Long-Term Outcomes of Living-Donor Liver Transplantation for Primary Biliary Cirrhosis: A Japanese Multicenter Study.

The factors that influence long-term outcomes after living-donor liver transplantation (LDLT) for primary biliary cirrhosis (PBC) are not well known. Compared with deceased-donor transplantation, LDLT has an increased likelihood of a related donor and a decreased number of human leukocyte antigen (HLA) mismatches. To clarify the effects of donor relatedness and HLA mismatch on the outcomes after LDLT, we retrospectively analyzed 444 Japanese patients. Donors were blood relatives for 332 patients, spouses for 105, and "other" for 7. The number of HLA A-B-DR mismatches was none to two in 141, three in 123, and four to six in 106 patients. The 15-year survival rate was 52.6%, and PBC recurred in 65 patients. Recipient aged 61 years or older, HLA mismatches of four or more (maximum of six), graft:recipient weight ratio less than 0.8, and husband donor were adverse indicators of patient survival. IgM 554 mg/dL or greater, donor-recipient sex mismatch, and initial immunosuppression with cyclosporine were significant risks for PBC recurrence, which did not affect patient survival. In subgroup analysis, conversion to cyclosporine from tacrolimus within 1 year diminished recurrence. Prospective studies are needed to determine the influence of pregnancy-associated sensitization and to establish an optimal immunosuppressive regimen in LDLT patients.

Long-term outcomes of hemostatic therapy for variceal bleeding and the challenge pending in the post-direct-acting antivirals era.

Background and study aims: This study evaluated the longterm outcomes of mainly endoscopic hemostatic therapy for gastrointestinal variceal bleeding and of the transition of hemostatic therapy. Patients and methods: Among 1,163 patients treated for gastrointestinal varices between April 2006 and June 2020, a total of 125 patients who underwent emergency hemostatic therapy were enrolled. Survival rates and secondary evaluation points were analyzed. Additionally, patients were classified into two groups: the previous and latter term. Patients' background, therapeutic method, and treatment results were compared between the groups. Results: 94.4% had cirrhosis. The average Child-Pugh score was 8.90. Successful primary hemostasis rate was 98.4%, and 5.6% died within 2 weeks, all with a Child-Pugh score ≥9. The respective 1- and 5-year survival rates for Child-Pugh grade A/B were 81.3% and 55.4%, while those for Child-Pugh grade C were 58.1% and 17.8%. Child-Pugh grade C or hepatocellular carcinoma was significantly associated with poor prognosis. In total, 21.6% experienced variceal re-bleeding; 62.9% of these cases were triggered by continued alcohol consumption. There was no significant difference in survival between patients with and without variceal re-bleeding and in post-treatment survival between the previous and latter terms. In the latter term, the number of cases caused by continued alcohol consumption significantly increased. Conclusions: Multidisciplinary treatment and continuation of proper management after hemostatic therapy for variceal bleeding are crucial. Continued alcohol consumption leads to variceal bleeding and re-bleeding; its proper management, including alcohol abstinence, is one of the major challenges left in the post-directacting antivirals era.

Characteristic genotypes of vascular endothelial growth factor are susceptible to ascites in patients with cirrhosis.

This study was designed to investigate whether different vascular endothelial growth factor (VEGF) genotypes are associated with ascites formation in cirrhotic patients. Seventy cirrhotic patients were included in the study: 25 cirrhotic patients with ascites and 45 cirrhotic patients without ascites. Patient characteristics were investigated and compared between the two groups. With regard to VEGF genotype, 42 patients were C/C and 28 patients were T/T or C/T. The genotypes T/T or C/T were observed in 23 cases (51%) among the non-ascites group, but in only five cases (20%) among the ascites group. Serum levels of albumin and creatinine, and the VEGF genotypes were significantly different between the two groups. Multiple regression analysis showed that serum levels of creatinine and the VEGF genotypes were significantly correlated with ascites formation. Thus, it can be concluded that VEGF genotyping might be a valuable susceptibility marker for ascites formation in cirrhotic patients.

Functional Fas ligand expression in thyrocytes from patients with Graves' disease.

Fas/Fas ligand (FasL) interaction has been suggested to play a role in the pathogenesis of Hashimoto's thyroiditis. This manuscript addressed a role for Fas/FasL interaction in the pathogenesis of Graves' disease (GD). Apoptosis was detected in 0.5-5.0% of GD thyrocytes, but not in normal thyrocytes from patients with adenoma (N). Fas was constitutively expressed on the basement membrane of both GD and N thyrocytes. Thyrocytes expressed Bcl-2 constitutively in both GD and N thyrocytes. FasL was detected at the messenger ribonucleic acid level in thyroid tissue and cultured thyroid cells by Northern blotting and RT-PCR. FasL protein was detected in the cytoplasm and basolateral surface of thyrocytes from GD, but not in N. Cell surface expression of FasL on cultured thyrocytes disappeared within 48 h after their isolation. However, it was retained by culturing the cells with a matrix metalloproteinase inhibitor. Coculture with thyrocytes induced apoptosis of Fas transfectants, which was blocked by an anti-FasL antibody. Although cultured thyrocytes expressed Fas on the surface, they were not killed by an agonistic anti-Fas antibody. Interferon-gamma-induced Fas up-regulation was suppressed by TSH. These results suggest that the increased expression of FasL in GD thyrocytes, the down-regulation of Fas expression by TSH or possibly by TSH receptor autoantibody, and the overexpression of Bcl-2, which could render thyrocytes resistant to FasL-mediated elimination, may thus be involved in the pathogenesis of GD.

Expression and role of vascular endothelial growth factor in liver regeneration after partial hepatectomy in rats.

Vascular endothelial growth factor (VEGF) plays a major role in angiogenesis, which is essential for both healing of injured tissue and proliferation of carcinoma cells. In this study we elucidated the expression and role of VEGF in rat liver regeneration after partial hepatectomy. VEGF expression was mainly detected in periportal hepatocytes and reached a maximal level 48-72 hr after partial hepatectomy by both immunohistochemistry and in situ hybridization. Similarly, immunohistochemistry for Ki-67 showed that the proliferative activity of sinusoidal endothelial cells was highest in the periportal area and reached a maximal level 72 hr after partial hepatectomy. Moreover, neutralization of VEGF significantly inhibited proliferative activity of hepatocytes (p<0. 0001), as well as sinusoidal endothelial cells (p<0.001), at 48 and 96 hr after partial hepatectomy. Conversely, injection of VEGF significantly promoted proliferative activity of hepatocytes (p<0. 0001) as well as sinusoidal endothelial cells (p<0.0005) at 48 hr after partial hepatectomy. These results suggest that VEGF promotes proliferation of hepatocytes through reconstruction of liver sinusoids by proliferation of sinusoidal endothelial cells. Furthermore, these data point to a new therapeutic strategy, the use of VEGF and other hepatocyte growth factors in fulminant or severe acute hepatitis.

The reticuloendothelial system and macrophage-monocyte system in thorotrast patients.

To evaluate the function of the reticuloendothelial system and macrophage-monocyte system, blood samples from Thorotrast patients and age-matched healthy controls were used to determine the titer of plasma antibodies to lipid A and the numbers of several lymphocyte subclasses in peripheral blood and for an autoradiographic study of peripheral blood monocytes. The titer of plasma IgM class antibodies to lipid A was significantly elevated in the Thorotrast patients. Counts of CD 11-positive lymphocytes and CD 57-positive lymphocytes, which correspond to monocytes and natural killer cells, respectively, were significantly increased in the Thorotrast patients. Autoradiography showed that alpha-particle tracks were emitted from the monocytes isolated from the peripheral blood of Thorotrast patients. Thus the depressed function of the reticuloendothelial system resulted in the activation of the macrophage-monocyte system in the Thorotrast patients.

High prevalence of anticardiolipin antibodies in hepatitis C virus infection: lack of effects on thrombocytopenia and thrombotic complications.

Hepatitis C virus (HCV) causes various extrahepatic immunologic abnormalities. Recently, an association between HCV infection and antiphospholipid syndrome, including thrombocytopenia, has been reported. However, the precise relationship between thrombocytopenia and anticardiolipin antibodies in patients with chronic HCV infection is not fully understood; likewise, the association of antiphospholipid syndrome and various liver diseases is not well understood. To evaluate the prevalence and importance of antiphospholipid antibodies in various chronic liver diseases, we determined the levels of anticardiolipin antibodies, platelet numbers, and levels of platelet-associated immunoglobulin G (PA-IgG) and thrombin-antithrombin III complex (TAT) in patients with chronic HCV infection, chronic hepatitis B virus (HBV) infection, and primary biliary cirrhosis (PBC). The prevalence of anticardiolipin antibodies in patients with HCV infection was significantly higher than that in control subjects or individuals with the other liver diseases examined. However, there was no significant correlation between anticardiolipin antibodies and platelet counts or TAT. The frequency of thrombotic complications was similar in anticardiolipin antibody-positive and -negative patients with chronic HCV infection. Further, sera from all but one anticardiolipin antibody-positive HCV patient were negative for phospholipid-dependent anti-beta2 glycoprotein I antibodies. Our results suggest that anticardiolipin antibodies are frequently found in patients with chronic HCV infection, but they do not appear to be of clinical importance. Immunologic disturbances induced by HCV or prolonged tissue damage in systemic organs as a result of the extrahepatic manifestations of HCV infection may induce the production of antibodies to various cardiolipin-binding proteins or phospholipids.

Polyarthritis nodosa with mesenteric aneurysms demonstrated by angiography: report of a case and successful treatment of the patient with prednisolone and cyclophosphamide.

Polyarteritis nodosa is a necrotizing angitis that predominantly affects small and medium-sized arteries. The prognosis of untreated polyarteritis nodosa is very poor. Since symptoms are diverse and no serologic test is specific for polyarteritis nodosa, the diagnosis is difficult and often delayed. We describe a patient with polyarteritis nodosa who had gastrointestinal involvement with multiple aneurysms of the inferior mesenteric artery; only abdominal angiography provided a conclusive diagnosis. Alleviation of symptoms and regression of aneurysms were observed after combination therapy of an immunosuppressive agent, cyclophosphamide, and prednisolone. We emphasize the importance of early diagnosis by angiography and aggressive therapy in patients in whom physical signs indicating definite polyarteritis nodosa are not present.

Erythropoietic protoporphyria with fatal liver failure.

A 33-year-old woman with a history of photosensitivity, persistent abdominal pain, and liver dysfunction was admitted to our department because of abdominal pain and progression of liver dysfunction. On admission, levels of protoporphyrin and coproporphyrin within erythrocytes were markedly increased. Autofluorescent erythrocytes were also detected, leading to a diagnosis of erythropoietic protoporphyria. A liver biopsy specimen revealed cirrhosis with dark brown granules filling hepatocytes, bile canaliculi, and bile ductules. Transfusion of washed erythrocytes, hemodialysis, and administration of cholestyramine and beta-carotene transiently improved levels of porphyrins and liver function. The patient died of rupture of esophageal varices followed by multiple organ failure. However, the treatments were believed to have extended survival.

OK-432 treatment increases matrix metalloproteinase-9 production and improves dimethylnitrosamine-induced liver cirrhosis in rats.

Kupffer cells are major matrix metalloproteinase-producing cells in the liver. The production of metalloproteinases in Kupffer cells may contribute to the improvement of liver fibrosis inducing liver cirrhosis. In this study, we examined the effect of the OK-432 (a biological response modifier) on the dimethylnitrosamine-induced liver cirrhosis in rats. Dimethylnitrosamine (10 microg/ml) was injected intraperitoneally into 20 male Wistar rats 3x/week for 4 weeks. For the subsequent 4 weeks, the animals were injected with saline (1 ml, 1x/week) (Group I, n=10) or OK-432 (1 Klinishe Einheit, 1x/week) (Group II, n=10). The control rats were injected with 1 ml saline for the initial 4 weeks and subsequent 4 weeks (Group III, n=10). The degree of hepatic fibrosis, the immunolocalization of type IV collagen, hyaluronic acid, and alpha-smooth muscle actin, and the mRNA expression by Northern blotting and the activity by gelatin zymography of metalloproteinase-9 were evaluated. Serum aminotransferase, hyaluronic acid, interleukin-1beta and tumor necrosis factor-alpha levels were measured. The deposition of á-smooth muscle actin and extracellular matrix containing type IV collagen and hyaluronic acid was markedly suppressed by OK-432. The mRNA expression and the activity of metalloproteinase-9 were markedly increased by OK-432. The serum aminotransferase and hyaluronic acid levels were decreased by OK-432. The serum interleukin-1 and tumor necrosis factor-alpha values were lower than the detectable limit in all samples from all three groups. These results indicate that OK-432 increased the production of metalloproteinase-9 and improved the rat dimethylnitrosamine-induced liver cirrhosis. OK-432 is suggested to be useful for the treatment of liver cirrhosis.

Increased expression of transforming growth factor-alpha in a patient with recurrent hepatocellular carcinoma following partial hepatectomy.

A 45-year-old woman with chronic hepatitis B underwent partial hepatectomy for hepatocellular carcinoma (HCC). However, the HCC recurred 2 months after surgery and rapid progression of the disease resulted in her death. Immunohistochemistry showed that transforming growth factor-alpha (TGFalpha) was barely expressed in the liver specimens obtained at hepatic resection, whereas autopsy specimens were strongly stained with anti-TGFalpha antibody in the cytoplasm of both non-tumourous and tumourous liver cells. A higher level of Ki67 expression, a proliferating marker, was observed in the recurrent HCC, similar to that of TGFalpha. Thus, we speculate that the partial hepatectomy increased the level of TGFalpha leading to recurrence and progression of HCC through an autocrine/paracrine mechanism.

Endotoxin increases paracellular permeability of isolated rat hepatocyte couplets.

Hyperbilirubinemia is frequently associated with endotoxemia. Regurgitation of bile constituents including bilirubin into the sinusoidal space is prevented by tight junctions which maintain paracellular permeability between hepatocytes. To investigate the mechanism of endotoxin-associated hyperbilirubinemia, we have studied the changes in paracellular permeability of primary hepatocyte couplets treated with endotoxin. In addition, we examined the effects of ursodeoxycholic acid (UDCA), which has been widely used for various liver diseases, on endotoxin-associated changes in paracellular permeability. The paracellular permeability of hepatocyte couplets was evaluated by paracellular penetration of fluorescein isothiocyanate (FITC)-dextran with molecular weights of 3, 10 and 70K using confocal laser scanning microscopy. Endotoxin increased the paracellular penetration of FITC-dextran 3 and 10K. These changes were prevented by treatment with UDCA. There was little paracellular penetration of FITC-dextran 70K under any conditions. These results suggested that endotoxin increased the paracellular permeability of hepatocyte couplets and these changes were prevented by treatment with UDCA. Furthermore, bile regurgitation through the paracellular route is involved in endotoxin-associated hyperbilirubinemia, and UDCA might be a potential therapeutic agent for endotoxin-associated hyperbilirubinemia.

Comparative study of magnetic resonance imaging, computed tomography and histology in the assessment of liver iron overload.

Magnetic resonance imaging, computed tomography, and liver biopsy findings were compared in ten patients with serum ferritin levels over 500 ng/ml. The liver was observed as a low-intensity area on magnetic resonance imaging in all four patients with serum ferritin levels above 2,000 ng/ml, while no abnormalities were detected in four of the six patients with a serum ferritin level below 2,000 ng/ml. Computed tomography revealed the liver to be a high density area in five of the seven patients tested. However, it demonstrated no abnormality in a patient with steatosis despite a high serum ferritin concentration. Liver biopsy demonstrated iron deposits in nine of the ten patients. These findings indicate that liver biopsy remains the most accurate mean of detection of liver iron overload. Both magnetic resonance imaging and computed tomography could be used to be monitor the progress of a patient with liver iron overload treated by phlebotomy.

Pulse intravenous cyclophosphamide treatment for steroid-resistant interstitial pneumonitis associated with polymyositis.

Interstitial pneumonitis (IP) is a serious complication in polymyositis/dermatomyositis (PM/DM), leading to significant morbidity or mortality. Here, we report the successful treatment by pulse intravenous administration of cyclophosphamide in the early course of lung involvement in PM, and with subsequent low-dosage oral administration of azathioprine in a patient with steroid-resistant IP associated with PM/DM. Although the precise pharmacological mechanism induced by cyclophosphamide in this disease remains unclear, such a cytotoxic drug raises the possibility of control of steroid-resistant PM/DM-associated IP when used in the early course of IP.

Fatal acute hepatitis B virus infection while receiving immunosuppressants after renal transplantation.

A 47-year-old man with acute hepatitis B virus (HBV) infection who had been receiving immunosuppressants after renal transplantation developed progressive liver failure. During the clinical course (approximately 7 months), anti-HBc IgM antibody and HBV-DNA polymerase levels remained high, but the serum alanine aminotransferase (ALT) level was consistently less than 150 K.U. Histopathologic examination of the liver showed submassive hepatic necrosis without significant inflammation accompanied by marked fibrosis. Most hepatocytes showed strong nuclear expression of HBc antigen by immunohistochemical staining and electron microscopy revealed numerous intranuclear core-like particles. Hepatitis B virus infection in immunosuppressed individuals occasionally insidiously progresses, resulting in liver failure. The clinical course of such patients thus merits close scrutiny.

Unusual accumulation of glycogen in liver parenchymal cells in a patient with anorexia nervosa.

Anorexia nervosa is an eating disorder characterized by a fear of weight gain and a preoccupation with body image. Although hepatic involvement has been reported in patients with anorexia nervosa, the mechanism is not fully understood. We describe a patient with anorexia nervosa with liver function abnormalities. Light and electron microscopic observations revealed a remarkable accumulation of glycogen in hepatocytes. These results suggest that adaptive responses to starvation may alter carbohydrate metabolism in patients with anorexia nervosa.

Budd-Chiari syndrome complicated by hepatocellular carcinoma with no evidence of infection with hepatitis virus: a case report.

Hepatocellular carcinoma occurs in patients with Budd-Chiari syndrome. However, the etiology of hepatocellular carcinoma accompanied with Budd-Chiari syndrome has not been elucidated. We report a case of Budd-Chiari syndrome with membranous obstruction of the inferior vena cava complicated by hepatocellular carcinoma in an 80 year-old man. There was no evidence of co-infection with hepatitis A, B, C, D, E, and G virus. Histologically, the non-cancerous liver tissue showed chronic venous congestion with no evidence of hepatitis virus-associated liver cirrhosis. This case suggests that chronic venous congestion of the liver may be one of the pathologic conditions that occurs in hepatocellular carcinoma.

Successful treatment for bronchial bleeding from invasive pulmonary metastasis of hepatocellular carcinoma: a case report.

Pulmonary metastasis is frequently seen in patients with advanced hepatocellular carcinoma. However, information is limited concerning life-threatening complications and effective treatment of pulmonary metastasis because of the poor prognosis of patients with advanced hepatocellular carcinoma. Recent remarkable progress in detection and treatment of hepatocellular carcinoma has improved prognosis, making management of pulmonary metastasis an important clinical issue. We describe a 68-year-old man with pulmonary metastasis of hepatocellular carcinoma and sudden onset of hemoptysis from bronchial invasion. Transcatheter embolization was performed successfully via the bronchial artery with disappearance of bloody sputum. Peribronchial pulmonary metastasis of hepatocellular carcinoma can cause life-threatening hemoptysis. Transcatheter arterial embolization may be one of therapeutics for hemoptysis from invasive pulmonary metastasis of hepatocellular carcinoma.

Asialoglycoprotein receptor function of hepatocytes in patients with autoimmune hepatitis.

To assess whether the hepatocyte asialoglycoprotein receptors are affected in patients with autoimmune hepatitis, the function of the hepatocyte asialoglycoprotein receptor was investigated in patients with autoimmune hepatitis or chronic hepatitis C. A new radionuclide liver imaging technique, Technetium-99m diethylenetriamine-pentaacetic acid-galactosyl human serum albumin, was applied to evaluate the function of the receptor. A Receptor Index (LHL 15) was calculated by dividing the radioactivity of the liver region-of-interest (ROI) by that of the liver plus heart ROI 15 min after radiolabeled ligand injection. Serum albumin, prothrombin time, hepaplastin test and plasma retention rate of indocyanine green at 15 min were not significantly different between patients in the autoimmune hepatitis group and chronic hepatitis C group. In addition, the Receptor Index of patients with autoimmune hepatitis, in whom the asialoglycoprotein receptor is a candidate target antigen for autoimmune response, was similar to that of patients with chronic hepatitis C. These results indicate that the hepatocyte receptor for asialoglycoproteins is not affected in patients with autoimmune hepatitis.

Function of asialoglycoprotein receptor of hepatocytes in patients with Wilson's disease.

The function of hepatocyte asialoglycoprotein receptors was analyzed in normal subjects, in patients with Wilson's disease and in patients with chronic hepatitis C. A new radionuclide liver imaging, using Technetium-99m diethylenetriamine-pentaacetic acid-galactosyl human serum albumin, was applied to evaluate the function of the receptor, and a Receptor Index, LHL 15, which was calculated by dividing the radioactivity of the liver region-of-interest (ROI) by that of the liver plus heart ROI at 15 min after the radiolabeled ligand injection, was evaluated. The values were similar between the patients with Wilson's disease and patients with chronic hepatitis C. Hepatocyte receptors for asialoglycoproteins were not affected specifically in patients with Wilson's disease, suggesting that the defect in patients with Wilson's disease involves steps other than receptor-mediated endocytosis of asialoceruloplasmin via asialoglycoprotein receptor.