Effect of direct-acting antivirals on platelet-associated immunoglobulin G and thrombocytopenia in hepatitis C virus-related chronic liver disease.

BACKGROUND & AIMS: Hepatitis C virus (HCV) infection has been known to cause various extrahepatic autoimmune disorders. The prevalence of platelet-associated immunoglobulin G (PA-IgG) has been high in patients with HCV infection. Because thrombocytopenia in HCV-related liver diseases is a notable problem, we performed prospective study on the effect of direct-acting antivirals (DAAs) treatment on PA-IgG and platelet count. METHODS: A total of 215 patients with HCV-related liver disease were enrolled in this study. The patients who discontinued DAAs or did not undergo adequate laboratory examinations and who did not achieve sustained virologic response were excluded and finally a total of 187 patients were investigated. RESULTS: A total of 171 patients (91.4%) were PA-IgG positive (>46 ng/107 cells) before starting DAAs (baseline). The PA-IgG level elevation was significantly correlated with higher liver inflammation and fibrosis markers (P < 0.05) and lower platelet count (P = 0.000019). The platelet count of the patients with low PA-IgG titer tended to be higher at baseline, end of treatment (EOT), and at 12 and 24 weeks after EOT. The platelet count increased at EOT (P < 0.05) and 24 weeks after EOT (P < 0.01). The PA-IgG levels were significantly decreased at EOT, 12 and 24 weeks after EOT (P < 0.01). Multiple regression analysis found that only platelet count at baseline was closely associated with negative conversion of PA-IgG at 24 weeks after EOT (P = 0.004). CONCLUSIONS: Eradication of HCV by DAAs treatment successfully decreased PA-IgG level and increased platelet count.

Recognition of infection, status of outpatient treatment, and treatment history before carcinogenesis in patients with viral hepatitis-associated liver cancer.

We conducted a survey on the recognition of infection, status of outpatient treatment, and treatment history in hepatitis virus-associated hepatocellular carcinoma patients admitted to our department between 2005 and 2014. We compared these parameters in 75 patients with primary hepatitis B virus-associated hepatocellular carcinoma (HBV-HCC) and 307 patients with hepatitis C virus-associated hepatocellular carcinoma (HCV-HCC). Based on the presence or absence of outpatient treatment in medical institutions at the time of HCC diagnosis, the patients were divided into an outpatient treatment-free group or an outpatient treated group. In addition, the latter group was divided into three subgroups depending on the department consulted:the Department of Internal Medicine group, the Department of Gastroenterology group, and a hepatologist-treated group. Patients in the outpatient treatment-free group accounted for 40.0% of patients with HBV-HCC. In the outpatient treated group (60.0%), 21.3% were treated in the Department of Internal Medicine, 22.7% in the Department of Gastroenterology, and 16.0% were treated by a hepatologist. The percentage of HBV-HCC patients in the outpatient treatment-free group was 1.9 times higher than that in the HCV-HCC group and 0.6-fold higher in the hepatologist-treated group. Of the HBV-HCC patients, non-recognizers who were not diagnosed with a viral infection accounted for 21.3%, and non-outpatients who had not consulted a hospital despite the recognition of infection accounted for 33.3%. These percentages were approximately 2 times higher than in HCV-HCC patients. Of the HBV-HCC patients, 66.7% in the hepatologist-treated group had received nucleic acid analogue preparations. On the other hand, one patient in each of the Department of Internal Medicine and Department of Gastroenterology groups (approximately 6.0%) had received a nucleic acid analogue, lamivudine, despite the appearance of a resistant strain. In the HBV-HCC patients, the proportions of "non-recognizers" and "non-outpatients" were higher than in the HCV-HCC patients, suggesting a lack of appropriate treatment.

Alleviation mechanisms against hepatocyte oxidative stress in patients with chronic hepatic disorders.

AIM: Autophagy induction and Mallory-Denk body (MDB) formation have been considered to have cytoprotective effects from cellular stress in liver diseases. We investigated the relations among oxidative stress, autophagy and MDB formation in patients with chronic hepatitis B (CHB), chronic hepatitis C (CHC) and non-alcoholic fatty liver disease (NAFLD) to clarify the alleviation mechanisms against oxidative stress of hepatocytes. METHODS: First, we treated cultured cells with proteasome inhibitor (PI) or free fatty acid (FFA) and evaluated endoplasmic reticulum (ER) stress, oxidative stress, ubiquitinated proteins and p62 by western blotting. Then, we used human liver biopsy samples to evaluate oxidative stress, autophagy and MDB formation by immunohistochemical analysis. RESULTS: Treatment with PI or FFA increased ER stress, oxidative stress, ubiquitinated proteins and p62 in cultured cells. Human liver biopsy samples of CHC and NAFLD showed that MDB formed in areas with strong oxidative stress and that the MDB-containing cells circumvented oxidative stress. Keratin 8 (K8) expression was strong in MDB-containing cells in CHC and NAFLD. However, in CHB samples, the expression of K8 was not increased in response to oxidative stress and MDB aggregates did not appear. Aminotransferase values were significantly lower in patients with CHC and NAFLD in whom light chain 3 antibody expression was increased in response to oxidative stress. CONCLUSION: Strong expression of K8 was considered to be important for MDB formation. MDB protect liver cells from oxidative stress at a cellular level and autophagy reduced hepatic damage when it was induced in the hepatocytes exposed to strong oxidative stress.

A case of idiopathic gastroesophageal submucosal hematoma and its disappearance observed by endoscopy.

A 74-year-old man was hospitalized due to hematemesis. Upper gastrointestinal endoscopy revealed a very large and dark red mass in the cardiac region of the stomach that extended from the upper esophagus. A biopsy specimen showed hemorrhagic tissue and no malignant cells. The tumor-like region ulcerated at 5 days after the administration of intravenous lansoprazole at a dose of 30 mg twice a day and resolved with scar formation at 2 months after a change to oral rabeprazole at a dose of 10 mg/day.We diagnosed the patient with gastroesophageal submucosal hematoma. Gastroesophageal submucosal hematoma is a rare complication. In this case, we could follow the process of its disappearance by endoscopy.

Hyperammonemia in a Woman with Late-onset Ornithine Transcarbamylase Deficiency.

A 52-year-old woman developed vomiting and disturbance of consciousness after consuming raw fish and sushi on a trip. A blood test showed hyperammonemia (310 µg/dL) with a normal liver function. She fell into a deep coma, and her serum ammonia level increased to 684 µg/dL. L-arginine was administered as a diagnostic treatment for urea cycle disorder (UCD) and serum ammonia, and her consciousness levels improved. She was diagnosed with ornithine transcarbamylase deficiency (OTCD) by analyses of plasma amino acids, urinary orotic acid, and the OTC gene mutation. UCD should be considered for patients with hyperammonemia without severe liver function abnormalities.

A Young Adult Patient with Nonalcoholic Steatohepatitis Developed Severe Gastroesophageal Varices Associated with Severe Obesity and Diabetes Mellitus.

Obesity is a major contributor to insulin resistance and nonalcoholic fatty liver disease, which is the most common cause of chronic liver diseases. Nonalcoholic steatohepatitis (NASH) can progress to liver cirrhosis and end-stage liver diseases. Some cases already show severe liver fibrosis at the time of diagnosis. We present the case of a 44-year-old male with overt obesity who was admitted with hematemesis due to the rupture of gastric varices. We diagnosed him with NASH with severe liver fibrosis. This case shows that we should be concerned about the progression of liver fibrosis due to NASH associated with severe obesity even in young patients.

Reactivation of Occult Hepatitis B Virus Infection 27 Months after the End of Chemotherapy Including Rituximab for Malignant Lymphoma.

A 68-year-old man with occult hepatitis B virus (HBV) infection was diagnosed with malignant lymphoma and achieved complete remission after treatment with a chemotherapy regimen including rituximab for 5 months. Entecavir (ETV) was also used during and after chemotherapy and was ended at 14 months after chemotherapy. However, reactivation of HBV was observed in blood tests, which showed not only elevation of HBV-DNA but also HBsAg and HBeAg, at 27 months after the end of chemotherapy. After restarting ETV, the HBV-DNA levels immediately subsided. In addition, anti-HBs became and remained positive at 31 months after chemotherapy. ETV was re-discontinued at 36 months after chemotherapy.

Bullous Pemphigoid Associated with the Dipeptidyl Peptidase-4 Inhibitor Sitagliptin in a Patient with Liver Cirrhosis Complicated with Rapidly Progressive Hepatocellular Carcinoma.

A 78-year-old man presented with cutaneous blisters of the limbs and abdominal distension. He had been treated for various diseases, including liver cirrhosis. He had begun receiving sitagliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor, for diabetes mellitus three years before the hospitalization. A skin biopsy demonstrated bullous pemphigoid. Ultrasonography (US) revealed multiple liver tumors, although he had been receiving regular US studies. We stopped sitagliptin and started insulin and corticosteroids. However, his renal dysfunction progressed, and he died 14 days after the hospitalization. We should therefore be careful of various complications, including bullous pemphigoid and progression of tumors, when using DPP-4 inhibitors.

Severe Alcoholic Hepatitis Effectively Treated with Vitamin E as an Add-on to Corticosteroids.

A 49-year-old woman with a history of heavy alcohol drinking was admitted to our hospital due to jaundice and abdominal distention. A blood test showed leukophilia, mild hypoalbuminemia, hyperbilirubinemia, hepatobiliary injury and coagulopathy. Image studies showed an extremely enlarged fatty liver and splenomegaly. The Japan alcoholic hepatitis score and Maddrey's discriminant function were 10 and 54 points, respectively. We diagnosed her with severe alcoholic hepatitis and treated her with corticosteroids, but her liver function did not improve. We therefore administered the vitamin E product tochopheryl acetate (150 mg/day) as an add-on therapy, after which her leukophilia, liver enzymes and coagulopathy improved immediately.

Daclatasvir and Asunaprevir Combination Therapy-induced Hepatitis and Cholecystitis with Coagulation Disorder due to Hypersensitivity Reactions.

A 70-year-old woman with chronic hepatitis C was admitted to our hospital due to liver injury, cholecystitis, and disseminated intravascular coagulation with a fever and skin rash. She had been on a combination regimen of daclatasvir and asunaprevir for 2 weeks of a 24-week regimen. Because of the symptoms, laboratory findings, results of a drug-induced lymphocyte stimulation test, and pathological findings of liver biopsy, we diagnosed her with drug-induced liver injury. Although daclatasvir and asunaprevir combination therapy is generally well-tolerated, some serious adverse effects have been reported. Our findings indicate that immunoallergic mechanisms were associated with daclatasvir and asunaprevir-induced liver injury.

Acute Liver Failure Complicated with Severe Heart Failure.

A young pregnant woman was hospitalized due to hepatitis B virus (HBV)-related acute liver failure (ALF). The cardiac function was normal on admission. However, she developed ALF concurrently with a coma and severe cardiac failure. The patient was diagnosed with severe acute cardiomyopathy due to diffuse hypokinesis of the left ventricle wall on ultrasound cardiography. Following intensive treatment, both the liver and cardiac function dramatically recovered. Although some factors, such as HBV, pregnancy and systemic inflammatory response syndrome, are possible causes of acute cardiomyopathy in the present case, ALF itself may be a risk factor for heart failure.

Hepatitis A complicated with acute renal failure and high hepatocyte growth factor: A case report.

A 58-year-old man was admitted to our hospital. Laboratory data showed severe liver injury and that the patient was positive for immunoglobulin M anti-hepatitis A virus (HAV) antibodies. He was also complicated with severe renal dysfunction and had an extremely high level of serum hepatocyte growth factor (HGF). Therefore, he was diagnosed with severe acute liver failure with acute renal failure (ARF) caused by HAV infection. Prognosis was expected to be poor because of complications by ARF and high serum HGF. However, liver and renal functions both improved rapidly without intensive treatment, and he was subsequently discharged from our hospital on the 21(st) hospital day. Although complication with ARF and high levels of serum HGF are both important factors predicting poor prognosis in acute liver failure patients, the present case achieved a favorable outcome. Endogenous HGF might play an important role as a regenerative effector in injured livers and kidneys.

Methotrexate-related primary hepatic lymphoma in a patient with rheumatoid arthritis.

A 56-year-old woman with rheumatoid arthritis treated with methotrexate (MTX) was admitted to our hospital due to multiple liver tumors. Contrast-enhanced computed tomography (CT) revealed multiple hypovascular masses, and 18F-fluorodeoxyglucose positron emission tomography CT showed diffuse abnormal accumulation in the liver only. We therefore made a diagnosis of MTX-related primary hepatic lymphoma (MTX-PHL) exhibiting features of diffuse large B-cell lymphoma. Although MTX has been reported to increase the risk of lymphoproliferative disorders, MTX-PHL has not been reported previously. The present case is the first case in which MTX appears to have been involved in the development of PHL.

Hepatic peribiliary cysts with rapidly progressive refractory obstructive jaundice and esophageal varices.

A 54-year-old man with decompensated alcoholic liver cirrhosis presented with acute cholangitis. Although no localized lesions were detected in the liver on contrast-enhanced computed tomography and no risky varices were noted on endoscopy, hepatic peribiliary cysts (HPBCs) developed along the intrahepatic portal vein in the course of only 40 days. Moreover, esophageal varices with the red color sign grew rapidly during the same period, and the patient ultimately died due to rupture. HPBC formation is a rare complication of liver disease, including cirrhosis. Although HPBCs are generally harmless, on rare occasions they may induce the rapid progression of esophageal varices.

Early decrease in serum IV-7S levels during IFN treatment predicts anti-fibrogenic effect in nonresponders with chronic hepatitis C.

BACKGROUND: We evaluated whether early changes in serum levels of fibrogenic markers during interferon (IFN) treatment can predict long-term anti-fibrogenic effects in patients with chronic hepatitis C (CHC). METHODS: We retrospectively examined the serum levels of N-terminal peptide of type III procollagen (P-III-NP) and 7S domain of type IV collagen (IV-7S) in 56 patients with CHC who were revealed to be IFN-nonresponders. We measured these markers before (T0) and 1 month (T1) after the commencement of IFN therapy, at the end of 24 weeks' IFN therapy (T24), and 1 year (T24-1) and more than 2 years (T24-2) after the cessation of IFN therapy. We also measured these markers twice, at intervals of more than 2 years, in 43 IFN-untreated patients with CHC as controls. RESULTS: In nonresponders, both P-III-NP and IV-7S levels at T24-2 were significantly decreased compared with those at T0. P-III-NP levels at T1 were significantly decreased compared with those at T0, and remained at significantly low levels until the end of the observation period. IV-7S levels at T1 were not significantly different from those at T0. In patients whose IV-7S levels at T24-2 were decreased compared with those at T0, IV-7S levels at T1 were significantly lower than those at T0. In patients whose IV-7S levels at T24-2 were elevated or unchanged compared with those at T0, IV-7S levels at T1 were significantly higher than those at T0. In untreated patients, both P-III-NP and IV-7S levels at more than 2 years after the initial time were significantly increased compared with those at the initial time. CONCLUSIONS: An early decrease in IV-7S levels after IFN treatment is a useful indicator of anti-fibrogenic effects in nonresponders.

Activation of hepatic macrophage contributes to hepatic necrosis after post-ischemic reperfusion in alcoholic fatty liver.

Fatty livers are vulnerable to ischemia/reperfusion (I/R) injury. We investigated the role of hepatic macrophages in the I/R injury in the fatty liver. Rats with alcoholic or nonalcoholic fatty liver were subjected to hepatic warm ischemia for 30 min. A bolus of gadolinium chloride (GdCl(3)) was injected intravenously twice before I/R to block hepatic macrophage activity. Alcoholic fatty liver developed more extensive hepatic necrosis with neutrophil infiltration in association with a higher production of cytokine-induced neutrophil chemoattractant (CINC)-1, a potent neutrophil chemokine in rat, after I/R than the nonalcoholic fatty liver or control liver without steatosis. Hepatic apoptosis after I/R increased to a similar degree (3-fold) in each of the two fatty liver models, compared with the control liver. Alcoholic fatty liver exposed to I/R showed a rapid increase in nuclear factor-kappa B (NF-kappaB) binding activity. The GdCl(3) pretreatment significantly reduced NF-kappaB binding activity, CINC-1 level and necrosis in alcoholic fatty liver, despite no significant decrease in the extent of apoptosis. Our results suggest that the activation of hepatic macrophages in alcoholic fatty liver may contribute to hepatic necrosis after I/R, and that the apoptosis might be less dependent on the macrophage activity.

Refractory primary hepatic actinomycosis with direct infiltration to the diaphragm and thorax: the usefulness of contrast-enhanced ultrasonography.

An 80-year-old man was admitted to our hospital with a diagnosis of primary hepatic actinomycosis determined based on a percutaneous aspiration biopsy. The abscesses and state of liquefaction were easily and effectively visualized on contrast-enhanced ultrasonography. Ampicillin/sulbactam was administered; however, lesions of hepatic actinomycosis suddenly infiltrated the diaphragm and right thorax six months later. A drainage tube was inserted into the right thoracic space, and the pleural effusion gradually decreased. The patient received continuous antibiotic therapy for nearly two years and remained free of hepatic actinomycosis on follow-up more than one year later.

Churg-Strauss syndrome manifesting as cholestasis and diagnosed by liver biopsy.

A 56-year-old woman was referred to our hospital due to fever and cholestatic liver dysfunction. Her eosinophil count was normal and she had no abdominal pain or neurological manifestations. We performed a liver biopsy and found fibrinoid necrosis of the hepatic artery with granulomatous reaction and eosinophilic infiltration in the portal area in the liver. Later, sensory abnormalities of the arms and legs appeared and the eosinophil count increased. Serum immunoglobulin E and immunoglobulin G4 were elevated and rheumatoid factor was strongly positive. Endoscopic retrograde cholangiopancreatography revealed no abnormality of the bile duct and pancreatic duct. We made a diagnosis of Churg-Strauss syndrome and began corticosteroid treatment. Fever and liver function immediately improved. In the present patient, Churg-Strauss syndrome manifested first in the liver, before hypereosinophilia and neural manifestations. We believe that Churg-Strauss syndrome is an autoimmune liver disease, and it is important to recognize that the liver may be involved in Churg-Strauss syndrome.

Poorly differentiated neuroendocrine carcinoma of the pancreas responsive to combination therapy with gemcitabine and S-1.

Poorly differentiated neuroendocrine carcinoma is a very rare malignancy, but it is characterized by agressive histological features and a poor clinical prognosis. We report a 42-year-old man who had poorly differentiated neuroendocrine carcinoma of the pancreas with multiple liver metastases. We administrated combined chemotherapy with S-1 and gemcitabine. This treatment was efficacious and well tolerated, and then this patient obtained objective partial response for 7 months and survived for 13 months after the diagnosis. This case suggests that S-1 and gemcitabine combination produce beneficial responses for patients with this disease.

A case of adult autoimmune hepatitis with histological features of giant cell hepatitis.

Giant cell hepatitis is rare in adult patients. This form of hepatitis shows fast progression to cirrhosis. A 65-year-old woman was admitted to our hospital with jaundice. She was negative for hepatitis virus markers and positive for antinuclear antibodies. We diagnosed her as autoimmune hepatitis. Liver biopsy findings revealed typical features of interface hepatitis and giant cell hepatitis. Giant cells were positive for keratin 8/18, but not for keratin 19, keratin 7 or Ki-67. These results suggest that giant cell formation is associated with the fusion of matured hepatocytes rather than the active proliferation of immature cells.