Two Cases with Isolated Splenic Sarcoidosis Diagnosed by an Ultrasound-guided Fine-needle Aspiration Biopsy.

Asymptomatic splenic nodules were detected incidentally in two middle-aged women at an annual checkup. They showed no abnormalities on laboratory tests, but imaging studies revealed splenic nodules. No other localized lesions were found. Splenic nodules were hypoechoic on ultrasonography (US), hypovascular on contrast-enhanced computed tomography, and showed a low intensity on T2-weighted magnetic resonance imaging. We performed US-guided percutaneous aspiration biopsies using 21-gauge needles without complications, including bleeding. Pathological specimens showed noncaseating granulomas, so both patients were diagnosed with isolated splenic sarcoidosis. A US-guided fine-needle aspiration biopsy is a safe and useful method for diagnosing splenic nodules.

Impact of Interferon-Free Direct-Acting Antivirals on the Incidence of Extrahepatic Malignancies in Patients with Chronic Hepatitis C.

BACKGROUND: The incidence of extrahepatic malignancies (EHMs) after hepatitis C virus (HCV) eradication by interferon (IFN)-based and IFN-free direct-acting antivirals (DAAs) treatment remains unclear. AIMS: The aim was to evaluate the cumulative incidence of EHMs diagnosed for the first time after the antiviral treatments. METHODS: We analyzed a total 527 patients with chronic HCV infection and without prior history of any malignancies who achieved sustained virological response by antiviral treatments, including IFN-based (n = 242) or IFN-free DAAs (n = 285). The baseline predictors for EHM occurrence were analyzed using Cox regression analysis. RESULTS: Thirty-two patients were diagnosed with EHMs, 14 in IFN-based and 18 in IFN-free DAAs, respectively. The total duration of follow-up was 1,796 person-years in IFN-based and 823 person-years in IFN-free DAAs. The incidence of EHMs in IFN-based and IFN-free DAAs was 7.8 and 21.9 per 1,000 person-years, respectively. The cumulative incidence of EHMs was significantly higher in IFN-free DAAs than IFN-based (p = 0.002). IFN-free DAAs was a single independent predictor for incidence of EHMs (p = 0.012). As for gender, the incidence of EHMs was significantly higher in IFN-free DAAs only in the female cohort (p = 0.002). After propensity score matching, IFN-free DAAs was a single independent predictor for incidence of EHMs in the female patients (p = 0.045). CONCLUSIONS: The incidence of EHMs after HCV eradication is higher in IFN-free DAAs than IFN-based regimens, especially in female patients. We should carefully follow-up not only HCC but also EHMs after IFN-free DAAs regimens.

Hepatocyte Growth Factor and Primary Systemic Amyloidosis.

A 75-year-old-man experienced liver dysfunction and was diagnosed with decompensated liver cirrhosis. His serum hepatocyte growth factor (HGF) was very high (16.24 ng/ml). Because the etiology was unclear, we considered the possibility of amyloidosis. Biopsy of the mucosa of the stomach, duodenum and rectum demonstrated amyloid deposition. From the findings of Congo red staining and immunohistochemical analyses, we made a diagnosis of systemic amyloid light-chain amyloidosis. Unfortunately, the patient died one month after the diagnosis. We considered that serum HGF was useful for the diagnosis and prediction of prognosis of primary systemic amyloidosis.

Rapid Progression of Liver Fibrosis Induced by Acute Liver Injury Due to Immune-related Adverse Events of Atezolizumab.

A 72-year-old woman with advanced lung cancer had received systemic chemotherapy including atezolizumab. About three months after the initial administration of atezolizumab, her liver enzyme levels increased. The histopathological findings of the initial liver biopsy revealed acute inflammatory infiltrate, predominantly CD3+, CD4+ and CD8+ T lymphocytes, in the hepatic lobules. We diagnosed her with atezolizumab-induced immune-related acute hepatitis. Oral corticosteroid therapy successfully improved the elevation of serum aminotransferases. A sequential liver biopsy demonstrated the rapid progression of liver fibrosis. Because hepatocellular carcinoma occurs most often in advanced cases of chronic liver disease, we should pay close attention to immune-related acute hepatic injury when treating patients with advanced liver diseases using atezolizumab.

Type 4B hereditary hemochromatosis due to heterozygous p.D157A mutation in SLC40A1 complicated with hypopituitarism.

Hemochromatosis is a clinical syndrome characterized by iron overload in various organs. We present here a case of type 4 hereditary hemochromatosis due to heterozygous mutation in SLC40A1 gene (p.D157A). SLC40A1 encodes ferroportin, a macromolecule only known as iron exporter from mammalian cells. He first presented symptoms correlated with hypopituitarism. Furthermore, marked hyperferritinemia and high transferrin saturation were revealed in combination with the findings of iron overload in the liver, spleen and pituitary gland by computed tomography and magnetic resonance imaging. Liver biopsy revealed iron deposition in both hepatocytes and Kupffer cells. SLC40A1 mutations are considered to cause wide heterogeneity by various ferroportin mutations. Thus, clinicopathological examinations seem to be very important for diagnosing phenotype of type 4 hemochromatosis in addition to the gene analysis. We diagnosed him as type 4B hereditary hemochromatosis (ferroportin-associated hemochromatosis) by the findings of high transferrin saturation and iron deposition in hepatocytes, and then started iron chelating treatment. We should suspect the possibility of hereditary hemochromatosis even in Japanese with severe iron overload. Although the same mutation in SLC40A1 gene (p.D157A) had been reported to cause "loss of function" phenotype, we considered that the mutation of our case caused "gain of function" phenotype.

Importance of a Liver Biopsy in the Management of Wilson Disease.

A 37-year-old Wilson disease patient treated with D-penicillamine visited our hospital for the evaluation of his liver function. Laboratory data showed a low serum copper level and ceruloplasmin. The ratio of urinary copper to urinary creatinine in a spot urinary analysis after 4 days' cessation of D-penicillamine was under 0.1. We concluded that the copper chelation was excessive and changed D-penicillamine to zinc acetate. However, his liver function test results did not normalize. We performed a liver biopsy and discovered a high copper content. The liver dysfunction was improved after resuming chelating therapy. Accurate measurement of the hepatic copper content via a biopsy is important for the adequate management of this disease.

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.

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.

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.

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.

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.

Association of a transcription factor 21 gene polymorphism with hypertension.

Various loci and genes that confer susceptibility to coronary artery disease (CAD) have been identified mainly in Caucasian populations by genome-wide association studies (GWASs). As hypertension is a major risk factor for CAD, certain polymorphisms may contribute to the genetic susceptibility to CAD through affecting the predisposition to hypertension. The aim of the present study was to examine a possible association of hypertension with 29 single-nucleotide polymorphisms (SNPs) previously identified by meta-analyses of GWASs as susceptibility loci for CAD. Study subjects comprised of 5,460 individuals (3,348 subjects with hypertension and 2,112 controls). The genotypes of SNPs were determined by the multiplex bead-based Luminex assay. The χ2 test revealed that genotype distributions and allele frequencies for rs12190287 of the transcription factor 21 gene (TCF21) and rs1122608 of the SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin, subfamily a, member 4 gene (SMARCA4) were significantly (P<0.05) associated with hypertension. Allele frequencies for rs9369640 of the phosphatase and actin regulator 1 gene (PHACTR1) and genotype distributions for rs599839 of the proline/serine-rich coiled-coil 1 gene (PSRC1) were also significantly associated with hypertension. Multivariable logistic regression analysis with adjustment for age, gender, body mass index and smoking status revealed that rs12190287 of TCF21 (P=0.0014; recessive model; odds ratio, 1.21) was significantly associated with hypertension, and the C allele represented a risk factor for this condition. Similar analyses revealed that rs1122608 of SMARCA4 (P=0.0305; dominant model; odds ratio, 0.86), rs9369640 of PHACTR1 (P=0.0119; dominant model; odds ratio, 0.82) and rs599839 of PSRC1 (P=0.0248; dominant model; odds ratio, 0.84) were also related to hypertension, with the minor T, C and G alleles, respectively, being protective against this condition. Thus, the present results indicate that rs12190287 (G→C) of TCF21 is a susceptibility locus for hypertension.

Association of a polymorphism of the interleukin 6 receptor gene with chronic kidney disease in Japanese individuals.

AIM: Various loci and genes that confer susceptibility to coronary artery disease (CAD) have been identified in Caucasian populations by genome-wide association studies (GWASs). The aim of the present study was to examine a possible association of chronic kidney disease (CKD) with 29 polymorphisms previously identified as susceptibility loci for CAD by meta-analyses of GWASs. METHODS: The study population comprised 2247 Japanese individuals, including 1588 subjects with CKD [estimated glomerular filtration rate (eGFR) of <60 mL min(-1) 1.73 m(-2) ] and 659 controls (eGFR of ≥90 mL min(-1) 1.73 m(-2) ). The genotypes for 29 polymorphisms of 28 candidate genes were determined. RESULTS: The χ(2) test revealed that rs4845625 (T→C) of IL6R, rs4773144 (A→G) of COL4A1, rs9319428 (G→A) of FLT1, and rs46522 (T→C) of UBE2Z were significantly (P < 0.05) related to CKD. Multivariable logistic regression analysis with adjustment for age, sex, body mass index, and the prevalence of smoking, hypertension, diabetes mellitus, and dyslipidaemia revealed that rs4845625 of IL6R (P = 0.0008; dominant model; odds ratio, 1.49), rs4773144 of COL4A1 (P = 0.0252; dominant model; odds ratio, 1.28), and rs9319428 of FLT1 (P = 0.0260: additive model; odds ratio, 0.77) were significantly associated with CKD. The serum concentration of creatinine was significantly (P = 0.0065) greater and eGFR was significantly (P = 0.0009) lower in individuals with the TC or CC genotype of IL6R than in those with the TT genotype. CONCLUSION: The rs4845625 of IL6R may be a susceptibility locus for CKD in Japanese individuals.

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.

Rapid progression of hepatocellular carcinoma in a patient with autoimmune hepatitis.

We describe a case of a 69-year-old woman who developed rapidly progressive hepatocellular carcinoma (HCC) associated with autoimmune hepatitis (AIH) after a 7-year follow-up. Markers for viral hepatitis were negative. Serum tumor markers including alpha-fetoprotein and prothrombin induced by vitamin K absence II rose suddenly, and a large tumor was detected in spite of regular surveillance for HCC. Surgical treatment was performed. The resected liver specimen revealed well to moderately differentiated HCC. Ki67 staining showed rapid proliferation of the HCC. Although the incidence of HCC in patients with AIH has been unclarified, the possible complication by HCC must not be overlooked.

Case of severe liver damage after the induction of tocilizumab therapy for rheumatoid vasculitis.

A 71-year-old male patient was diagnosed with rheumatoid arthritis (RA) in 2000. Various disease-modifying anti-rheumatic drugs (DMARDs) and an anti-tumor necrosis factor biologic etanercept were administrated, but were unable to control the disease activity of RA. He was then diagnosed with rheumatoid vasculitis and received a total of 3 courses of an anti-interleukin-6 receptor antibody, tocilizumab. After the 3 courses of tocilizumab therapy, ascites and renal dysfunction gradually appeared and he was admitted to our hospital. Biochemical data suggested that he had developed decompensated liver cirrhosis. His renal function deteriorated rapidly, and he died 9 days after the admission. Serum aminotransferase levels had been relatively low during the treatment with tocilizumab, however, autopsy showed marked atrophy of the liver. Immunohistochemical analysis revealed that the hepatocytes had fallen into apoptosis and that hepatic regeneration had been extremely suppressed. Although molecular target drugs such as tocilizumab are being widely used and are important emerging treatment options in adult patients with moderate to severe RA, these drugs could induce liver failure by inhibiting liver regeneration as in this case. Physicians need to stay alert to the impact of these drugs on liver regeneration and should follow up with ultrasonography or computed tomography.

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.

Three cases of locally advanced pancreatic cancer successfully treated with chemoradiation and chemotherapy.

We report three cases with unresectable locally advanced pancreatic cancer (PC) treated with a combination of chemoradiotherapy (CRT) and systemic chemotherapy, using gemcitabine (GEM) and/or S-1. All three cases were diagnosed as having locally advanced unresectable PC without distant metastatic lesions based on computed tomography, endoscopic retrograde pancreatography and/or blushing cytology. In Cases 1 and 2, we applied a so-called sandwich therapy, which consisted of induction chemotherapy before CRT and maintenance chemotherapy after CRT. The induction and maintenance chemotherapy in Cases 1 and 2 used a combination of GEM and S-1, whereas maintenance therapy with GEM or S-1 was applied in Case 3. S-1-based CRT was performed in Cases 1 and 2, and GEM-based CRT in Case 3. Survivals were 27 and 65 months, respectively, in two cases, and the disease remained stable in the other case 30 months after diagnosis. We show three cases with unresectable locally advanced PC who achieved long-term survival (27-65 months) after treatment with a combination of CRT and systemic chemotherapy, using GEM and/or S-1. Our findings indicate that sandwich therapy might be particularly effective for locally advanced PC.