Spontaneous Resolution of Chronic Hepatitis C – A Case Report

We experienced a case of chronic hepatitis C showing spontaneous resolution. The patient was diagnosed as having chronic hepatitis with moderate activity, non-A non-B type, after laparoscopy with liver histology in 1982, and was followed up thereafter at our out-patient clinic. His aspartate aminotransferase (AST)and alanine aminotransferase (ALT) levels fluctuated but had stabilized by 1990. A second laparoscopy with liver histology, conducted in 1993, revealed non-specific reactive hepatitis. Serum hepatitis C virus RNA (HCV-RNA) had been strongly positive in 1982 but was negative in 1990. Interferon therapy may not be indicated in such cases.     

Acetaminophen-induced Liver Injury: from Animal Models to Humans

Drug-induced liver injury is an important clinical problem and a challenge for drug development. Whereas progress in understanding rare and unpredictable (idiosyncratic) drug hepatotoxicity is severely hampered by the lack of relevant animal models, enormous insight has been gained in the area of predictable hepatotoxins, in particular acetaminophen-induced liver injury, from a broad range of experimental models. Importantly, mechanisms of toxicity obtained with certain experimental systems, such as in vivo mouse models, primary mouse hepatocytes, and metabolically competent cell lines, are being confirmed in translational studies in patients and in primary human hepatocytes. Despite this progress, suboptimal models are still being used and experimental data can be confusing, leading to controversial conclusions. Therefore, this review attempts to discuss mechanisms of drug hepatotoxicity using the most studied drug acetaminophen as an example. We compare the various experimental models that are used to investigate mechanisms of acetaminophen hepatotoxicity, discuss controversial topics in the mechanisms, and assess how these experimental findings can be translated to the clinic. The success with acetaminophen in demonstrating the clinical relevance of experimental findings could serve as an example for the study of other drug toxicities.     

HBcrAg Predicts Hepatocellular Carcinoma Development in Chronic B Hepatitis Related Liver Cirrhosis Patients Undergoing Long-Term Effective Anti-Viral

Hepatitis B core-related antigen (HBcrAg) is a predictor of hepatocellular carcinoma (HCC) in chronic hepatitis B (CHB) patients. Studies on anti-viral therapy have shown that the use of NUC therapy in HBV patients could reduce the incidence of HCC. However, the incidence of HCC continues to increase after long-term anti-viral therapy. The relationship between HBcrAg and HCC development in CHB-related liver cirrhosis (LC) patients undergoing long-term anti-viral therapy is still unclear. This study enrolled 1108 treatment-naïve CHB patients diagnosed with HBV-related LC receiving NUC therapy from April 1999 to February 2015. The baseline biomarkers, disease history, and following results were collected by the hospital. Among the 1108 patients, 219 developed HCC within a median follow-up period of 6.85 years. A multivariable Cox regression model was used, with adjustment for age, gender, FIB-4, DM, and HBsAg-HQ. The adjusted hazard ratios for the HBcrAg tertile levels were 1.70 (95%CI: 1.21, 2.39) and 2.14 (95%CI: 1.50, 3.05) for levels 3.4–4.9 and >4.9 logU/mL, respectively, compared with levels ≤3.4. The effect of the HBcrAg level on HCC incidence was found to be significantly modified by HBsAg-HQ, where lower HBsAg-HQ (≤ 3) values were associated with a significantly higher risk, but HBsAg-HQ levels >3 were not. Our results highlight that, after adjustment for potential confounding factors, patients with CHB-related LC and higher HBcrAg levels are at significant risk for HCC development, even while undergoing long-term effective anti-viral therapy. The HBcrAg level is therefore an independent risk factor for HCC development, especially for patients with HBsAg-HQ levels <3.     

Characteristics of Upper Abdominal Pain in Those with Chronic Liver Disease

Chronic hepatitis has many causes. Symptoms include upper abdominal pain. To allow for a better understanding of this pain we compare HCV patients with other liver diseases and normal controls on their reporting of pain over one month and describe associations. A cross-sectional, case control study was performed. Three groups are studied: (1) normal individuals (NC) (N = 64), (2) patients with chronic liver diseases other than HCV (LD) (N = 53), and (3) HCV infection (N = 64). A dyspepsia questionnaire was utilized, which inquired about a one-month symptom presence of upper abdominal pain and associated symptoms. There was a one-month period prevalence of upper abdominal pain of 45.3% in the HCV group vs 32% in the LD and 20.3% in the NC groups (P = 0.01). The LD (22.6%) and HCV (26.6%) groups had markedly more pain that was worsened by eating compared with NC (1.6%) (P = .003). On univariate analysis, when comparing those with upper abdominal pain to those without, there was a lower age (41.3 vs 44.5), a higher BMI (30.3 vs 26), and more symptoms of fatigue, bloating, and pain worsened by eating and early satiety. On multivariate analysis, age < 50 (OR 5.1; CI 1.5–17), BMI > 30 (OR 4.1; CI 1.5–10.9), nausea (OR 4.1; CI 1.6–10.4), and pain with eating (OR 30: CI 6.7–133) predicted upper abdominal pain. In conclusion, upper abdominal pain is more commonly reported over one month in those with chronic liver diseases. That the abdominal pain worsened after meals in liver patients but not in the normal subjects was a surprise. Possible explanations for this finding are offered.     

药物性肝损伤伴自身免疫现象1例

病例：患者男,80岁,因＂乏力伴尿色加深20 d、加重5 d＂于2010年1月23日入院.患者20 d前体检发现ALT106 U/L,伴轻度乏力、尿色加深,无皮肤、巩膜黄染,无厌油、纳差、恶心、呕吐、腹痛、腹胀等,未予以诊治.5d前因尿黄加重于我院消化科门诊复查示ALT 866 U/L、AST 614 U/L、总胆红素（TBIL）62.8μmol/L、直接胆红素（DBIL）36μmol/L;HBsAg（-）、抗-HEV IgM（-）、抗-HAV IgM（-）;尿常规示胆红素少量;腹部B超示肝囊肿.遂以＂转氨酶升高原因待查＂收入消化科.患者自发病以来,精神可,纳可,睡眠欠佳,大便正常,体质量无明显改变.     

慢性肝炎病人结肠粘膜机械屏障的损伤

目的：搪塞慢性肝病时内毒素及其它肠腔抗原进入门脉系统的途径。方法：本研究共收集ＨＢｓＡｇ阳性的慢性肝炎病人１３例，纤维内镜下取乙状结肠粘膜，进行病理和超微病理学观察。结果：研究发现，结肠粘膜上皮细胞表面糖衣减少或消失，微绒毛排列紊乱、变形、紧密连接松解、线粒体和内质网变性等。病变与肝损伤严重程度相关。轻度慢性肝炎没有或病变很轻，重度慢性肝炎及肝硬变明显。结论：严重肝损伤可引起肠粘膜病变，成为内毒素     

Hepatitis B Virus Genomes of Chronic Hepatitis Patients Do Not Contain Specific Mutations Related to Acute Exacerbation

To determine the specific viral variants associated with acute exacerbation of chronic hepatitis from hepatitis B virus (HBV) infection, we analyzed the complete nucleotide sequences of the HBV genome in serial serum samples from two chronic active hepatitis patients who seroconverted from HBeAg to anti-HBe. HBV DNA was amplified by polymerase chain reaction (PCR) and sequenced. A 1896 precore stop codon mutant (G to A at nt 1896) coexisting with the wild sequence was found in both patients prior to seroconversion from HBeAg to anti-HBe. Core promoter mutations at nucleotide positions 1762 (A to T) and 1764 (G to A) were found in both patients throughout the observation period. Mutations were observed in the HBV genome of the two patients at different time points, and there was no correlation between the mutations and liver disease or DNA polymerase levels. The nucleotide divergence rate and the composition of quasispecies in the HBV sequence at the time of acute exacerbation were almost the same as were found at other time points. These results suggest that acute exacerbation does not appear to be caused by a characteristic HBV species. The multiple factors that cause generalized HBV replication activation may contribute to acute exacerbation.     

Factors Related to Sleeping Disorder Due to Pruritus in Patients with Chronic Liver Disease

Objective This study evaluated cases of pruritus, which is known to be associated with sleep disorder, in chronic liver disease (CLD) patients. Methods Questionnaires were given to 339 enrolled CLD outpatients in winter (November 2019 to March 2020) and again in summer (April to October 2020) (median interval: 104 days). Relative changes in symptoms shown by a visual analogue scale (VAS) and Kawashima''s pruritus score between winter and summer were evaluated in Study 1 (n=199), while Study 2 examined the clinical features of patients with sleep disorder based on the results of the second questionnaire (n=235, median age 70 years old; 141 men, liver cirrhosis 37%). Results Study 1. There was a significant relationship in VAS between daytime and nighttime for each season, as well as between winter and summer for each time period (p<0.001). A comparison of Kawashima''s pruritus scores for the daytime and nighttime showed no significant seasonal differences (p=0.436 and 0.828, respectively). When Kawashima''s score increased, so did the average VAS for both daytime (0:1:2:3:4=0.4±0.2:1.4±0.9:3.0±1.8:5.9±2.1:6.2±2.3) and nighttime (0:1:2:3:4=0.3±0.1:1.4±1.5:3.5±2.3:6.7±2.6:6.9±1.8) (p<0.001 for both). Study 2. Twenty subjects (8.5%) complained of sleep disorder. An elevated FIB-4 index (≥3.07) showed a good predictive value for sleep disorder (p<0.01). The cut-off for the daytime and nighttime VAS values for existing sleep disorder were 1.6 [area under the curve (AUC) 0.901] and 3.4 (AUC 0.931). The respective sensitivity, specificity, and positive and negative predictive values for sleep disorder based on Kawashima''s score (≥2) were 0.85, 0.28, 0.10, and 0.95 for the daytime and 1.00, 0.29, 0.12, and 1.00 for the nighttime. Conclusion Intervention against pruritus is recommended in CLD patients with a high Kawashima''s score (≥2) in any season, especially with an elevated FIB-4 index.     

慢性乙型肝炎患者肝组织炎症与肝功能和乙型肝炎病毒标志物的关系

目的：探讨慢性乙型肝炎（乙肝）和活动性肝硬变肝组织病变与乙肝病毒标志物（HBVM）和肝功能的关系。方法：在Knodell的乙肝肝组织炎性活性指标（HAI）分类上采用3次密码读片。用常规的方法检测血清胆红素（SB）、丙氨酸转氨酶（ALT）、天冬氨酸转氨酶（AST）、白蛋白／球蛋白（A／G）比率，肝内HBsAg,HBcAg检测用PAP法。结果：SB、ALT、AST值随HAI记分值的增高而增高，慢性肝炎，活动肝硬变患者血清A、G的含量及A／G随HAI记分值的增高而变化，结论：HAI能客观定量的反映肝组织病变的程度，为疾病的诊断，治疗和预后判断提供一种实用的病理指标，并有利于微机图像阅片和统计学分析。     

Laparoscopic and Histopathologic Features of the Liver in Severe Chronic Active Epstein-Barr Virus Infection Syndrome: A Case Report

Abstract: A 40-year-old man was admitted to our hospital with persistent fever, generalized lymphadenopathy and hepatosplenoamegaly. Immunological examination demonstrated high titers of several anti-Epstein-Barr virus (EBV) antibodies, including anti-viral capsid antigens 1gG-antibody 1: 20, 480, anti-early antigens-DR IgG-antibody 1: 5, 120, and reduced activity of EBV-specific cytotoxic T lymphocytes. Laparoscopic features resembled those of chronic active viral hepatitis, including an uneven surface appearance and diffuse hepatic enlargement. Histopathological examination of a liver biopsy specimen showed inflammatory cell infiltration along sinusoidal surfaces (single file appearance) and enlarged portal areas with intralobular punched-out necrosis. The diagnosis was confirmed by detecting the EB viral genome in serum. Despite treatments with natural alpha-interferon, adenosine arabinocide and recombinant human interleukin-2, the patient died of progressive hepatic failure.     

Antibodies to Hepatitis E and A Viruses among Patients with Non-Alcoholic Chronic Liver Disease in Taiwan

Tsai J-F, Jeng J-E, Chang W-Y, Lin Z-Y, Tsai J-H. Antibodies to hepatitis E and A viruses among patients with non-alcoholic chronic liver disease in Taiwan. Scand J Gastroenterol 1994;29:651-654

Background: The prevalence of hepatitis E virus (HEV) and hepatitis A virus (HAV) infection in patients with non-alcoholic chronic liver disease (CLD) was assessed.

Methods: Antibody levels to HEV (anti-HEV) and HAV (anti-HAV) were evaluated in 100 pairs of CLD patients and healthy controls.

Results: The prevalence of anti-HEV was higher in patients (10.0%) than in controls (0%; p = 0.0001). There was no difference in anti-HAV positivity between patients (95%) and controls (93%). The patient group with anti-HEV was older (p equals; 0.024) and had more smokers (p equals; 0.03), having a higher prevalence of antibodies to hepatitis C virus (p equals; 0.02). Patients with anti-HAV were older than patients without (p equals; 0.0001). The prevalence of anti-HAV in patients more than 30 years old was higher than younger patients (95.1% versus 73.6%, p equals; 0.011). Conclusion: HEV may superinfect on chronic liver disease in an area hyperendemic for hepatitis A and B.     

Case Report: Interferon induced coma in Sheehan's syndrome

A 54-year-old woman who was being treated with 10 million units (mu) of natural interferon (IFN)-α per day for chronic active hepatitis C at a local clinic, developed coma on the fourth day of treatment. On admission to Yamagata University Hospital, she was still in a state of semicoma with severe hyponatraemia (122 mEq/L) and hypochloraemia (89 mEq/L). After the administration of electrolytes, her condition improved remarkably. Endocrinological loading tests showed a hypofunction of the anterior pituitary gland. In consideration of these results, and her past experiences of haemorrhage during childbirth and subsequent amenorrhoea, we diagnosed her illness as a coma as a result of Sheehan's syndrome which had become overt during IFN therapy. She recovered completely after treatment with hydrocortisone and 1-thyroxine.     

Diagnostic Accuracy of Laparoscopic Liver Biopsy in Chronic Liver Diseases,Comparison of Laparoscopic and US-Guided Liver Biopsy Results

Liver biopsies were carried out using three different needles, a Vim-Silverman needle 2.5 mm in outer caliber, an 18-Gauge (18G) Majima needle, and a 17-Gauge (17G) Majima needle. The biopsies were obtained from nearby locations on the liver surface under laparoscopic observation, to ascertain differences in histological diagnosis according to the size of the biopsy specimen. The biopsy specimens obtained with the Vim-Silverman needle were wider than those obtained with the other two needles. The agreement in histological diagnoses of the liver, obtained with the Vim-Silverman needle versus the 18G Majima needle, was 26.0%, while that between the Vim-Silverman needle and the 17G Majima needle was 40.0%. Histological diagnosis tended to be underestimated in small biopsy specimens in advanced chronic liver diseases. A questionnaire survey, conducted in 92 hospitals affiliated with Okayama University Medical School, revealed US-guided liver biopsy to be the practice of choice in 57 of 92 (62.0%) hospitals, and 18G needles were used in US-guided liver biopsy in 35 of 78 (45.2%) hospitals.     

Case Report: Agranulocytosis induced by interferon-α therapy for chronic hepatitis C

A 60-year-old woman presented with chronic active hepatitis C whose HCV-RNA genotype was II according to Okamoto's classification and serum HCV-RNA concentration was 10⁴ copies/mL. Agranulocytosis was induced 13 days from the commencement of interferon (IFN)-α 2b (6 MU/day) therapy, so the IFN therapy was immediately discontinued. The agranulocytosis improved rapidly with the administration of a granulocyte colony stimulating factor (G-CSF). The possibility that IFN was associated with maturational arrest of myeloid progenitor cells was considered. During the course of 3 years of follow-up, her liver function has remained normal and serum HCV-RNA remains negative.     

Hepatitis B Virus Gene in Liver Tissue Promotes Hepatocellular Carcinoma Development in Chronic Hepatitis C Patients

The hepatitis B virus (HBV) gene has been detected in hepatocellular carcinoma (HCC) tissue negative for the hepatitis B surface antigen and positive for the hepatitis C virus (HCV) antibody, but the precise role of the HBV gene in hepatocarcinogenesis has yet to be clarified. We studied the HBV gene in liver tissue several years before the emergence of HCC. Eleven patients diagnosed with HCV-positive chronic liver disease and who developed HCC were assigned to group A. HBV DNA was detected in 8 of the 11 patients (73%). Twenty-five patients, who did not develop HCC, were selected as group B. Six of the group B patients were classified as DNA-positive (24%). The HBV DNA in liver tissue was found to be significantly related to HCC development (P < 0.01). Thus, the presence of the HBV gene in patients with chronic HCV associated-liver injury appears to promote hepatocarcinogenesis, although prospective studies are needed to confirm this result.     

Fas、FasL在慢性乙型肝炎肝组织中的表达

探讨Fas、FasL在慢性乙型肝炎肝组织中的表达特点。对 30例慢性乙型肝炎患者进行肝穿刺肝组织病理检查及免疫组化法检测肝组织中的Fas/FasL表达强度。 (1)Fas、FasL在肝组织肝细胞膜及胞浆均有不同程度表达 ,其表达阳性细胞主要位于汇管区小叶内及周边碎屑状坏死区 ,呈弥漫分布 ,在其周围浸润的淋巴细胞上多为FasL阳性细胞 ,亦可见到Fas阳性细胞。 (2 )肝组织中Fas、FasL表达随着慢性肝炎程度即炎症和纤维化程度加重而加强 (P均 <0 0 0 1)。Fas-FasL系统介导的细胞凋亡 ,确实参与了慢性乙型肝炎的发病机制 ,且在慢性乙型肝炎的发生发展中起重要作用。     

Traditional Chinese Medicine Induced Liver Injury

Traditional Chinese Medicine (TCM) is popular around the world and encompasses many different practices with particular emphasis on herbal TCM. Using the PubMed database, a literature search was undertaken to assess the extent herbal TCM products exert rare hepatotoxicity. Analysis of reported cases revealed numerous specified herbal TCM products with potential hepatotoxicity. Among these were An Shu Ling, Bai Fang, Bai Xian Pi, Ban Tu Wan, Bo He, Bo Ye Qing Niu Dan, Bofu Tsu Sho San, Boh Gol Zhee, Cang Er Zi, Chai Hu, Chaso, Chi R Yun, Chuan Lian Zi, Ci Wu Jia, Da Chai Hu Tang, Da Huang, Du Huo, Gan Cao, Ge Gen, Ho Shou Wu, Hu Bohe You, Hu Zhang, Huang Qin, Huang Yao Zi, Hwang Geun Cho, Ji Gu Cao, Ji Ji, Ji Xue Cao, Jiguja, Jin Bu Huan, Jue Ming Zi, Kamishoyosan, Kudzu, Lei Gong Teng, Long Dan Xie Gan Tang, Lu Cha, Ma Huang, Mao Guo Tian Jie Cai, Onshido, Polygonum multiflorum, Qian Li Guang, Ren Shen, Sairei To, Shan Chi, Shen Min, Shi Can, Shi Liu Pi, Shou Wu Pian, Tian Hua Fen, White flood, Wu Bei Zi, Xi Shu, Xiao Chai Hu Tang, Yin Chen Hao, Zexie, Zhen Chu Cao, and various unclassified Chinese herbal mixtures. Causality was firmly established for a number of herbal TCM products by a positive reexposure test result, the liver specific scale of CIOMS (Council for International Organizations of Medical Sciences), or both. Otherwise, the quality of case data was mixed, especially regarding analysis of the herb ingredients because of adulteration with synthetic drugs, contamination with heavy metals, and misidentification. In addition, non-herbal TCM elements derived from Agaricus blazei, Agkistrodon, Antelope, Bombyx, Carp, Fish gallbladder, Phellinus, Scolopendra, Scorpio, and Zaocys are also known or potential hepatotoxins. For some patients, the clinical course was severe, with risks for acute liver failure, liver transplantation requirement, and lethality. In conclusion, the use of few herbal TCM products may rarely be associated with hepatotoxicity in some susceptible individuals, necessitating a stringent pretreatment evaluation of the risk/benefit ratio, based on results of multicenter, randomized, double-blind, placebo-controlled clinical trials.     

强肝胶囊对慢性肝病肝纤维化指标的影响

目的 :了解强肝胶囊对慢性肝病患者血清肝纤维化指标 [透明质酸 (HA)、 型胶原 (C )、 型前胶原 (PC )、层粘连蛋白 (L N) ]的影响。方法 :12 1例慢性肝炎患者随机分为两组 :治疗组 (6 9例 )给予强肝胶囊 ,每日3次 ,每次 5粒 ,连服 3个月 ;对照组 (5 2例 )采用常规护肝降酶等治疗。治疗前、后分别检测两组血清 HA、C 、PC 、L N水平。结果 :治疗组血清 HA、C 、PC 、L N明显下降 ,与对照组比较差异有显著性意义 (P <0 .0 1)。结论 :强肝胶囊有较好的抗肝纤维化作用 ,是治疗肝纤维化的有效药物。     

Hepatitis C Virus Infection among Patients with Chronic Liver Disease in an Area Hyperendemic for Hepatitis B

Tsai J-F, Jeng J-E, Chang W-Y, Lin Z-Y, Tsai J-H. Hepatitis C virus infection among patients with chronic liver disease in an area hyperendemic for hepatitis B. Scand J Gastroenterol 1994;29:550-552.

Background: The prevalence of hepatitis C virus (HCV) infection was assessed in patients with nonalcoholic chronic liver disease (CLD).

Methods: Antibody levels to HCV (anti-HCV) were assessed in 100 pairs of CLD patients and healthy controls.

Results: The prevalence of anti-HCV was higher in patients (26.0%) than in controls (2.0% p = 0.0001). The patient group with anti-HCV was older (p equals; 0.0001) and had more smokers (p equals; 0.034), fewer hepatitis B surface antigen carriers (p equals; 0.0001), and more patients with active liver disease (p equals; 0.023) and a history of blood transfusion (p equals; 0.026). Multivariate analysis showed that anti-HCV (odds ratio, 8.1; 95% confidence intervals, 3.7-17.6) was strongly associated with CLD.

Conclusions: HCV infection is a risk factor of non-alcoholic CLD, and HCV causes more severe hepatocellular damage than HBV.