Gut-liver axis in liver cirrhosis: How to manage leaky gut and endotoxemia

A "leaky gut" may be the cutting edge for the passage of toxins, antigens or bacteria into the body, and may play a pathogenic role in advanced liver cirrhosis and its complications. Plasma endotoxin levels have been admitted as a surrogate marker of bacterial translocation and close relations of endotoxemia to hyperdynamic circulation, portal hypertension, renal, cardiac, pulmonary and coagulation disturbances have been reported. Bacterial overgrowth, increased intestinal permeability, failure to inactivate endotoxin,activated innate immunity are all likely to play a role in the pathological states of bacterial translocation. Therapeutic approach by management of the gut-liver axis by antibiotics, probiotics, synbiotics, prebiotics and their combinations may improve the clinical course of cirrhotic patients. Special concern should be paid on anti-endotoxin treatment. Adequate management of the gut-liver axis may be effective for prevention of liver cirrhosis itself by inhibiting the progression of fibrosis.

Pneumatosis cystoides intestinalis following alpha-glucosidase inhibitor treatment:A case report and review of the literature

A 69-year-old man was diagnosed as having myasthenia gravis (MG) in September 2004,and treated with thymectomy and prednisolone. He was then diagnosed as having steroid-induced diabetes mellitus,and received sulfonylurea (SU) therapy in May 2005. An alpha-glucosidase inhibitor (αGI) was added in March 2006,resulting in good glycemic control. He experienced symptoms of abdominal distention,increased flatus,and constipation in October 2007,and was admitted into our hospital in late November with hematochezia. Plain abdominal radiography revealed small linear radiolucent clusters in the wall of the colon. Computed tomography (CT) showed intramural air in the sigmoid colon. Colonoscopy revealed multiple smooth surfaced hemispherical protrusions in the sigmoid colon. The diagnosis of pneumatosis cystoides intestinalis (PCI) was made on the basis of these findings. As the αGI voglibose was suspected as the cause of this patient's PCI,treatment was conservative,ceasing voglibose,with fasting and fluid supplementation. The patient progressed well,and was discharged 2 wk later. Recently,several reports of PCI associated with αGI therapy have been published,predominantly in Japan where αGIs are commonly used. If the use of αGIs becomes more widespread,we can expect more reports of this condition on a global scale. The possibility of PCI should be considered in diabetic patients complaining of gastrointestinal symptoms,and the gastrointestinal tract should be thoroughly investigated in these patients.

Differentiation of embryonic stem cells into insulin-producing cells promoted by Nkx2.2 gene transfer

AIM： To investigate the ability of a genetically altered embryonic stem （ES） cell line to generate insulin-producing cells in vitro following transfer of the Nkx2.2 gene.METHODS： Hamster Nkx2.2 genes were transferred into mouse ES cells. Parental and Nkx2.2-transfected ES cells were initiated toward differentiation in embryoid body （EB） culture for 5 d and the resulting EBs were transferred to an attached culture system. Dithizone （DTZ）, a zincchelating agent known to selectively stain pancreatic beta cells, was used to detect insulin-producing cells.The outgrowths were incubated in DTZ solution （final concentration, 100μg/mL） for 15 rain before being examined microscopically. Gene expression of the endocrine pancreatic markers was also analyzed by RT-PCR. In addition, insulin production was determined immunohistochemically and its secretion was examined using an ELISA.RESULTS： DTZ-stained cellular clusters appeared after approximately 14 d in the culture of Nkx2.2-transfected ES cells （Nkx-ES cells）, which was as much as 2 wk earlier, than those in the culture of parental ES cells （wt-ES）. The frequency of DTZ-positive cells among total cultured cells on day 28 accounted for approximately 1.0% and 0.1% of the Nkx-ES- and wt-ES-derived EB outgrowths, respectively. The DTZ-positive cellular clusters were found to be immunoreactive to insulin, while the gene expressions of pancreatic-duodenal homeobox 1 （PDX1）, proinsulin 1 and proinsulin 2 were observed in the cultures that contained DTZ-positive cellular clusters.Insulin secretion was also confirmed by ELISA, whereas glucose-dependent secretion was not demonstrated.CONCLUSION： Nkx2.2-transfected ES cells showed an ability to differentiate into insulin-producing cells.

Decreased phagocytic activity of Kupffer cells in a rat nonalcoholic steatohepatitis model

AIM: To investigate Kupffer cell dynamics and phagocytic activity,using a rat nonalcoholic steatohepatitis (NASH) model. METHODS: Male F344 rats were fed either a control diet or a choline-deficient L-amino acid-defined (CDAA) diet,followed by contrast enhanced ultrasonography (CEUS) using Levovist. The uptake of latex beads by the Kupffer cells was determined by fluorescent microscopy. The status of the Kupffer cells was compared between the two groups,using the immunohistochemical staining technique. RESULTS: After 4 or more wk of the CDAA diet,CEUS examination revealed a decrease in the signal intensity,20 min after intravenous Levovist. Fluorescent microscopic examination showed that the uptake of latex beads by the Kupffer cells was reduced at week 1 and 2 in the study group,compared with the controls,with no further reduction after 3 wk. Immunohistochemical staining revealed no significant difference in the Kupffer cell counts between the control group and the CDAA group. CONCLUSION: CEUS examination using Levovist demonstrated reduced contrast effect and phagocytic activity in the liver parenchymal phase,although the Kupffer cell numbers were unchanged,indicating reduced phagocytic function of the Kupffer cells in the rat NASH model. We believe that CEUS examination using Levovist is a useful screening modality,which can detect NASH in fatty liver patients.

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-18immunopositive 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-18expression and HOMA-R were signifi cantly 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.

Promoted differentiation of cynomolgus monkey ES cells into hepatocyte-like cells by co-culture with mouse fetal liver-derived cells

AIM: To explore whether a co-culture of cynomolgus monkey embryonic stem (cES) cells with embryonic liver cells could promote their differentiation into hepatocytes. METHODS: Mouse fetal liver-derived cells (MFLCs) were prepared as adherent cells from mouse embryos on embryonic d (ED) 14, after which undifferentiated cES cells were co-cultured with MFLCs. The induction of cES cells along a hepatic lineage was examined in MFLC- assisted differentiation, spontaneous differentiation, and growth factors (GF) and chemicals-induced differentiations (GF-induced differentiation) using retinoic acid, leukemia inhibitory factor (LIF), FGF2, FGF4, hepatocyte growth factor (HGF), oncostatin M (OSM), and dexamethasone. RESULTS: The mRNA expression of α-fetoprotein, albumin (ALB), α-1-antitrypsin, and hepatocyte nuclear factor 4α was observed earlier in the differentiating cES cells co-cultured with MFLCs, as compared to cES cells undergoing spontaneous differentiation and those subjected to GF-induced differentiation. The expression of cytochrome P450 7a1, a possible marker for embryonic endoderm-derived mature hepatocytes, was only observed in cES cells that had differentiated in a co-culture with MFLCs. Further, the disappearance of Oct3/4, a representative marker of an undifferentiated state, was noted in cells co-cultured with MFLCs, but not in those undergoing spontaneous or GF-induced differentiation. Immunocytochemical analysis revealed an increased ratio of ALB-immunopositive cells among cES cells co-cultured with MFLCs, while glycogen storageand urea synthesis were also demonstrated. CONCLUSION: MFLCs showed an ability to induce cES cells to differentiate toward hepatocytes. The co-culture system with MFLCs is a useful method for induction of hepatocyte-like cells from undifferentiated cES cells.

Do vasopressin V2 receptor antagonists benefit cirrhotics with refractory ascites?

Hyponatremia is a frequent complication of advanced cirrhosis with ascites associated with increased morbidity and mortality. It is caused by an impairment in the renal capacity to eliminate solute-free water and is considered to be related to persistent secretionof vasopressin despite low serum osmolality. This nonosmotic release of vasopressin is mediated by the autonomic nervous system, which senses the underfilling of arterial vascular component. This reduction of effective arterial blood volume is closely related to the development of ascites. Although the short-time effects of vasopressin V2 receptor antagonists(vaptans) on hyponatremia and ascites have been repeatedly reported, their effects on the long-term management of cirrhotic ascites have not been established yet. Considering that their effects on water diuresis and their safety are limited by severe underfilling state of patients, cautious approaches with adequate monitoring are needed to advanced cirrhosis. Proper indication, adequate doses and new possibility of combination therapy should be explored in the future controlled study. As hyponatremia is frequent obstacle to ascites management, judicious combination with low-dose diuretics may decrease the incidence of refractory ascites. Although vaptans show much promise in the treatment of advanced cirrhosis, the problem of high cost should be solved for the future.

Innate immune reactivity of the liver in rats fed a choline-deficient L-amino-acid-defined diet

AIM： To investigate the innate immune reactivity of tumor necrosis factor-alpha （TNF-α）, Toll-like receptor 4 （TLR4）, and CD14 in the liver of non-alcoholic steatohepatitis （NASH） model rats. METHODS： Male F344 rats were fed a cholinedeficient L-amino-acid-defined （CDAA） diet. The rats were killed after 4 or 8 wk of the diet, and their livers were removed for immunohistochemical investigation and RNA extraction. The liver specimens were immunostained for TNF-α, TLR4, and CD14. The gene expressions of TNF-α, TLR4, and CD14 were determined by reverse-transcriptase polymerase chain reaction （RT-PCR）. Kupffer cells were isolated from the liver by Percoll gradient centrifugation, and were then cultured to measure TNF-α production. RESULTS： The serum and liver levels of TNF-~ in the CDAA-fed rats increased significantly as compared with the control group, as did the immunohistochemical values and gene expressions of TNF-α, TLR4, and CD14 with the progression of steatohepatitis. TNF-α production from the isolated Kupffer cells of the CDAAfed rats was elevated by lipopolysaccharide stimulation. CONCLUSION： The expressions of TNF-α, TLR4, and CD14 increased in the NASH model, suggesting that

Combined treatment of vitamin K_2 and angiotensin-converting enzyme inhibitor ameliorates hepatic dysplastic nodule in a patient with liver cirrhosis

Although it is well known that the hepatocellular carcinoma (HCC) is an ominous complication in patients with liver cirrhosis, there has been no approved drug to prevent the development of HCC to date. We previously reported that the combined treatment of vitamin K2 (VK) and angiotensin-converting enzyme inhibitor (ACE-I) significantly suppressed the experimental hepatocarcinogenesis. A 66-year-old Japanese woman with hepatitis C virus (HCV)-related liver cirrhosis developed a dysplastic nodule in the liver detected by enhanced computed tomography along with elevation of the tumor markers, namely, alpha-fetoprotein (AFP) and lectin-reactive demarcation (AFP-L3), suggesting the presence of latent HCC. After oral administration of VK and ACE-I, the serum levels of both AFP and AFP-L3 gradually decreased without any marked alteration of the serum aminotransferase activity. After one-year treatment, not only the serum levels of AFP and AFP-L3 returned to the normal ranges, but also the dysplastic nodule disappeared. Since both VK and ACE-I are widely used without serious side effects, this combined regimen may become a new strategy for chemoprevention against HCC.

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-def icient,L-amino acid-def ined (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-α (TNF-α),interferon-γ (IFN-γ),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-α). We then extracted Kupffer cells from the collagenase-perfused livers using the Percoll gradient centrifugation method,and measured the TNF-α levels in the supernatant (in vitro TNF-α production by Kupffer cells) using an enzyme-linked immunosorbent assay kit.RESULTS:In comparison to the NASH group,serumALT elevation was mild,production of serum and liver TNF-α and IFN-γ 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-α immunohistochemical staining showed fewer stained cells in the NASH + Y-40138 group than in the NASH group. The TNF-α 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.

Embryonic stem cells develop into hepatocytes after intrasplenic transplantation in CCl_4-treated mice

AIM： To transplant undifferentiated embryonic stem （ES） cells into the spleens of carbon tetrachloride （CCl4）-treated mice to determine their ability to differentiate into hepatocytes in the liver. METHODS： CCh, 0.5 mL/kg body weight, was injected into the peritoneum of C57BL/6 mice twice a week for 5 wk. In group 1 （n = 12）, 1 × 10^5 undifferentiated ES cells （0.1 mL of 1 × 10^6/mL solution）, genetically labeled with GFP, were transplanted into the spleens 1 d after the second injection. Group 2 mice （n = 12） were injected with 0.2 mL of saline twice a week, instead of CCh, and the same amount of ES cells was transplanted into the spleens. Group 3 mice （n = 6） were treated with CCh and injected with 0.1 mL of saline into the spleen, instead of ES cells. Histochemical analyses of the livers were performed on post-transplantation d （PD） 10, 20, and 30. RESULTS： Considerable numbers of GFP-immunopositive cells were found in the periportal regions in group 1 mice （CCh-treated） on PD 10, however, not in those untreated with CCh （group 2）. The GFP-positive cells were also immunopositive for albumin （ALB）, alpha-1 antitrypsin, cytokeratin 18, and hepatocyte nuclear factor 4 alpha on PD 20. Interestingly, most of the GFP-positive cells were immunopositive for DLK, a hepatoblast marker, on PD 10. Although very few ES-derived cells were demonstrated immunohistologically in the livers of group 1 mice on PD 30, improvements in liver fibrosis were observed. Unexpectedly, liver tumor formation was not observed in any of the mice that received ES cell transplantation during the experimental period CONCLUSION： Undifferentiated ES cells developed into hepatocyte-like cells with appropriate integration into tissue, without uncontrolled cell growth.

Cryptogenic cirrhosis in the region where obesity is not prevalent

AIM： Recent studies have demonstrated that obesity is the common feature of cryptogenic cirrhosis （CC） and non-alcoholic steatohepatitis. However, there is little information on CC in the region where obesity is not prevalent, METHODS： The clinical features, and the liver-related morbidity and mortality of CC were analyzed in Japan where the prevalence of obesity is low. Among 652 cirrhotic patients, we identified 29 patients （4.4%） with CC. Of these, 24 CC patients who were followed up for more than 6 months were compared in a case-control study with age-, sex-, and Child-Pugh score-matched controls having cirrhosis of viral etiology. RESULTS： Obesity （BMI≥25 kg/m^2）, diabetes mellitus, and hypertriglyceridemia were more frequent, and the visceral fat area was larger in the CC patients than in the controls. The indices of insulin resistance were higher and the serum aminotransferase levels were lower in the CC patients than in the controls. Logistic regression analysis identified the elevated hemoglobin A1c, BMI ≥ 25 kg/m^2, and normal aminotransferase levels as independent predictors of CC. Kaplan-Meier analysis demonstrated lower occurrence of hepatocellular carcinoma and higher survival rate in the CC than in the controls in contrast to the similar cumulatlve probability of liverrelated morbidity between those groups.CONCLUSION： CC more frequently presents with the clinical features suggestive of non-alcoholic steatohepatitis compared with controls even in the region where obesity is not prevalent. The lower occurrence of hepatocellular carcinoma and higher survival rate may indicate an indolent clinical course in CC as compared with viral cirrhosis.

Eosinophilic cholecystitis along with pericarditis caused by Ascaris lumbricoides: A case report

Although the etiology of eosinophilic cholecystitis is still obscure, the postulated causes include allergies, parasites, hypereosinophilic syndrome, and eosinophilic gastroenteritis. It is sometimes accompanied by several complications, but a simultaneous onset with pericarditis is very rares. A 28-year-old woman complained of acute right hypocondrial pain and dyspnea associated with systemic eruption. Several imaging modalities revealed acute cholecystitis and pericarditis with massive pericardial effusion. A marked peripheral blood eosinophilia was observed, and the eruption was diagnosed as urticaria. Her serum had a high titer of antibody against Ascaris lumbricoides . Treatment with albendazole drastically improved all clinical manifestations along with normalization of the imaging features and eosinophilia. We report herein a rare case of simultaneous onset of acute cholecystitis and pericarditis associated with a marked eosinophilia caused by parasitic infection.

Local regulator adrenomedullin contributes to the circulatory disturbance in cirrhotic rats

AIM： To investigate whether adrenomedullin, a potent vasodilator peptide, plays a role in the circulatory disturbance in cirrhosis. METHODS： Cirrhosis was induced in rats by weekly gavage of carbon tetrachloride. Hemodynamic studies were performed in vivo using radioactive microspheres and in vitro using isolated aortic rings. The adrenomedullin concentrations were measured by radioimmunoassay. RESULTS： Acute administration of adrenomedullin to the control rats reduced the systemic arterial pressure along with an increase of serum levels of the stable metabolite of nitric oxide （NOx）, in a dose-dependent manner. Chronic infusion of adrenomedullin reduced the vascular resistance and increased the blood flow in the systemic and splanchnic circulation. Intravenous administration of anti-adrenomedullin antibody did not affect any hemodynamic parameters in the cirrhotic rats, whereas this antibody ameliorated the blunted contractile response to phenylephrine, o-adrenergic receptor agonist, in the aortic rings of the cirrhotic rats. The adrenomedullin concentrations in the aorta were higher in the cirrhotic rats than in the controls, and correlated with the mean arterial pressure in the cirrhotic rats. Moreover, adrenomedullin blunted the contractile response to phenylephrine in both of the control aorta and cirrhotic aorta, but not in the presence of NG-nitro L-arginine methyl ester, an NO synthase inhibitor. CONCLUSION： Adrenomedullin overproduced in the vascular wall may contribute to the circulatory disturbance in cirrhosis as a local regulator of the vascular tonus rather than a circulating hormone.

Interferon augments the anti-fibrotic activity of an angiotensin-converting enzyme inhibitor in patients with refractory chronic hepatitis C

AIM： To evaluate the effect of combination treatment with the interferon （IFN） and angiotensin-converting enzyme inhibitor （ACE-Ⅰ） on several fibrotic indices in patients with refractory chronic hepatitis C （CHC）. METHODS： Perindopril （an ACE-Ⅰ; 4 mg/d） and/or natural IFN （3 MU/L; 3 times a week） were administered for 12 mo to refractory CHC patients, and several indices of serum fibrosis markers were analyzed. RESULTS： ACE-Ⅰ decreased the serum fibrosis markers, whereas single treatment with IFN did not exert these inhibitory effects. However, IFN significantly augmented the effects of ACE-Ⅰ, and the combination treatment exerted the most potent inhibitory effects. The serum levels of alanine transaminase and HCV-RNA were not significantly different between the groups, whereas the plasma level of transforming growth factor-β was significantly attenuated almost in parallel with suppression of the serum fibrosis markers. CONCLUSION： The combination therapy of an ACE-Ⅰand IFN may have a diverse effect on disease progression in patients with CHC refractory to IFN therapy through its anti-fibrotic effect.

A case of severe acalculous cholecystitis associated with sorafenib treatment for advanced hepatocellular carcinoma

Sorafenib,a multikinase inhibitor,is the first and only drug,which improves significantly the overall survival in patients with advanced hepatocellular carcinoma(HCC).However,many patients experience diverse side effects,some of them severe and unexpected.To date,acute acalculous cholecystitis has not been documented in association with a HCC patient treated with sorafenib.Here,we report the case of a 43-yearold woman with hepatitis C virus-related advanced HCC.She received sorafenib,and later complained ofa sudden onset of severe right hypocondrial pain with rebound tenderness and muscle defense.Laboratory examination showed mild elevation of transaminases,biliary enzymes,bilirubin,inflammation markers,and a marked peripheral eosinophilia.Abdominal computed tomography(CT) revealed a swollen gallbladder with exudate associated with severe inflammation without stones or debris.Consequently,sorafenib treatment was stopped immediately,and steroid-pulse therapy was performed.Steroid therapy drastically improved all clinical manifestations along with normalization of CT findings,eosinophilia,and liver functions.In summary,we herein report a rare case of acute severe acalculous cholecystitis associated with sorafenib in the patient with advanced HCC.

Eosinophilic cholecystitis as a rare manifestation of visceral larva migrans

Eosinophilic cholecystitis is an infrequent form of cholecystitis. The etiology of eosinophilic cholecystitis is still obscure, and it is sometimes accompanied with several complications, but a simultaneous onset with pericarditis is very rare. We would like to make an alternative interpretation of our recent report "Kaji K, Yoshiji H, Yoshikawa M, Yamazaki M, Ikenaka Y, Noguchi R, Sawai M, Ishikawa M, Mashitani T, Kitade M, Kawaratani H, Uemura M, Yamao J, Fujimoto M, Mitoro A, Toyohara M, Yoshida M, Fukui H. Eosinophilic cholecystitis along with pericarditis caused by Ascaris lumbricoides: A case report. World J Gastroenterol 2007; 13: 3760-3762."

Cholangiocarcinoma developed in a patient with IgG4-related disease

A 77-year-old man with jaundice and a pancreatic head tumor was referred to our hospital in August2006.The initial laboratory tests,computed tomography(CT)scan,magnetic resonance imaging(MRI),and endoscopic retrograde cholangiopancreatography suggested IgG4-related cholangitis and autoimmune pancreatitis.Oral prednisolone(PSL)was then administered.This treatment reduced the size of the pancreatic parenchyma,and the lower common bile duct(CBD)returned to its normal size.Thus,the oral PSL was gradually tapered to a maintenance dose.In February 2010,a CT scan and MRI showed segmental wall thickening and stenosis of the middle CBD,the progression of which led to extrahepatic obstructive jaundice.We suspected the emergence of a cholangiocarcinoma rather than the exacerbation of the IgG4-related sclerosing cholangitis because the stricture of the CBD was short and localized.Then,a percutaneous transhepatic biliary drainage was performed.The biopsy specimens obtained via the percutaneous transhepatic tract indicated an abnormal glandular formation,suggesting the presence of a moderate,well-differencated adenocarcinoma.The gross examination,microscopic examination and immunohistochemical analysis of the pancreaticoduodenectomy specimen suggested that a cholangiocarcinoma developed from the IgG4-related sclerosing cholangitis.

A histologically proven case of progressive liver sarcoidosis with variceal rupture

Sarcoidosis is a chronic multi-systemic granulomatous disease,and liver involvement frequently occurs.in most cases,no evidence of liver dysfunction is ob-served,and portal hypertension due to sarcoid liver diseases is a rareoccurrence.Moreover,no case of liver sarcoidosis has ever been reported with confirma-tion of the disease progression.Herein we describe a patient having hepatic sarcoidosis with severe portal hypertension and liver dysfunction.The diagnosis was histologically confirmed from granulomatous status to established liver cirrhosis over 10 years.A 46-year-old woman developed massive hematemesis due to the rupture of gastric cardial varices.She underwent emer-gency endoscopic injection sclerotherapy,and clear evi-dence of chronic hepatic failure.Twelve years ago,she was diagnosed as having sarcoidosis with respiratoryclinicalsymptoms.Liver biopsy revealed asymptomatic incidental granulomas without fibrosis development.After a couple of years,features of liver dysfunction were manifest and progressed.Ten years after the first biopsy,a second liver biopsy was performed,and well established dense fibrosis was revealed.Although significant liver dysfunction with portal hypertension is rarely seen in sarcoidosis,this case indicates that we have to consider the possibility that sarcoidosis may cause end-stage liver cirrhosis.