Secondary immunoglobulin A nephropathy with gross hematuria leading to rapidly progressive glomerulonephritis following severe acute respiratory syndrome coronavirus 2 vaccination: a case report.

BACKGROUND: The outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has been followed by many reports of the development and relapse of autoimmune diseases associated with SARS-CoV-2 vaccination. Some of these reports have involved relapse or onset of immunoglobulin A (IgA) nephropathy following SARS-CoV-2 vaccination. Here, we report on a patient with IgA nephropathy who presented with gross hematuria and rapidly progressive glomerulonephritis following SARS-CoV-2 vaccination. CASE PRESENTATION: A 63-year-old male patient with a history of habitual tonsillitis underwent bilateral tonsillectomy. He had a history of alcoholic cirrhosis of the liver and microscopic hematuria and proteinuria were indicated during a health checkup 2 years before hospital admission. He developed hematuria after the SARS-CoV-2 vaccination, which led to rapidly progressive glomerulonephritis, for which he was hospitalized. A renal biopsy led to the diagnosis of IgA nephropathy. Although pulse steroid therapy during his condition resulted in hepatic encephalopathy, three courses combined with mizoribine improved his renal function. CONCLUSION: SARS-CoV-2 mRNA vaccines activate T cells, which are involved in the pathophysiology of IgA nephropathy. Therefore, this case suggests that the exacerbation of IgA nephropathy by the vaccine favors the vasculitis aspect of the disease.

[Influence of habitual drinking and viral hepatitis type C in the progression of liver cirrhosis].

Recently prevalence of alcoholic liver disease has been increasing in Japan associated with an increase in alcoholic beverage consumption. In the present study, we addressed the recent trend in the etiology of liver cirrhosis (LC) in Japan, and investigated the influence of habitual drinking and viral hepatitis type C in the progression of LC. We carried out nation-wide survey by asking for the hospitals that are approved by the Japanese Society of Gastroenterology for the etiology of in-patients with LC, and compared to that in our hospital. Regarding the cases in nation-wide survey, 1274 cases (14%) of 9126 patients with LC were pure (without any markers of hepatitis virus) heavy drinkers, and 580 cases (6%) were heavy drinkers with any markers of hepatitis virus. However, in our general hospital, 24 cases of 101 patients with LC (24%) were pure heavy drinker, and 31 cases (30%) were heavy drinkers with any markers of hepatitis virus. In conclusion, although influence of hepatitis virus infection in alcoholic LC has been decreasing, it still plays an important role in the progression of alcoholic LC, especially in the general hospitals. Education of abstinence or low risk drinking is important not only heavy drinkers but also habitual drinkers with hepatitis virus infection.

Effect of a herbal medicine on fatty liver in rats fed ethanol chronically.

AIM: The objective of this study was to determine whether Cardiotopic Pills (CP) affects fatty liver in rats fed ethanol chronically. MATERIALS AND METHODS: Male Wistar rats were treated with liquid diet that contained ethanol (36% of total calories) or an isocaloric carbohydrate instead of ethanol for 6 weeks. CP, an oral herbal medicine including Danshen (Salviae Miltiorrhiza), Panax notoginseny and Dyroblanops aromatica gaertn, have been clinically used for vascular diseases such as coronary diseases and cerebral infarction. CP was administered orally with the liquid diets for 2 weeks 0.4 mg/kg body weight/day with the liquid diet thereafter. Serum triglyceride and total cholesterol levels, total protein, albumin, and AST and ALT activities are measured. Histological examination was also carried out. In another set of experiments, autofluorescence of NAD(P)H, an indicator of mitochondrial O2 consumption and redox status, was measured by an intravital microscopy, and peroxisome proliferators-activated receptor-(PPAR)-alpha and gamma mRNA levels were evaluated by real time quantitative PCR methods. RESULTS: Chronic ethanol consumption elevated serum triglyceride level, and caused fatty degeneration of liver. After administration of CP, fatty degeneration was not observed in rats fed ethanol chronically. Elevation of serum triglyceride level was not noted after treatment with CP (Ethanol: 79.4 +/- 9.3 mg/dl, Ethanol+CP: 48.0 +/- 4.4, respectively, p<0.05). CP did not affect any other laboratory data or NAD(P)H levels. Chronic ethanol consumption did not affect PPAR-gamma mRNA levels, while it decreased PPAR-alpha mRNA levels in the liver. CP prevented the ethanol-induced decrease in PPAR-alpha mRNA levels. CP and its components could enhance expression of PPAR-alpha mRNA levels. CONCLUSION: These results suggest that CP may be useful to prevent alcoholic fatty liver via enhanced expression of PPAR-alpha.

Ameliorating effects of compounds derived from Salvia miltiorrhiza root extract on microcirculatory disturbance and target organ injury by ischemia and reperfusion.

Ischemia and reperfusion (I/R) exerts multiple insults in microcirculation, frequently accompanied by endothelial cell injury, enhanced adhesion of leukocytes, macromolecular efflux, production of oxygen free radicals, and mast cell degranulation. Since the microcirculatory disturbance results in injury of organ involved, protection of organ after I/R is of great importance in clinic. Salvia miltiorrhiza root has long been used in Asian countries for clinical treatment of various microcirculatory disturbance-related diseases. This herbal drug contains many active water-soluble compounds, including protocatechuic aldehyde (PAl), 3,4-dihydroxyphenyl lactic acid (DLA) and salvianolic acid B (SalB). These compounds, as well as water-soluble fraction of S. miltiorrhiza root extract (SMRE), have an ability to scavenge peroxides and are able to inhibit the expression of adhesion molecules in vascular endothelium and leukocytes. Moreover, lipophilic compounds of SMRE also prevent the development of vascular damage; NADPH oxidase and platelet aggregation are inhibited by tanshinone IIA and tanshinone IIB, respectively, and the mast cell degranulation is blunted by cryptotanshinone and 15,16-dihydrotanshinone I. Thus, the water-soluble and lipophilic compounds of SMRE appear to improve the I/R-induced vascular damage multifactorially and synergically. This review will summarize the ameliorating effect of compounds derived from SMRE on microcirculatory disturbance and target organ injury after I/R and will provide a new perspective on remedy with multiple drugs.

Rho/Rho kinase is a key enzyme system involved in the angiotensin II signaling pathway of liver fibrosis and steatosis.

BACKGROUND AND AIM: The molecular mechanisms underlying the involvement of the renin-angiotensin system in hepatic fibrosis are unclear. Recently, it was reported that a Rho kinase inhibitor prevented fibrosis of various tissues and that the Rho/Rho kinase pathway was involved in the renin-angiotensin system of vascular smooth muscle cells. In this study, the involvement of the Rho/Rho kinase pathway on angiotensin II signaling in liver fibrogenesis and generation of steatosis was investigated. METHODS: Rats were fed a choline-deficient/L-amino acid-defined (CDAA) diet continuously and treated with a Rho kinase inhibitor, Y-27632, and an angiotensin II receptor blocker, TCV-116. Liver histology and hepatic stellate cell activation were analyzed. Free radical production was detected by 4-hydroxynonenal and 8-hydroxy-2'-deoxyguanosine immunostaining and the expression of tumor necrosis factor-alpha was examined. Isolated hepatic stellate cells were pretreated with a Rho kinase inhibitor, Y-27632, or an angiotensin II receptor blocker, CV-11974, and stimulated with angiotensin II, and mRNA expression of transforming growth factor-beta and alpha-smooth muscle actin was analyzed. RESULTS: Both the angiotensin II receptor blocker and the Rho kinase inhibitor improved fibrosis and steatosis of the liver in CDAA-fed rats. The increase in the number of hepatocytes positive for 4-hydroxynonenal and 8-hydroxy-2'-deoxyguanosine in CDAA-fed rats was significantly prevented by the angiotensin II receptor blocker and the Rho kinase inhibitor. The levels of tumor necrosis factor-alpha mRNA in the liver of CDAA-fed rats were significantly increased and this increase was significantly inhibited by treatment with the angiotensin II receptor blocker and the Rho kinase inhibitor. mRNA expression of transforming growth factor-beta and alpha-smooth muscle actin stimulated by angiotensin II was also significantly suppressed by these two drugs. CONCLUSION: These results suggest that the Rho/Rho kinase pathway is at least partly involved in the renin-angiotensin system and plays an important role in hepatic fibrosis and steatosis.

Role of microsomal enzymes in development of alcoholic liver diseases.

Chronic ethanol consumption results in the proliferation of the membranes of the smooth endoplasmic reticulum. Although these microsomal changes can be interpreted as adaptive alterations secondary to induction of the membranes after chronic ethanol ingestion, some injurious consequences may ensue. Accelerated ethanol metabolism results in enhanced production of acetaldehyde and exacerbation of its various toxic manifestations including enhanced lipid peroxidation. The latter may also be promoted more directly through enhanced free radical formation by the induced microsomes and cytochrome P4502E1 (CYP2E1). Ethanol-inducible CYP2E1 is of interest because of its ability to metabolize and activate many toxicologically important substrates including ethanol, CCl(4), acetaminophen, and N-nitrosodimethylamine, to more toxic products. Major interest in CYP2E1 reflects the ability of this enzyme to oxidize ethanol, to generate reactive products from ethanol oxidation (e.g. acetaldehyde and 1-hydroxyethyl radical), to activate various agents including CCl(4) and acetaminophen into reactive products, and to generate reactive oxygen species. There is considerable interest in the role of ethanol-induced oxidative stress and generation of reactive oxygen species in the mechanisms by which ethanol becomes hepatotoxic. To understand the basic effects and actions of CYP2E1, an approach has been established to utilize the cell lines that constitutively express human CYP2E1. This review article briefly describes a role of microsomal enzymes in the development of alcoholic liver injury as well as the usefulness of this cell line to further clarify the mechanisms of CYP2E1-related hepatotoxicity.

Helicobacter pylori, chronic atrophic gastritis, inactive aldehyde dehydrogenase-2, macrocytosis and multiple upper aerodigestive tract cancers and the risk for gastric cancer in alcoholic Japanese men.

BACKGROUND: Gastric carcinoma occurs at a high rate in alcoholic Japanese men. Inactive heterozygous aldehyde dehydrogenase-2 (ALDH2*1/2*2) and macrocytosis (mean corpuscular volume [MCV] > or = 106 fl) enhance the risk for esophageal carcinoma, which frequently occurs with gastric carcinoma in this population. Whether alcoholism affects Helicobacter pylori-induced chronic atrophic gastritis (CAG) is unknown. METHODS: This study of Japanese alcoholic men with (n = 45) and without (n = 281) gastric carcinoma included assessment of H. pylori IgG antibody, serum pepsinogen-confirmed CAG, MCV, and ALDH2 genotype. RESULTS: The gastric carcinoma cases had a significantly higher age-adjusted prevalence of H. pylori-positivity (78%vs 57%), CAG (78%vs 42%), ALDH2*1/2*2 (36%vs 14%), MCV > or =106 fl (38%vs 20%), and concurrent esophageal/oropharyngolaryngeal carcinoma (18%vs 5%) than controls. Among gastric cancer-free controls, the prevalence of CAG was higher than generally reported in Japan, regardless of H. pylori status (H. pylori-positive, 56%vs 35-36% for Japanese general population; H. pylori-negative, 8%vs 1-3%). Alcoholism may accelerate the progression of CAG. Each of these factors increased the risk of gastric carcinoma (OR(s) = 3.7 for H. pylori-positive, 2.7 for non-severe CAG, 8.7 for severe CAG, 3.5 for ALDH2*1/2*2, 2.5 for MCV > or =106 fl, and 3.7 for concurrent carcinoma). A multivariate analysis showed that CAG and ALDH2*1/2*2 were independently related to the risk of gastric carcinoma. Combinations of CAG and ALDH2*1/2*2 showed greater risks of gastric carcinoma (OR(s) = 4.0 for non-severe CAG alone, 17.6 for severe CAG alone, 9.7 for ALDH2*1/2*2 alone, 17.1 for non-severe CAG plus ALDH2*1/2*2, and 39.2 for severe CAG plus ALDH2*1/2*2). CONCLUSIONS: Combining blood tests for H. pylori, CAG, MCV and ALDH2 genotype could offer a new means of predicting risk of gastric carcinoma in Japanese alcoholic men.

Evaluation of platelet kinetics in patients with liver cirrhosis: similarity to idiopathic thrombocytopenic purpura.

BACKGROUND: Thrombocytopenia is a common manifestation of liver cirrhosis (LC), but its underlying mechanism is not fully understood. The purpose of the present paper was to evaluate the platelet kinetics in LC patients by examining several non-invasive convenient markers. METHODS: Fifty-seven LC patients, 32 patients with idiopathic thrombocytopenic purpura (ITP), 12 with aplastic anemia (AA), and 29 healthy individuals were studied. Plasma thrombopoietin was measured by enzyme-linked immunosorbent assay. Absolute reticulated platelet (RP) count and plasma glycocalicin were used as indices for thrombopoiesis, and the indices for platelet turnover were the RP proportion and the plasma glycocalicin normalized to the individual platelet count (GCI). RESULTS: There was no difference in thrombopoietin levels between LC patients and healthy controls. The RP proportion and GCI were significantly higher and the absolute RP count and glycocalicin significantly lower in LC patients than in healthy controls. These markers in ITP and LC patients were comparable, but significantly different from those in AA patients. The bone marrow megakaryocyte density in LC and ITP patients was similar, and significantly higher than in AA patients. CONCLUSIONS: Cirrhotic thrombocytopenia is a multifactorial condition involving accelerated platelet turnover and moderately impaired thrombopoiesis. Thrombopoietin deficiency is unlikely to be the primary contributor to cirrhotic thrombocytopenia.

p53 Protein accumulation, cancer multiplicity, and aldehyde dehydrogenase-2 genotype in Japanese alcoholic men with early esophageal squamous cell carcinoma.

Synchronous multiple intra-esophageal squamous cell carcinomas (SCCs) or oropharyngolaryngeal SCCs are common in alcoholics with esophageal SCC, and more frequently found in those with inactive heterozygous aldehyde dehydrogenase-2 (ALDH2). p53 alterations have been suspected as key molecular events in such multifocal esophageal carcinogenesis. We studied 95 Japanese alcoholic men with Tis and mucosal invasive esophageal SCC and found very high levels of p53 protein accumulation occurring in early esophageal SCC. Synchronous cancer multiplicity in the upper aerodigestive tract was found in 40 patients. p53 expression was not correlated with either cancer multiplicity or ALDH2 genotype. The risk for cancer multiplicity was associated with inactive heterozygous ALDH2 alone (OR=4.22) among the risk factors investigated, which also included smoking, less-active alcohol dehydrogenase-1B, and macrocytosis, enhancing the validity of the link between acetaldehyde exposure and cancer multiplicity.

[Alcoholic liver diseases and hepatitis virus C in Japan].

Recently incidence of alcoholic liver disease (ALD) has been increasing in Japan associated with an increase in alcoholic beverage consumption. There have been a large number of reports about the relationship between alcohol and hepatocarcinogenesis, but it remains controversial. In the present study, we addressed the recent trend in incidence of ALD including liver cirrhosis (LC), and hepatocellular carcinoma (HCC) in heavy drinkers in Japan. We carried out nation-wide survey by asking for the hospitals that are approved by the Japanese Society of Gastroenterology for recent aspects of in-patients with ALD. Except for HCC, percentage of ALD without viral hepatitis is more than 70%, which is increased when compared to the national survey carried out in 1992. In alcoholic LC patients, those who did not have viral hepatitis were 81%. However, the percentage of HCC without viral hepatitis was 34% of all of the heavy drinkers with HCC. Regarding the case in our university hospital, 138 cases (32%) of 432 patients with HCC were heavy drinkers. However, regarding in our general hospital, 15 cases of 23 patients with HCC (61%) were heavy drinkers. In conclusion, since the consumption of alcohol is increasing in Japan, the frequency and number of cases of alcoholic liver cirrhosis are increasing. Viral hepatitis infection, however, still plays an important role in hepatocarcinogenesis in heavy drinkers.

Risk of squamous cell carcinoma of the upper aerodigestive tract in cancer-free alcoholic Japanese men: an endoscopic follow-up study.

Asian case-control studies have shown a strong relationship between the development of squamous cell carcinoma (SCC) of the esophagus and alcohol consumption combined with inactive aldehyde dehydrogenase-2 (ALDH2*1/*2), less-active alcohol dehydrogenase-1B (ADH1B*1/*1), high mean corpuscular volume (MCV), and self-reported facial flushing in response to alcohol. However, little is known about whether these risk factors prospectively influence cancer development in cancer-free alcoholics. Between 1993 and 2005, 808 Japanese alcoholic men diagnosed as cancer-free by an initial endoscopic screening examination received follow-up examinations ranging from 1 to 148 months (median, 31 months) later, and SCC of the upper aerodigestive tract was diagnosed in 53 of them (esophagus in 33 and oropharyngolarynx in 30). Cox proportional hazards analysis showed that the age-adjusted relative hazard for SCC was 11.55 [95% confidence interval (95% CI), 5.73-23.3] in ALDH2*1/*2 heterozygotes compared with ALDH2*1/*1 homozygotes, 2.02 (95% CI, 1.02-4.02) in ADH1B*1/*1 homozygotes compared with ADH1B*1/*2 heterozygotes or *2/*2 homozygotes, 2.64 (95% CI, 1.49-4.67) in patients with flushing compared with those who had never experienced flushing, 2.91 (95% CI, 1.63-5.20) in those with an MCV >or= 106 compared with those with an MCV < 106, 2.52 (95% CI, 1.22-5.22) in those who smoked >or=30 cigarettes per day compared with those who smoked 0 to 19 cigarettes per day, 7.26 (95% CI, 3.99-13.23) in those with esophageal dysplasia compared with those without distinct iodine-unstained lesions >or=5 mm, and 0.28 (95% CI, 0.09-0.85) in those with body mass index >or= 23.2 (highest quartile) compared with those with body mass index < 19.0 (lowest quartile). These predictors are useful for selecting appropriately patients for careful follow-up examinations.

Role of erythrocytes as a reservoir for ribavirin and relationship with adverse reactions in the early phase of interferon combination therapy for chronic hepatitis C virus infections.

We investigated the relationship between serum ribavirin concentrations and clearance, as well as therapeutic efficacy and adverse reactions, in 97 Japanese patients with chronic hepatitis C virus infections treated with a 6-month course of high-dose alpha2b interferon (6 million units/day) plus ribavirin (600 to 800 mg/day) combination therapy. This randomized trial showed that the saturation of ribavirin uptake after taking ribavirin capsules does not occur within a dose range of 600 to 800 mg/day, which is a standard dosage used clinically in Japan. Serum ribavirin concentrations and clearance did not correlate with sustained virological response rates. Fourteen patients discontinued therapy because of adverse reactions, and sustained virological response rates were significantly reduced by discontinuation of therapy, while dose reduction of ribavirin did not alter the therapeutic effects. Ribavirin concentrations after 1 week and ribavirin clearance were significantly correlated with discontinuation of ribavirin; however, a multiple-regression analysis revealed that only hemoglobin concentration, but not ribavirin clearance, was a significant factor for discontinuation of therapy (odds ratio, 0.514; 95% confidence interval, 0.311 to 0.85; P = 0.0095). It appears that peripheral erythrocytes may act as a reservoir for ribavirin and regulate serum ribavirin levels in the very early phase of treatment.

Increased serum and hepatic tissue levels of interleukin-18 in patients with fulminant hepatic failure.

BACKGROUND: Fulminant hepatic failure is a serious clinical condition associated with a high mortality rate. Interleukin (IL)-18 is a pro-inflammatory cytokine that is associated with several inflammatory diseases. The purpose of the present paper was therefore to investigate whether IL-18 is elevated in patients with fulminant hepatic failure. METHODS: Serum levels of IL-18 were measured in patients with fulminant hepatic failure before and after liver transplantation. Native liver tissue samples were collected and the tissue levels of IL-18 were determined. Liver tissues were stained immunohistochemically with antihuman IL-18 antibody. The serum levels of IL-1beta, IL-6, IL-8, IL-12, interferon-gamma, and tumor necrosis factor-alpha were also determined in patients with fulminant hepatic failure before and after liver transplantation. RESULTS: Elevated levels of IL-18 in serum and hepatic tissue were observed in patients with fulminant hepatic failure. Native liver tissue samples were immunohistochemically positive for IL-18. Interleukin-18 levels were markedly reduced after liver replacement. No other inflammatory cytokines were substantially elevated in patients with fulminant hepatic failure. CONCLUSION: The serum levels of IL-18 levels are elevated much more than those of other cytokines in patients with fulminant hepatic failure.

Induction therapy with twice-daily interferon-beta does not improve the therapeutic efficacy of consensus interferon monotherapy for chronic hepatitis C.

We examined therapeutic superiority of induction therapy with twice-daily IFN-beta (3X2=6 million units/day) onto 6-months consensus interferon monotherapy for chronic hepatitis C. Patients were randomly assigned to monotherapy without (group I, n=16) and with induction therapy (group II, n=12). The mean age of group II was older than that of group I, and other baseline condition was not statistically significant. Sustained virological response (SVR) rates of group I and II were 81.3% (13/16) and 58.3% (7/12), respectively (p=0.365). SVR rates in patients with genotype 1b were 66.7% (4/6) and 0% (0/2, because of drop-out), and those with high viral load were 70% (7/10) and 75% (6/8) in group I and II, respectively (p=1.000). Drop-out rates during therapy were 6.3% (1/16) and 33.3% (4/12) in group I and II, respectively (p=0.176). Age less than 50 years was the only independent factor that was shown by multivariate logistic model analysis to be associated with a sustained virological response. Although randomization failed to produce and equal age distribution in the two groups in this study, our results suggest that induction therapy with twice-daily IFN-beta has no beneficial effect on the efficacy of monotherapy with consensus interferon, probably because of the higher drop-out rates and incidence of adverse reactions with induction therapy.

Melanosis and squamous cell neoplasms of the upper aerodigestive tract in Japanese alcoholic men.

Melanosis is frequently observed in the upper aerodigestive tract of Japanese alcoholic men, and the prevalences of squamous cell dysplasia and SCC in the upper aerodigestive tract of Japanese alcoholic men are high. This study evaluated associations between melanosis and both neoplasms of the upper aerodigestive tract and factors contributing to the development of melanosis in Japanese alcoholic men. Endoscopic screening of 643 Japanese alcoholic men (aged 50-79 years) was combined with oropharyngolaryngeal inspection and esophageal iodine staining, and ALDH2 genotyping was carried out in 425 of them. Melanosis was frequently (20.8%) observed in the upper aerodigestive tract. The palate was the most common site of melanosis (11.2%), followed by the pharynx (9.5%), and by the esophagus (7.0%). The incidence of melanosis was higher in those with esophageal dysplasia (31/126, 24.6%), esophageal SCC (19/42, 45.2%), and oropharyngolaryngeal SCC (8/14, 54.1%) than in cancer- and dysplasia-free controls (69/437, 15.8%). The presence of melanosis was associated with a higher risk of esophageal dysplasia, esophageal SCC, and oropharyngolaryngeal SCC (OR 1.69, 4.03, and 6.61, respectively). Multivariate analysis showed that older age, heavier smoking, and heterozygosity for inactive ALDH2 were positively associated with the presence of melanosis. The presence of melanosis indicates a high risk for neoplasms in the upper aerodigestive tract of Japanese alcoholic men. Melanosis and neoplasms have the same causes, including older age, heavy smoking, and high acetaldehyde exposure.

[Current trends of NASH/NAFLD in Asia-Pacific region].

In Japan, much attention has been paid to NASH and NAFLD for the past several years and the prevalence of this disease entity has been estimated, and NASH is thought to be present in 10% of those who have fatty liver diseases. Other points out the prevalence of NASH in Japan as 6 to 8 hundred thousand patients. The last two or three decades have seen the evolution of Western-style life of near complete inactivity, energy-dense food choices and liberal fiscal resources to obtain them and other means to avoid physical activity. Moreover, what is increasingly apparent is that NASH and NAFLD is not a Western disease and many population groups in the Asia-Pacific region are particularly prone to type 2 diabetes. Thus, it is not surprising that NASH has increasingly been diagnosed in several regions in Asia including Indonesia, Malaysia, Philippines, Thailand and India.