carcinoma (HCC), no effective therapeutic modalities have been fully established yet. Recent studies have shown that the renin-angiotensin-aldosterone-system plays an important role in NASH. The aim of our current study was to elucidate the effects of aldosterone (Ald) inhibition on the progression of NASH. In the choline-deficient L-amino acid-defined diet-induced rat NASH model, the effects of a clinically used selective Ald blocker (SAB) were elucidated in conjunction with the activated hepatic stellate cells (HSC) and neovascularization, which are both known to play important roles in liver fibrosis development and hepatocarcinogenesis, respectively. Liver fibrosis development and the glutathione-S-transferase placental form-positive pre-neoplastic lesions were both markedly attenuated by SAB along with the suppression of the activated HSC and neovascularization. SAB inhibited the hepatic expression of transforming growth factor-beta 1 and also that of the vascular endothelial growth factor. Our in vitro study showed that SAB also inhibited the Ald-induced HSC proliferation and in vitro angiogenesis in a dose-dependent manner. These results indicated that Ald plays a pivotal role in the progression of NASH. Considering that SAB is already widely used in clinical practice, this drug could represent a potential new strategy against NASH in the future.

Salvage effect of E5564, Toll-like receptor 4 antagonist on d-galactosamine and lipopolysaccharide-induced acute liver failure in rats.

BACKGROUND AND AIMS: The transmembrane protein Toll-like receptor 4 (TLR4), which exists mainly in macrophages such as Kupffer cells of the liver, plays an important role in recognizing and mediating macrophage activation and pro-inflammatory cytokine release. Activation of the pro-inflammatory cytokine cascade, including tumor necrosis factor-alpha (TNF-alpha), has a pivotal role in the progression of severe liver injury. D-galactosamine (GalN) and lipopolysaccharide (LPS)-induced liver injury in rats is an experimental model of fulminant hepatic failure, where TNF-alpha plays a central role in the progression of liver injury. E5564, a synthetic analogue of the lipid A component of endotoxin, inhibits endotoxin-stimulated inflammation and is under study for patients with sepsis. In the present study, we sought to explore the salvage effect of TLR4 antagonist E5564 on GalN+LPS-induced acute liver failure (ALF) in rats. METHODS: ALF was induced in male Wistar rats by the intraperitoneal injection of GalN (500 mg/kg) and LPS (50 microg/kg). Immediately after GalN+LPS injection, rats were treated with intravenous injection of E5564 (3 mg/kg). The cumulative survival rates of GalN+LPS-induced ALF rats were compared between those with and without E5564 treatment. RESULTS: The intravenous injection of E5564 reduced the elevation of serum total bilirubin, aspartate aminotransferase, alanine aminotransferase and TNF-alpha levels in rats at 3 h after GalN+LPS injection, and improved the survival rate of GalN+LPS-induced ALF rats at 24 h (8% vs 43%). CONCLUSIONS: TLR4 antagonist E5564 reduced GalN+LPS-induced acute liver injury in rats and improved the overall survival rate of GalN+LPS-induced ALF rats. It may contribute to the treatment of ALF through blocking endotoxin-induced TNF-alpha overproduction of macrophages.

Selective aldosterone blocker, eplerenone, attenuates hepatocellular carcinoma growth and angiogenesis in mice.

AIM: The renin-angiotensin-aldosterone system (RAAS) has become known as a prerequisite for tumor angiogenesis, including hepatocellular carcinoma (HCC). Although angiotensin II is known to play an important role in tumor growth and angiogenesis, the role of aldosterone (Ald) is still obscure. The aim of our current study was to elucidate the effect of eplerenone, a clinically used selective Ald blocker (SAB), on murine HCC development especially in conjunction with angiogenesis. METHODS: To create an allograft model, we injected 1 x 10(6) of BNL-HCC cells into the flanks of BALB/c mice. After the tumor was established, SAB was administrated at dose of 100 mg/kg per day. RESULTS: Administration of SAB significantly suppressed HCC development along with inhibition of angiogenesis and expression of the vascular endothelial growth factor (VEGF), a potent angiogenic factor. SAB treatment resulted in a marked increase of apoptosis in the tumor, whereas tumor cell proliferation was not altered. Our in vitro study showed that SAB significantly suppressed the Ald-induced endothelial proliferation and tubular formation through inhibition of phosphorylation of the extracellular signal-regulated kinase 1/2. On the contrary, neither Ald nor SAB affected the proliferation of HCC cells in vitro. CONCLUSION: Ald plays a pivotal role in HCC development through VEGF-mediated tumor angiogenesis, and SAB may be a potential new strategy in HCC therapy in the future.

Attenuation of insulin-resistance-based hepatocarcinogenesis and angiogenesis by combined treatment with branched-chain amino acids and angiotensin-converting enzyme inhibitor in obese diabetic rats.

BACKGROUND: Insulin resistance (IR) is reportedly involved in the progression of hepatocellular carcinoma (HCC). Because neovascularization plays an important role in HCC, including hepatocarcinogenesis, an angiostatic therapy would be a promising approach for chemoprevention against HCC. The aim of the present study was to examine the combined effect of clinically used branched-chain amino acids (BCAAs) and an angiotensin-converting enzyme inhibitor (ACE-I), in conjunction with neovascularization, on hepatocarcinogenesis under the condition of IR. METHODS: The combined effect of the treatment on the development of liver enzyme-altered preneoplastic lesions, angiogenesis, and several indices was elucidated in obese diabetic rats. We also performed several sets of in vitro experiments to examine the mechanisms involved. RESULTS: When used individually, both BCAAs and ACE-I at clinically comparable low doses significantly attenuated the development of preneoplastic lesions, along with the suppression of both angiogenesis and vascular endothelial growth factor (VEGF) expression. The combination treatment with both agents exerted a more potent inhibitory effect than that of either single agent. Our in vitro study showed a similar combined effect on endothelial cell tubule formation. CONCLUSION: This combination regimen showed a marked chemopreventive effect against hepatocarcinogenesis, along with suppression of neovascularization and VEGF expression, in obese diabetic rats. Because both BCAAs and ACE-Is are widely used in clinical practice, this combination therapy may represent a potential new strategy for chemoprevention against IR-based HCC in the future.

Potential role of enhanced cytokinemia and plasma inhibitor on the decreased activity of plasma ADAMTS13 in patients with alcoholic hepatitis: relationship to endotoxemia.

BACKGROUND: Deficiency of ADAMTS13 (adisintegrin-like and metalloproteinase with thrombospondin type-1 motifs 13) results in an increase in unusually large von Willebrand factor multimer (UL-VWFM) of the plasma and finally causes microcirculatory disturbance. Our previous study demonstrated that the imbalance of increased UL-VWFM over decreased ADAMTS13 activity may contribute to the development of multiorgan failure in patients with alcoholic hepatitis (AH). The aim of this study was to explore the potential mechanism to reduce the activity of plasma ADAMTS13. METHODS: Plasma cytokine levels including interleukin (IL)-6, IL-8, and tumor necrosis factor-alpha (TNF-alpha), plasma endotoxin concentration, and the plasma inhibitor against ADAMTS13 were determined together with ADAMTS13 activity, VWF antigen (VWF:Ag), and UL-VWFM in 24 patients with AH and 5 patients with severe alcoholic hepatitis (SAH). RESULTS: The concentrations of IL-6, IL-8, and TNF-alpha on admission were significantly higher in patients with SAH than in those with AH and controls. The ADAMTS13 activity concomitantly decreased, and the VWF:Ag progressively elevated with increasing concentrations of these cytokines from normal range to over 100 pg/ml. Plasma endotoxin concentration was markedly higher in patients with SAH (mean 52.3 pg/ml) and AH (21.7 pg/ml) than in controls (7.9 pg/ml). The endotoxin concentration inversely correlated with ADAMTS13 activity and was higher in patients with UL-VWFM than those without. The inhibitor was detected in 4 patients with SAH (0.9 to 2.1 BU/ml) and 6 patients with AH (0.5 to 1.6 BU/ml). Patients with the inhibitor showed lower functional liver capacity, higher endotoxin concentration, and marked inflammatory signs than those without. At the recovery stage, the ADAMTS13 activity increased to normal range, the VWF:Ag decreased, and the UL-VWFM disappeared with the decrease in the concentrations of cytokines and endotoxin, and the disappearance of the inhibitor. CONCLUSION: Decreased ADAMTS13 activity and increased VWF:Ag could be induced not only by pro-inflammatory cytokinemia, but also by its inhibitor, both of which may be closely related to enhanced endotoxemia in patients with AH and SAH.

Crosstalk between angiogenesis, cytokeratin-18, and insulin resistance in the progression of non-alcoholic steatohepatitis.

AIM: To elucidate the possible crosstalk between angiogenesis, cytokeratin-18 (CK-18), and insulin resistance (IR) especially in patients with non-alcoholic steatohepatitis (NASH). METHODS: Twenty-eight patients with NASH and 11 with simple fatty liver disease (FL) were enrolled in this study and underwent clinicopathological examination. The measures of angiogenesis, CK-18, and IR employed were CD34-immunopositive vessels, CK-18-immunopositive cells, and homeostasis model assessment of IR (HOMA-IR), respectively. The correlations of these factors with NASH were elucidated. RESULTS: Significant development of hepatic neovascularization was observed only in NASH, whereas almost no neovascularization could be observed in FL and healthy liver. The degree of angiogenesis was almost parallel to liver fibrosis development, and both parameters were positively correlated. Similarly, CK-18 expression and HOMA-R were significantly increased in NASH as compared with FL and healthy liver. Furthermore, CK-18 and HOMA-IR were also positively correlated with the degree of neovascularization. CONCLUSION: These results indicate that the crosstalk between angiogenesis, CK-18, and IR may play an important role in the onset and progression of NASH.

Immunotherapy for nonalcoholic steatohepatitis using the multiple cytokine production modulator Y-40138.

AIM: To investigate the possible use of the multiple cytokine production modulator, Y-40138, as a novel immunotherapy in the rat nonalcoholic steatohepatitis (NASH) model. METHODS: We allocated 6-wk-old male F344 rats to choline-supplemented, L-amino acid-defined (CSAA) diet (control group), CSAA diet + Y-40138 (control + Y-40138 group), choline-deficient, L-amino acid-defined (CDAA) diet (NASH group), or CDAA diet + Y-40138 (NASH + Y-40138 group). In each group, we measured the plasma alanine aminotransferase (ALT) levels, and the plasma and liver levels of tumor necrosis factor-alpha (TNF-alpha), interferon-gamma (IFN-gamma), and interleukin-10 (IL-10). Tissue specimens of phosphate buffered saline-perfused liver were subjected to hematoxylin and eosin staining, Azan staining, Sirius red staining, and immunohistochemical staining (for Kupffer cells and TNF-alpha). We then extracted Kupffer cells from the collagenase-perfused livers using the Percoll gradient centrifugation method, and measured the TNF-alpha levels in the supernatant (in vitro TNF-alpha production by Kupffer cells) using an enzyme-linked immunosorbent assay kit. RESULTS: In comparison to the NASH group, serum ALT elevation was mild, production of serum and liver TNF-alpha and IFN-gamma was inhibited, and IL-10 production was increased in the NASH + Y-40138 group. Amelioration of liver histology was also noted in the NASH + Y-40138 group. Kupffer cell immunohistochemical staining revealed no differences between groups, whereas TNF-alpha immunohistochemical staining showed fewer stained cells in the NASH + Y-40138 group than in the NASH group. The TNF-alpha levels in the in-vitro Kupffer cell culture supernatant were lower in the NASH + Y-40138 group than in the NASH group. CONCLUSION: Administration of Y-40138 to NASH model rats reduced hepatic inflammation and suppressed fibrosis. These results indicate that the multiple cytokine production modulator, Y-40138, is promising as a novel treatment for NASH.