Keiji Mita

Superiority of CT Arterioportal Angiography to Contrast-Enhanced CT and MRI in the Diagnosis of Hepatocellular Carcinoma in Nodules Smaller than 2 cm

To evaluate the effectiveness of computed tomography (CT) arterioportal angiography in the diagnosis of hepatocellular carcinoma (HCC) in nodules smaller than 2 cm, we compared the findings of CT during arteriography (CTA) and CT during arterial portography (CTAP) with those of enhanced CT and enhanced magnetic resonance imaging (MRI). Sixty-eight nodules smaller than 2 cm in 53 patients with liver cirrhosis were classified into three groups of CTA and CTAP: (group 1) hyperattenuation on CTA, and hypoattenuation on CTAP (56 nodules, 41 patients); (group 2) hypoattenuation on CTA, and hypoattenuation on CTAP (10 nodules, 10 patients); (group 3) hypoattenuation on CTA, and hyperattenuation on CTAP (2 nodules, 2 patients). Histologically, 96% (54/56), 80% (8/10), and 100% (2/2) of the nodules in groups 1, 2 and 3, respectively, were diagnosed as HCC. In group 1, enhanced CT or enhanced MRI confirmed hypervascularity in only 77% (30/39) and venous washout in 21% (8/39). In groups 2 and 3, enhanced CT or enhanced MRI on 7 and 2 nodules, respectively, revealed no hypervascularity (0%). The results suggested that CT arterioportal angiography is superior to enhanced CT and MRI in nodules smaller than 2 cm for diagnosing HCC (p < 0.01 group 1, p < 0.01 group 2).

CEA producing primary hepatic carcinoid

Imaging studies of a hepatic tumor in a 53-year-old woman with elevated serum levels of neuron-specific enolase (NSE), carcinoembryonic antigen (CEA) and 5-hydroxyindole acetic acid (5HIAA) revealed a hypervascular tumor in the right lobe. Grossly, the brownish tumor was measured 13.5x12 cm with four daughter nodules. Microscopically, the majority of these columnar and round tumor cells had ribbon-or rosette-like patterns with the expression of neuroendocrine marker proteins, such as Grimelius, NSE, chromogranin A, and synaptophysin, and moderate expression of CEA but without the expression of cytokeratin nos 7,8,14,18,19 and OV-6; the minority had glandular patterns with a strong expression of CEA but without the expression of cytokeratin nos 7,8,14,18,19 and OV-6. Ultrastructurally, most tumor cells contained populations of electron-dense core granules ranging between 100 and 200 nm in diameter. After hepatectomy, serum CEA, NSE, and 5HIAA reverted to normal ranges and persisted for 19 months. These findings suggested that the diagnosis of primary hepatic carcinoid was tenable and that the tumor might derive from hepatic stem cells which acquired the additional nature of producing CEA without cytokeratins characteristic of hepatocytes or bile duct cells. Some molecular based approaches have attributed unique biological behavior and histogenesis to this carcinoid tumor.

Multiple hypervascular liver nodules in a heavy drinker of alcohol

Abstract  A case of hypervascular nodules in the liver, but without hepatitis B or C virus infection in a 38‐year‐old woman with a history of alcohol abuse is presented. An ultrasound disclosed 1–2‐cm hypoechoic tumors in the right and left lobes. Magnetic resonance imaging showed high‐intensity tumors at both the T1‐weighted and T2‐weighted sequences. Incremental dynamic computed tomography and hepatic angiography revealed hypervascular tumors. Ultrasound‐guided needle biopsy revealed no evidence of hepatocellular carcinoma, metastatic liver cancer, hemangioendothelioma, inflammatory pseudotumors or pseudolymphoma, but demonstrated stellate‐scar fibrosis septa, which contained small unpaired arteries without hyperplasia dividing the nodule. Moreover, marked pericellular fibrosis, neutrophilic infiltration and Mallory bodies were observed in the cytoplasm. There was no evidence of bile duct proliferation. From these findings, the diagnosis of alcohol‐induced fibrosis, distinctly different from focal nodular hyperplasia, was tenable. Further studies may provide insights into the pathogenesis of nodule formation and hypervascularity in heavy drinkers of alcohol.

Eosionophilic pseudotumor of the liver due to Ascaris suum infection

A case of eosinophilic pseudotumor of the liver due to Ascaris (A) suum is described in a 34-year-old-man with a high serum level of immunoglobulin E and hypereosinophilia ascribed to a history of atopic dermatitis since childhood. Multiple hepatic hypoechoic nodules detected by ultrasound were confirmed as low-density nodules on computed tomography (CT), and as low and high signal intensity lesions on T1-and T2-weighted magnetic resonance imaging (MRI), respectively. CT during arteriography (CTA) and arterial portography revealed multiple nodules with ring-shaped enhancement and perfusion defect, respectively. Biopsied liver tissue specimens did not contain tumor cells or atypical cells; instead, they showed marked infiltration of eosinophils with necrosis and Charcot-Leyden crystals in the portal tracts and hepatic sinusoides, suggesting parasitic infection, although neither larvae nor eggs were detected. The diagnosis of visceral larva migrans (VLM) due to A. suum was based on immunoserological tests. The patient was a habitual consumer of raw bovine liver, which may explain the A. suum infection. After drug therapy with albendazole, the hypoechoic nodules disappeared. Differential diagnoses and the possible transfection route of A. suum are discussed.

Acute Pancreatitis Associated with Pegylated Interferon and Ribavirin Treatment of Chronic Hepatitis C, Genotype 1b with High Viral Load.

Acute pancreatitis, an uncommon side effect of pegylated interferon α (PEG-IFN α) and ribavirin (RBV) combination therapy, has rarely been reported in the English language literature. Here, acute pancreatitis associated with PEG-IFN plus RBV treatment is described in three patients with chronic hepatitis C, genotype 1b with high serum hepatitis C virus RNA levels. The patients had been started on weekly subcutaneous injections of PEG-IFN α (60, 80, and 90 μg) plus a daily oral dose of RBV (600 mg). The therapy was discontinued, however, because of the onset of acute pancreatitis (after 15 weeks, 48 weeks, and 3 weeks respectively). The drug-induced pancreatitis was diagnosed on the basis of elevated levels of amylase and lipase and the absence of other identifiable causes. High tumor necrosis factor-α was found in one patient and high interleukin-6 in the other two. The immune system stimulated by PEG-IFN and RBV combination therapy might have caused the acute pancreatitis. Further study is needed to clarify the mechanism of the onset of drug-induced pancreatitis by PEG-IFN and RBV combination therapy.

Usefulness of a new immunoradiometric assay of HCV core antigen to predict virological response during PEG-IFN/RBV combination therapy for chronic hepatitis with high viral load of serum HCV RNA genotype 1b.

We investigated the clinical usefulness of a new immunoradiometric (IRM) assay of hepatitis C virus (HCV) core antigen in predicting virological response during pegylated interferon plus ribavirin (PEG-IFN/RBV) combination therapy for chronic hepatitis with high viral loads of serum HCV RNA genotype 1b. Thirty-nine patients received a regimen of PEG-IFNα-2b (1.5 µg/kg/week s.c.) in combination with RBV (600–1,000 mg/day). Of the 39 patients, 18 (46.2%) achieved sustained virological response (SVR), 11 (28.2%) attained partial response (PR) and 10 (25.6%) showed no response (NR). Four weeks after the start of therapy, 1- and 2-log reductions in the amount of HCV core antigen were observed in 20 (2/10) and 0% (0/10) showing NR, 91 (10/11) and 63.6% (7/11) with PRs, and 88.9 (16/18) and 55.6% (10/18) of patients with SVR, respectively. The 1- and 2-log reductions 4 weeks after the start of therapy were not a definingcondition for PR and SVR. The amount of HCV core antigen was significantly different between SVR and PR patients on days 1 and 7, and between patients with NR and SVR at all points of time. In conclusion, this new IRM assay is useful in predicting virological response during PEG-IFN/RBV therapy.

Development of multicentric hepatocellular carcinoma after completion of interferon therapy

6 international units (IU) of IFNα, 3 days a week for a total of 24 weeks. After the IFN therapy, the patient demonstrated a normal serum ALT level, and was continuously negative for HCV-RNA, and histology improved from chronic active hepatitis to chronic persistent hepatitis. Follow-up studies with ultrasonography (US) every 3 months and computed tomography (CT) every 6 months revealed no space-occupying lesion (SOL) for 3 years after IFN treatment.US-guided biopsies of two 15-mm hypoechoic SOLs in segments eight (S8) and seven (S7) 34 and 74 months, respectively, after IFN treatment showed well-differentiated hepatocellular carcinoma (HCC). Clinical data, imaging studies, and histologic examinations showed that both tumors were multicentric HCC. Further studies may provide insights into the possible role of HCV in hepatocarcinogenesis in patients demonstrating HCV eradication by IFN treatment.

Outcome and early viral dynamics with viral mutation in PEG-IFN/RBV therapy for chronic hepatitis in patients with high viral loads of serum HCV RNA genotype 1b.

We investigated whether sustained virological response (SVR) and non-SVR by chronic hepatitis C patients to pegylated interferon plus ribavirin (PEG-IFN/RBV) combination therapy are distinguishable by viral factors such as the IFN/RBV resistance-determining region (IRRDR) and by on-treatment factors through new indices such as the rebound index (RI). The first RI (RI-1st; the viral load at week 1 divided by the viral load at 24 h) and the second RI (RI-2nd; the viral load at week 2 divided by the viral load at 24 h) were calculated. The subject patients were divided into 3 groups based on RI-1st and RI-2nd: an RI-A group (RI-1st ≤1.0), an RI-B group (RI-1st >1.0 and RI-2nd <0.7) and an RI-C group (RI-1st >1.0 and RI-2nd ≧0.7). The SVR rate was 71.4% (10/14) in the RI-A group, 46.2% (6/13) in the RI-B group and 20.0% (3/15) in the RI-C group (p = 0.005 between the RI-A group and the RI-C group). In IRRDR ≧6 and IRRDR ≤5 the SVR rate was 81.3% (13/16) and 23.1% (6/26) (p = 0.0002), respectively. By combining RI and IRRDR as a predicting factor, the SVR rate was 87.5% (7/8) in the RI-A group (≧6 mutations in the IRRDR) and 7.7% (1/13) in the RI-C group (≤5 IRRDR mutations) (p = 0.0003).

Double-Filtration Plasmapheresis plus IFN for HCV-1b Patients with Non-Sustained Virological Response to Previous Combination Therapy: Early Viral Dynamics

Double-filtration plasmapheresis (DFPP) was approved in Japan in April 2008 for the retreatment of chronic hepatitis C patients with genotype 1b and high viral loads, whose hepatitis C virus was not eradicated by earlier IFN therapy or by pegylated IFN plus ribavirin (PEG-IFN/RBV) combination therapy. In this study, we assessed the early viral dynamics of 9 patients with non-sustained virological response to the combination therapy. The overall viral dynamics of DFPP plus IFN treatment with or without RBV for 4 weeks showed a reduction of ≧1 log in the viral load in 22% (2 of 9 patients), 55.6% (5/9), 77.8% (7/9) and 77.8% (7/9) at 24 h, 1, 2 and 4 weeks after the start of treatment. By contrast, DFPP plus consecutive intravenous IFN-β for 4 weeks reduced the viral load by ≧1 log in 33% (2/6), 50% (3/6), 83.3% (5/6) and 83.3% (5/6) at 24 h, 1, 2 and 4 weeks. The viral load declined by ≧2 log in 50% (3/6) at 4 weeks after the start of treatment. DFPP plus consecutive intravenous IFN-β for 4 weeks is a promising treatment for non-sustained virolgical response patients.

Pegylated Interferon plus Ribavirin Combination Therapy for Chronic Hepatitis C with High Viral Load of Serum Hepatitis C Virus RNA, Genotype 1b, Discontinued on Attaining Sustained Virological Response at Week 16 after Onset of Acute Pancreatitis

Recent clinical trials have shown that pegylated interferon-α (PEG-IFN-α) in combination with ribavirin (RBV) improves the rate of sustained virological response (SVR), with over 50% of patients demonstrating a positive response to treatment. However, no SVR has been reported when PEG-IFN/RBV combination therapy is discontinued by week 16, especially in cases of chronic hepatitis with a high viral load of serum hepatitis C virus (HCV) RNA, genotype 1b. Here, we describe SVR in a 67-year-old woman whose PEG-IFN/RBV combination therapy for chronic hepatitis C with a high viral load of serum HCV RNA, genotype 1b, was discontinued after 16 weeks because of the onset of PEG-IFN plus RBV-induced acute pancreatitis. Among viral factors, substitution of amino acid 70 (Arg) and 91 (Leu) in the core region and HCV RNA negativity were observed after 8 weeks. Host factors including low body weight, no alcohol consumption, no coinfection with hepatitis B virus, slight fibrosis, and viral factors including early viral clearance, double wild type in the core region, may have contributed to the SVR irrespective of the discontinuation of the combination therapy at week 16. Moreover, PEG-IFN plus RBV-induced acute pancreatitis might have been related to the SVR.