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BACKGROUND/AIMS: In diabetic patients, reduced urinary pH (UpH) is a predictive factor for cardiorenal-vascular disorders. Synthesis of glutathione, an anti-oxidative stress substance, is induced to counteract renal oxidative stress. UpH declines as glutamate is consumed, as does the synthesis of ammonia from glutamate. Glutathione is synthesized from glutamate and cysteine; however, in diabetes, the relationship between lowered UpH and the roles of renal amino acids is unknown. We, therefore, examined the relationship between amino-acid kinetics, UpH, and renal function. METHODS: This cross-sectional study targeted 100 non-diabetic obese individuals (OG: obese group) and 100 diabetics (DG: diabetic group). We investigated their blood amino acids, urinary amino-acid excretion, the reabsorption rates of various amino acids, and their relationship with the UpH and estimated glomerular filtration rate (eGFR). RESULTS: The DG subjects showed higher blood cysteine concentration, urinary glutamate, and cysteine excretions than the OG subjects. Although the glutamate reabsorption rate declined in the DG subjects, that of cysteine increased due to the lowered eGFR. The DG subjects' urinary cysteine excretion correlated positively with UpH, making this urinary cysteine excretion the sole independent risk factor for lower UpH. CONCLUSION: In patients with diabetes, the reabsorbed amount of cysteine, not glutamate, regulates the amount of glutathione synthesis in the kidneys. The more an amount of cysteine reabsorption increases concurrently with a decline in eGFR, the more its urinary excretion decreases. Under these conditions, concurrently, the glutamate consumption then increases, resulting in decreased ammonia synthesis and UpH.

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We frequently encounter brownish-red, cloudy urine in some obese subjects, which occurs due to pink urine syndrome (PUS). PUS is a phenomenon in which uric acid precipitates into the urine due to reduced urinary pH (UpH). The mechanism underlying urinary acidification has not been elucidated so far. UpH level is adjusted by urinary excretion of ammonia synthesized from glutamate or glutamine, suggesting that renal synthesis of ammonia from glutamate or glutamine is decreased in PUS. However, this hypothesis has not been examined yet. We therefore examined the changes in the urinary excretion of these amino acids in PUS. One-hundred-fifty male students who had undergone a physical examination were enrolled. To determine the presence [PUS (+), n = 72] or absence [PUS (-), n = 78] of PUS, urinary amino acid excretion and UpH were evaluated. Independent risk factors of lower UpH were determined using multiple regression analyses. The PUS (+) subjects, who had lower UpH values than PUS (-) subjects, showed lower urinary excretion of glutamate and some other glucogenic amino acids. Thus, UpH correlated positively with the urinary excretion of glutamate in the PUS (+) subjects. A reduction in urinary glutamate but not in glutamine excretion proved to be an independent risk factor for reduced UpH. In conclusion, PUS appears to occur when a reduction in the synthesis of ammonia from glutamate causes a decrease in UpH. Our results showed that urinary glutamate excretion was reduced in PUS because renal glutamate was consumed by a reaction different from ammonia production.

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BACKGROUND: Pink urine syndrome (PUS) is attributed to the precipitation of uric acid caused by low urinary pH (U-pH). However, the reasons for the lower U-pH are unclear. OBJECTIVES: To investigate the occurrence of PUS and verified the cause of U-pH reduction. METHODS: Participants comprised 4,940 students who had undergone a physical examination. Data on the presence [PUS (+)] or absence [PUS (-)] of PUS, as well as age, gender, body mass index (BMI), blood pressure (BP), heart rate (HR), and U-pH were collected. Of these participants, 300 randomly selected individuals were evaluated for their waist circumference, as well as their levels of urinary C-peptide, angiotensinogen, methylglyoxal, thiobarbituric acid-reactive substances (TBARS), and Na(+) excretion. Independent risk factors of lower U-pH were decided by a multiple-regression analysis. RESULTS: PUS was observed in 216 students (4.4 %). A greater number of men comprised the PUS (+) group compared with the PUS (-) group, and subjects in this group had high BMI, BP, and HR values, as well as low U-pH. A logistic regression analysis revealed that the BMI and U-pH were independent risk factors for PUS (+). The decrease of U-pH was closely related to the progress of chronic kidney disease (CKD). BMI value was related to PUS (+) in the CKD (-) subjects. On the other hand, low U-pH was related to PUS (+) in the CKD (+) subjects. All factors other than HR showed a significant negative correlation with U-pH. However, multiple-regression analysis revealed that TBARS and angiotensinogen were independent risk factors. CONCLUSION: Obesity and lower U-pH were each independently related to PUS, whereas increased intrarenal oxidative stress and exacerbation of the renin-angiotensin system activation were associated with the lowering of U-pH. U-pH low value is related to potential CKD.

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A 79-year-old woman, who had been treated because of mixed connective tissue disease (MCTD), was admitted to the hospital for the intensive examination of a hepatic tumor that was unexpectedly found on computed tomography. The hepatic tumor was approximately 40 mm in diameter. Her transaminase levels were slightly elevated but hepatic virus markers were negative. However, a liver aspiration biopsy revealed moderately differentiated hepatocellular carcinoma (HCC). In the surrounding non-tumor area, nonspecific reactive hepatitis was detected. MCTD associated with HCC has not yet been reported in the past. This case appears to be very interesting in terms of the etiology of HCC.

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A 20-year-old woman given a diagnosis of hyperthyroidism (Basedow's disease) had been subsequently treated with methimazole since 1999. As she could not be made euthyroid, surgery was planned to relieve the symptoms. Because of liver dysfunction after discontinuation of methimazole and administration of iodine, she was admitted to the hospital. She was negative for hepatitis A, B and C virus serologies, but positive for anti-nuclear antibodies. A liver biopsy, which showed features of chronic active hepatitis, led to the diagnosis of autoimmune hepatitis (AIH). Interestingly, normalization of serum T4 correlated with improvement of serum aminotransferases. This leads us to speculate that this patient's liver dysfunction may have been AIH exacerbated by the liver dysfunction of hyperthyroidism rather than acute deterioration of AIH itself.

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A 23-year-old woman was admitted to our hospital with jaundice and hepatic coma. She had taken a weight-loss supplement for one month before admission. Her clinical and laboratory findings were consistent with fulminant hepatic failure and fulfilled the criteria of autoimmune hepatitis. Despite corticosteroid pulse therapy and plasma exchange, her symptoms and laboratory findings deteriorated. Her condition improved after she received a living donor-liver transplant from her sister. Autoimmune hepatitis usually follows a chronic course, but it should be considered a type of fulminant hepatic failure and treated promptly.

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Hepatic hydrothorax is often resistant to various treatments. A failure in the treatment for hepatic hydrothorax may be associated with poor prognosis. We report two cases of intractable hepatic hydrothorax successfully treated by combining chemical pleurodesis using OK-432 with nasal continuous positive airway pressure. Combination therapy may provide a minimally invasive and effective treatment for intractable hepatic hydrothorax.

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A 46-year-old woman was diagnosed with palmoplantar pustulosis (PPP) at the Department of Dermatology, Fukushima Medical University Hospital in 2000, and was treated with ointment. However, because liver dysfunction developed in 2003, she was referred to our department, where primary biliary cirrhosis (PBC) was also diagnosed on the basis of clinical findings. One year later, at the age of 49, she developed manifestations of Behçet's disease (BD), including erythema nodosum in the lower extremities. Because she had a history of uveitis, recurrent oral ulceration was present, and the HLA typing was positive for B51, BD was additionally diagnosed. Liver function normalized within three months of the start of treatment with ursodesoxycholic acid (UDCA). This is the first case of PBC associated with BD and PPP.

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OBJECTIVE: : The possible involvement of eosinophils in primary biliary cirrhosis (PBC) has been suggested for many years. Activated eosinophils release basic granule proteins and are thought to be involved in the tissue damage of PBC. Eosinophil peroxidase (EPO) is one of the eosinophilic granule proteins and is toxic to epithelial cells. In this study, we examined whether autoantibodies to EPO are present in sera of patients with PBC and we evaluated the relationship between the presence of anti-EPO antibodies and the clinical features of PBC. METHODS: : Sera obtained from 61 patients with PBC, 31 patients with autoimmune hepatitis (AIH), 87 patients with chronic viral hepatitis (CVH), 27 patients with bronchial asthma, and 20 healthy controls were examined. Enzyme-linked immunosorbent assay (ELISA) and Western blot methods were used for detection of anti-EPO antibodies. RESULTS: : The mean OD value of anti-EPO antibodies, as determined by ELISA, was significantly (p<0.01) higher in patients with PBC (0.197+/-0.121) than in patients with AIH (0.124+/-0.077), CVH (0.090+/-0.038) or bronchial asthma (0.073+/-0.025) and in healthy controls (0.072+/-0.029). The results of ELISA showed that 32 (52.5%) of the 61 patients with PBC, 9 (29.0%) of the 31 patients with AIH, 7 (8.0%) of the 87 patients with CVH, and 1 (3.7%) of the 27 patients with bronchial asthma were positive for anti-EPO antibodies. In addition, PBC patients who were positive for anti-EPO antibodies had a significantly smaller number of peripheral eosinophils than did patients who were negative for anti-EPO antibodies (99.2+/-54.4cells/mul versus 176.9+/-117.5cells/mul, p<0.01). However, there was no correlation between the titers of anti-EPO antibodies and those of AMA or AMA-M2, ANA or serum levels of IgM. CONCLUSIONS: : This is the first report of the detection of anti-EPO antibodies in patients with PBC. Further study is needed to clarify the role of anti-EPO antibodies in the pathogenesis of PBC.

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A 23-year-old man was admitted to our department due to hemorrhage from gastric varices. He had been diagnosed as having Wilson's disease at the age of 17. Abdominal ultrasonography and computed tomography (CT) showed portal thrombosis and a large mass occupying most of the right lobe in the liver. The tumor was diagnosed as hepatocellular carcinoma (HCC) by image views and tumor markers. He died 3 months after the diagnosis, and an autopsy was performed. Histologic examination of the tumor showed moderately to poorly differentiated HCC. The nontumorous lesion of the liver revealed cirrhosis. HBX-DNA sequence was not detected in the liver. Hepatic cirrhosis is a well-recognized complication of Wilson's disease, but HCC is extremely rare. We describe the clinical findings of this patient and discuss the relationship of the development of HCC with a review of the relevant literature.

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Six cases of primary biliary cirrhosis (PBC) complicated by psoriasis are presented. Three of six patients had psoriasis vulgaris and three had palmoplantar pustulosis. PBC was diagnosed before the onset of psoriasis in three patients and after the onset of psoriasis in the other three patients. Interestingly, all three cases of psoriasis vulgaris were diagnosed after the onset of PBC. We recognized no obvious characteristics specific to PBC complicated by psoriasis except that all cases were in an early stage of PBC. Although the etiologies of psoriasis and PBC remain unknown, the two diseases have many common features as to pathogenesis. We believe that case of PBC-psoriasis overlap hold the key to clarifying the nature of these diseases.

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We report a case of idiopathic portal hypertension (IPH) complicated with mixed connective tissue disease (MCTD). The patient, a 41-year-old woman, was admitted to another hospital because of tarry stools in March 2000. Emergency endoscopy revealed bleeding from the esophageal varices, and she was referred to our hospital. Twelve years before, she had been diagnosed as having MCTD, because she exhibited Raynaud's phenomenon, pleuritis, pericarditis, and had high titers of anti nuclear antibody (ANA) and anti-U1 ribonucleoprotein (RNP). Laboratory examinations, imaging examinations, and liver biopsy indicated that the esophageal varices were caused by IPH. The association of IPH and MCTD is very rare; to the best of our knowledge, only five cases of MCTD, associated with pulmonary hypertension (PH), have been reported.

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Background and aim: Alternative splicing of human glucocorticoid receptor (hGR) premessenger RNA (mRNA) generates two highly homogenous isoforms, termed hGRalpha and hGRbeta. hGRalpha is a ligand-activated transcription factor, which, in the hormone-bound state, modulates the expression of glucocorticoid-responsive genes by binding to specific glucocorticoid response element DNA sequences. In contrast, hGRbeta may be an endogenous inhibitor of glucocorticoid action and transcriptionally inactive. hGRbeta protein has been known to correlate with the development of glucocorticoid resistance. Glucocorticoids can effectively relieve autoimmune hepatitis (AIH), but some patients with this disease are refractory even when glucocorticoids are administered. The aim of this study was to determine the incidence of hGRbeta mRNA in patients with AIH by reverse transcription polymerase chain reaction (RT-PCR), and to compare the clinical characteristics of hGRbeta-positive and -negative patients with AIH. Materials and methods: RNA was obtained from peripheral blood mononuclear cells (PBMCs) of 62 patients, consisting of 26 with AIH, 10 with primary biliary cirrhosis (PBC), seven with chronic viral hepatitis (CVH), 10 with ulcerative colitis (UC), six with pemphigus, and three with systemic lupus erythematosus (SLE), and 10 healthy volunteers. The total RNA obtained was reverse transcribed, the resulting complementary DNA amplified using specific primers for hGRalpha and hGRbeta. Results: The hGRalpha mRNA was detected in RNA from PBMCs of all patients and healthy volunteers. The hGRbeta mRNA was detected in 15 (57.6%) patients with AIH. This incidence was significantly higher than that for patients with PBC (0%) or CVH (28.6%) or for healthy volunteers (20.0%) ( [Formula: see text] ). Of the hGRbeta-positive and -negative groups, serum ALT and total bilirubin (TB) levels were significantly higher in the positive group ( [Formula: see text] ). The total dose of glucocorticoid was higher in the positive group, but the difference was not statistically significant. However, the average monthly dose was significantly higher in the positive group ( [Formula: see text] ). The rate of relapse of AIH was significantly higher in the positive group (60.0%) than in the negative (10.0%) ( [Formula: see text] ). The rate of usage of immunosuppressive drugs was higher in the positive group (33.3%) than in the negative (18.2%), but the difference was not statistically significant. Conclusions: These data show that hGRbeta expression in PBMCs of patients with AIH assessed by RT-PCR is closely associated with resistance to glucocorticoids which affects the outcome of therapy with this drug.

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We report a series of five patients with autoimmune hepatitis (AIH) accompanied by systemic lupus erythematosus (SLE) (AIH-SLE overlap). Serologic tests showed that all patients were positive for antinuclear antibody and double-stranded DNA antibody. Histological examination of the liver showed that three of the patients had chronic hepatitis with severe activity. One of the other two had acute and severe hepatitis with submassive necrosis in both portal and lobular areas. The last patient already had liver cirrhosis. All patients had a mild form of SLE and showed a rapid response to corticosteroid. There was no serious involvement of organs other than the liver in any of the patients, and the prognoses were comparatively good in all patients.

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Hepatic manifestations are a common phenomenon in patients with systemic lupus erythematosus (SLE). However, their cause may be difficult clinically to determine. A significantly increased frequency of anti-ribosomal P antibody has recently been found in patients with SLE-associated hepatitis. Thus, we examined the prevalence of anti-ribosomal P antibody and clinical differences between anti-ribosomal P antibody positive and negative SLE patients with liver dysfunction using ELISA kits against recombinant ribosomal P0 protein. Sera of 61 patients with SLE and 20 patients with autoimmune hepatitis (AIH) were assayed. Of 34 SLE patients with liver dysfunction, anti-ribosomal P antibody was detected in 15 (44.1%), consisting of 11 (68.8%) of 16 patients with SLE-associated hepatitis, 2 (28.6%) of 7 patients with fatty liver, 1 (16.7%) of 6 patients with drug-induced hepatitis, and 1 (20.0%) of 5 patients with SLE complicated by AIH. This antibody was not detected in patients with AIH. Except for those with SLE-associated hepatitis, anti-ribosomal P antibody positive patients were complicated by renal dysfunction and CNS lupus. The positive rate of anti-ribosomal P antibody was significantly higher in patients with SLE-associated hepatitis (68.8%) than in patients with SLE complicated by AIH (20%) ( [Formula: see text] ) and AIH (0%) ( [Formula: see text] ). These findings suggest that anti-ribosomal P antibody may be a useful marker of SLE-associated hepatitis to differentiate it from AIH and other liver dysfunctions in SLE patients without renal dysfunction or CNS lupus.

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Interactions between leukocytes and sinusoidal endothelial cells are known to be involved in the pathogenesis of acute liver injury. Various adhesion molecules and chemokines play key roles in these cell-to-cell interactions, and the expression of these adhesion molecules and the production of chemokines are regulated by inflammatory cytokines such as tumor necrosis factor-alpha (TNF-alpha), interleukin-1 (IL-1), and interferon-gamma (IFN-gamma). We have shown that the expression of intercellular adhesion molecule-1 (ICAM-1) on cultured rat sinusoidal endothelial cells stimulated with TNF-alpha increases in a dose-dependent manner. The number of neutrophils that adhered to sinusoidal endothelial cells pretreated with TNF-alpha also increased in a dose-dependent manner and significantly decreased upon incubation with an anti-ICAM-1 antibody. In endotoxin-induced rat liver injury, the number of neutrophils infiltrating the sinusoids increased after serum TNF-alpha, macrophage inflammatory protein-2 (MIP-2) and cytokine-induced neutrophil chemoattractant (CINC) reached their peak levels. In addition, the level of ICAM-1 expression on sinusoidal endothelial cells greatly increased from 8 h after exposure to endotoxin, and these cells were adhered to neutrophils that expressed both LFA-1 and Mac-1. Moreover, lipo-prostaglandin E1 (PGE1) reduced the extent of liver injury, and also reduced the number of neutrophils that infiltrated the liver, was reduced the production of MIP-2 and CINC, but not that of TNF-alpha, in rats injected with endotoxin.

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Inflammatory pseudotumor (IPT) of the liver is an unusual non-neoplastic benign lesion. A 75-year-old man was hospitalized for esophageal varices and gastric cancer. Three years before admission, he had been diagnosed as having primary biliary cirrhosis (PBC) without Sjögren's syndrome. Computed tomography (CT) and magnetic resonance imaging (MRI) scans showed multiple masses (S3, S5, S6) less than 2 cm in diameter in the liver. Since these masses were difficult to distinguish from hepatocellular carcinoma, or metastatic liver carcinoma, one of the masses (S5) was removed during an operation for gastric cancer. Histological examination demonstrated marked infiltration of plasma cells and some histiocytes, findings consistent with the histological features of IPT. The coexistence of hepatic IPT and PBC in this case may have been an accidental event. However, the immunological and environmental factors associated with PBC are thought to be involved in the development of IPT; in addition, cholangitis associated with PBC could have contributed to the development of IPT.

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A case of autoimmune hepatitis (AIH) complicated by primary sclerosing cholangitis (PSC) in a 36-year-old woman is reported. AIH overlapping with PSC has been rarely reported, and to the best of our knowledge, there have been no reports in Japan. Based on the criteria for diagnosis of AIH and on typical endoscopic retrograde cholangiograph (ERC) findings, the patient was diagnosed as having AIH overlapping with PSC. Her transaminase levels normalized within 1 month after administration of prednisone, azathioprine and ursodeoxycholic acid, but her cholestatic enzyme level remained elevated. The effect of treatment on the cholestatic features is thought to be an important factor for predicting the prognosis of AIH overlapping with PSC.

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BACKGROUND AND AIMS: Hepatitis C virus (HCV)-specific cytotoxic T lymphocytes (CTL) may contribute to viral clearance and liver cell injury in patients with chronic hepatitis C. In the present study, we attempted to determine the serial HCV-specific CTL activity during interferon-beta (IFN-beta) therapy in patients with chronic hepatitis C and whether there is any relationship between the CTL response and clinical response to IFN-beta therapy. METHODS: Eight HLA-A2-positive patients with chronic hepatitis C were treated initially with 6 million U/ml of IFN-beta every day for 8 weeks and then 3 times weekly for the subsequent 16 weeks. Peripheral blood mononuclear cells (PBMC) were collected before the start, 4 weeks after the start, and after the end of IFN treatment and were stimulated with 2 peptides corresponding to core sequences, which were previously reported to have an HLA-A2 restricted-CTL epitopes. Cytolytic activity was determined by a standard 51Cr-release assay using allogenic HLA-matched EBV-transformed B lymphoblastoid cell lines (B-LCL). RESULTS: HCV-specific CTL responses were detected in 2 of the 8 patients before treatment with IFN-beta. One of 2 patients was not observed HCV-specific CTL responses after 4 weeks of IFN-beta treatment, however these two patients showed CTL responses at the end of IFN-beta treatment, and finally HCV-RNA was negative. In addition, HCV-specific CTL responses were observed in 4 patients after 4 weeks of IFN-beta treatment. Three of these 4 patients showed CTL responses only at 4 weeks after IFN-beta treatment. However, there were no differences between clinical parameters or between IFN efficacy in HCV specific CTL response-positive (n = 4) and -negative (n = 4) patients at 4 weeks after the start of IFN-beta treatment. CONCLUSIONS: These findings suggest that there are few relations between peripheral HCV-specific CTL response and clinical response to IFN therapy in patients with chronic hepatitis C, although IFN enhances the host immune response against HCV synergistically with antiviral activities.

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