Serum amyloid A and C-reactive protein positive nodule in alcoholic liver cirrhosis, hard to make definite diagnosis.

We describe a case of serum amyloid A (SAA) and C-reactive protein (CRP) positive nodule detected by immunohistochemical analysis in a 37-year-old woman with alcohol-related cirrhosis. Imaging studies at first admission pointed to hepatocellular carcinoma (HCC), a dysplastic nodule, an inflammatory pseudotumor or focal nodular hyperplasia (FNH). Ultrasonography-guided biopsy in Segment 2 showed minimal atypical changes, except for a slight increase in cell density and micronodular cirrhosis in the non-nodular portion. gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid-enhanced magnetic resonance imaging carried out after a year and a half revealed hypervascularity in the arterial phase and isointensity in the hepatobiliary phase. Three years thereafter, however, the imaging displayed a change from isointensity to a defect in the hepatobiliary phase, and the nodule demonstrated minimal histological atypia. Immunohistochemical staining of the nodule was positive for SAA, CRP, liver fatty acid-binding protein and glutamine synthetase, but negative for ß-catenin, heat shock protein 70 and Glypican 3. Organic anion transporter (OATP)8 staining was weaker in the nodule than in the non-nodular portion of the alcohol-related micronodular cirrhosis. The nodule was diagnosed as an SAA and CRP positive nodule, and HCC was ruled out. Despite the change from isointensity to a defect in the hepatobiliary phase, no evidence of HCC was found in the biopsy specimen. The change may be explained more by the weak OATP8 staining compared with that of alcohol-related liver cirrhosis than by malignant transformation into HCC.

Histopathological diagnosis of early HCC through biopsy: efficacy of Victoria blue and cytokeratin 7 staining.

OBJECTIVES AND METHODS: Findings of histological analyses of 2 cases of liver biopsy revealing hypovascular nodules are described. RESULTS: Ultrasound examination revealed hypovascular and hypoechoic nodules (8 mm in diameter) in segment 1 (case 1) and (8 mm) in segment 8 (case 2). The nodules were detected by only Gd-EOB-DTPA-enhanced MRI. Hematoxylin and eosin staining of ultrasound-guided biopsy of the nodules revealed slight hypercellularity without the features of early hepatocellular carcinoma (HCC) such as cell atypia, fatty change and pseudoglandular formation. Early HCC was suspected; however, Victoria blue staining disclosed terminal portal tract invasion, the most important finding of early HCC. Also, cytokeratin 7 staining revealed decreased ductular reaction compatible with early HCC. Taken together, these histological analyses confirmed the two nodules to be early HCC. CONCLUSION: Based on the criteria of the International Consensus Group, the two nodules were diagnosed as early HCC through biopsy.

Well-differentiated hepatocellular carcinoma detected as hypovascularity by only CT during hepatic arteriography.

We describe a well-differentiated hepatocellular carcinoma (HCC) with alcohol-related liver cirrhosis in a 69-year-old man. Ultrasonography (US) disclosed a 10 mm hypoechoic nodule in segment 4; Sonazoid contrast-enhanced US and gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid (Gd-EOB-DTPA)-enhanced magnetic resonance imaging (MRI) revealed no defect in either the Kupffer phase or the hepatobiliary phase. Computed tomography during hepatic arteriography (CTHA), however, revealed a hypovascular nodule, but CT during arterial portography showed no perfusion defect. Histological analysis indicated a well-differentiated HCC. Thus, our detection of well-differentiated HCC disclosed by only CTHA attested to the efficiency of this modality, suggesting that it is more sensitive than Gd-EOB-GTPA-enhanced MRI.

Correlation between insulin resistance and outcome of pegylated interferon and ribavirin therapy, hepatic steatosis, hepatic fibrosis in chronic hepatitis C-1b and high viral load.

BACKGROUND/AIMS: Insulin resistance (IR) has been reported to be an independent predictor of treatment outcome in chronic hepatitis C patients. METHODS: We analyzed the relationship between IR and the outcome of pegylated interferon and ribavirin (PEG-IFN/RBV) therapy, taking into account host factors of body mass index and histological index, such as rate of fatty change and fibrosis. Japanese patients (n = 30; 19 men and 11 women; median age 60.0 ± 8.7 years) with chronic hepatitis C-1b with a high viral load were treated with PEG-IFN-α2b/RBV for 48 weeks. RESULTS: Sustained virological response (SVR) was seen in 60% (18/30) and non-SVR in 40% (12/30). HOMA-IR (homeostasis model of assessment-insulin resistance index) at the start and at 24 weeks of treatment showed no statistical difference between SVR and non-SVR. Correlation was observed between HOMA-IR and body mass index (r = 0.45, p = 0.013). Among 20 patients, steatosis and fibrosis were assessed by biopsy. Correlation was observed between HOMA-IR and steatosis (r = 0.57, p = 0.0093), whereas no correlation was observed between HOMA-IR and fibrosis. CONCLUSION: A larger prospective study is needed to clarify the role of IR in the outcome of PEG-IFN/RBV combination therapy and hepatic fibrosis in Japanese patients.

A case of takotsubo cardiomyopathy with ventricular fibrillation after gastroenterological endoscopy.

We describe a case of takotsubo cardiomyopathy with ventricular fibrillation after gastroenterological endoscopy in a 66-year-old woman. Ten minutes after the upper and lower gastrointestinal endoscopic examinations, the patient lost consciousness, went into respiratory arrest, and became cyanotic; an electrocardiogram (ECG) showed ventricular fibrillation. Electrical defibrillation was applied three times resulting in the patient's recovery. Subsequently, the ECG showed ST elevation in V2-V3; ultrasound cardiography showed a severely hyperkinetic base of the left ventricle, with the rest of the ventricle akinetic; and cardiac catheterization disclosed a normal coronary artery and normal contraction of the left ventricle.

Diagnostic sensitivity of imaging modalities for hepatocellular carcinoma smaller than 2 cm.

AIM: To compare the imaging results with histology and to evaluate the diagnostic sensitivity of imaging modalities for hepatocellular carcinoma (HCC) smaller than 2 cm. METHODS: Nodules smaller than 2 cm (n = 34) revealed by ultrasonography (US) in 29 patients with liver cirrhosis were analyzed. Histological diagnosis of HCC was performed by ultrasonographic guidance: moderately-differentiated HCC (n = 24); well-differentiated HCC (n = 10). The patterns disclosed by the four imaging modalities defined the conclusive diagnosis of HCC: (1) contrast-enhanced computed tomography (CECT), hypervascularity in the arterial phase and washout in the equilibrium phase; (2) Sonazoid contrast-enhanced US (CEUS), hypervascularity in the early vascular phase and defect in the Kupffer phase; (3) gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid (Gd-EOB-DTPA)-enhanced magnetic resonance imaging (MRI), hypervascularity in the arterial phase and/or defect in the hepatobiliary phase; and (4) CT arterioportal angiography: hypervascularity by CT during arteriography and/or perfusion defect by CT during arterial portography. RESULTS: Overall, the sensitivity of diagnosing HCC smaller than 2 cm was 52.9% (18/34) (95% CI: 35.1-70.2) by CECT; 67.6% (23/34) (95% CI: 49.5-82.6) by Sonazoid CEUS; 76.5% (26/34) (95% CI: 58.8-89.3) by Gd-EOB-DTPA MRI; and 88.2% (30/34) (95% CI: 72.5-96.7) by CT arterioportal angiography. The diagnostic sensitivity of detecting moderately-differentiated HCC by CECT, Sonazoid CEUS, Gd-EOB-DTPA MRI and CT arterioportal angiography was 62.5% (15/24) (95% CI: 40.6-81.2), 79.2% (19/24) (95% CI: 57.8-92.9), 75.0% (18/24) (95% CI: 53.3-90.2) and 95.8% (23/24) (95% CI: 78.9-99.9), respectively. A significant difference (P < 0.05) was observed between CECT and CT arterioportal angiography in all nodules. There was no difference between Sonazoid CEUS, Gd-EOB-DTPA MRI, and CT arterioportal angiography. The combined sensitivity of Sonazoid CEUS and Gd-EOB-DTPA MRI was 94.1% (32/34). CONCLUSION: Changing the main diagnostic modality for HCC smaller than 2 cm from CT arterioportal angiography to Sonazoid CEUS and Gd-EOB-DTPA MRI is recommended.

Autoimmune thrombocytopenic purpura during pegylated interferon α treatment for chronic hepatitis C.

We describe a 72-year-old woman with chronic hepatitis C and autoimmune thrombocytopenic purpura (AITP) during pegylated interferon (PEG-IFN) alpha. Immunoglobulin G and antinuclear antibody were 2,113 mg/dL and 1,280 at the start, respectively. A liver biopsy negated autoimmune hepatitis. After a 48-week combination therapy with ribavirin, PEG-IFN alpha-2a was administered. At the 30th month, the platelet count was decreased to 1.1 x 10(4)/microL. Bone marrow biopsy disclosed normocellular marrow compatible with AITP. The platelet-associated IgG (PAIgG) titer rose to 500 ng/10(7) cells. Corticosteroid therapy was successful, and the platelet count and PAIgG titer reverted to 6.4 x 10(4)/microL and 57.3 ng/10(7) cells, respectively.

Scirrhous hepatocellular carcinoma displaying atypical findings on imaging studies.

We describe a 15-mm scirrhous hepatocellular carcinoma (HCC) in a 60-year-old man with B-type cirrhosis. Ultrasound disclosed a 15-mm hypoechoic nodule in segment 7. Contrast-enhanced US revealed heterogeneous, not diffuse, hypervascularity in the early phase and a defect in the Kupffer phase. Contrast-enhanced computed tomography (CT) revealed a heterogeneous hypervascular nodule in the early phase and a low-density area in the late phase. Magnetic resonance imaging (MRI) revealed iso- to hypointensity at T1 and high intensity at T2-weighted sequences. Contrast-enhanced MRI also revealed a heterogeneous hypervascular nodule in the early phase and washout in the late phase. Super-paramagnetic iron oxide-MRI revealed a hyperintense nodule. CT during hepatic arteriography and CT during arterial portography revealed heterogeneous hyperattenuation and a perfusion defect, respectively. Based on these imaging findings the nodule was diagnosed as a mixed well-differentiated and moderately-differentiated HCC. Histologically, the nodule was moderately-differentiated HCC characterized by typical cytological and structural atypia with dense fibrosis. Immunohistochemically, the nodule was positive for heterochromatin protein 1 and alpha-smooth muscle actin, and negative for cytokeratin 19. From the above findings, the nodule was diagnosed as scirrhous HCC. Clinicians engaged in hepatology should exercise caution with suspected scirrhous HCC when imaging studies reveal atypical findings, as shown in our case on the basis of chronic liver disease.

Two cases of non-alcoholic steato-hepatitis developing from simple fatty liver.

We describe two cases of non-alcoholic steatohepatitis (NASH) developing from simple fatty liver and detected by histological examination in two women. In both cases hypertension and diabetes mellitus showed no exacerbation during follow-up; hepatitis C antibody and hepatitis B surface antigen were negative; ultrasound (US) and computed tomography (CT) revealed fatty liver (moderate in one patient and severe in the other). Body mass index (BMI) was 48 and 44 in 2004 and 2007, respectively, in one and 24 in both 2006 and 2007, respectively, in the other. Liver function tests showed some fluctuation in aspartate aminotransferase and alanine aminotransferase. The first US-guided liver biopsy showed simple fatty liver; the second biopsy after two and a half years on one patient and one and a half years on the other, revealed histological features of NASH characterized by predominantly macrovesicular fatty change (40% in one and 80% in the other) with occasional ballooning, fibrosis (moderate in one and slight in the other) extending from zone 3 to zone 1, intraacinar inflammation with neutrophil infiltration, and mild portal chronic inflammation with piecemeal necrosis. Fibrosis progressed from stage 0 to stage 2 in two and a half years in one patient, and from stage 0 to stage 1 in one and a half years in the other. Clinicians should be vigilant during the clinical course of NASH developing from simple fatty liver.

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.

Utility of Gd-EOB-DTPA-Enhanced MRI in Diagnosing Small Hepatocellular Carcinoma.

We describe an 8-mm hepatocellular carcinoma (HCC) with hepatitis C virus-related cirrhosis in a 74-year-old woman. Ultrasound (US) revealed an 8-mm hyperechoic nodule in segment 6 of the liver. Contrast-enhanced computed tomography (CT) and US revealed no hypervascularity in the early phase and no washout in the late phase and the Kupffer phase, respectively. CT during arteriography revealed no hypervascularity and CT during arterial portography disclosed no perfusion defect. Gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid (Gd-EOB-DTPA)-enhanced magnetic resonance imaging (MRI) revealed no hypervascularity in the early phase, but disclosed a defect in the hepatobiliary phase. Histologically, the nodule was diagnosed as well-differentiated HCC characterized by more than two-fold the cellularity of the non-tumorous area, with a high nuclear:cytoplasmic ratio, increased cytoplasmic eosinophilia, fatty change, and slight cell atypia with an irregular thin trabecular pattern. Our case demonstrates the utility of Gd-EOB-DTPA-enhanced MRI in the diagnosis of small HCC.

Case of adult genotype C HBV carrier after acute hepatitis B, losing HBsAg and acquiring HBsAb after IFN and lamivudine treatment.

Here we report the case of a 48-year-old man, carrier of genotype C HBV for longer than 6 months after contracting sexually transmitted acute hepatitis B, who eventually lost HBsAg and acquired HBsAb by IFN/lamivudine therapy. The patient had been negative for HBsAg in 2001, but, during his stay in China from January to July in 2003, he developed acute hepatitis B after having an extra-marital sexual contact there. HBsAg was still positive and a liver biopsy indicated chronic hepatitis when he was admitted to our hospital in December 2003 for detailed examination of liver dysfunction. HBV DNA in his serum, revealed to segregate to genotype C by sequencing on admission, decreased to undetectable levels at the end of a 3-month IFN therapy, and remained undetectable during and after the successive 6-month lamivudine therapy. HBeAg seroconverted to HBeAb during the therapy, and HBsAb appeared after the therapy. To our knowledge, this is the first case of genotype C chronic hepatitis B occurring after acute hepatitis.

Well-differentiated HCC manifesting hyperattenuation on CT during arterial portography.

A rare case of well-differentiated minute hepatocellular carcinoma (HCC) with hepatitis C virus-related cirrhosis, with unusual radiologic features, is presented. A 10-mm hypoechoic nodule disclosed by ultrasound in segment six showed hypoattenuation on computed tomography hepatic arteriography and hyperattenuation on computed tomography during arterial portography, indicating that the portal vein may have been the dominant vascularity of the nodule. Contrast-enhanced ultrasound revealed hypovascularity in the early arterial phase, isovascularity in the late vascular phase, and the same perfusion as that surrounding the liver parenchyma in the post-vascular phase, with the same pattern observed on the two imaging techniques. These findings were considered not compatible with those of well-differentiated HCC. Ultrasound-guided biopsy showed histological features of well-differentiated HCC with over two-fold the cellularity of the non-tumorous area with a high nuclear/cytoplasmic ratio, increased cytoplasmic eosinophilia, slight atypia and fatty change with an irregular thin trabecular pattern. Further studies may provide insights into the correlation between tumor neovascularity in multistep hepatocarcinogenesis and dual hemodynamics, including the artery and the portal vein.

Primary sclerosing cholangitis and hepatitis C virus infection.

Two cases of primary sclerosing cholangitis with hepatic C virus infection in a 62-year-old man and a 60-year-old woman are presented. The infection in the man was eradicated with interferon therapy in 1992. Seven years thereafter, endoscopic retrograde cholangiography revealed a diffuse 2.5-cm-long stenotic lesion in the common bile duct which was consequently resected. Histological examination of the resected specimen revealed proliferation of epithelial cells, plasma cell infiltration, and fibrosis in the submucosal layer of the common bile duct. The human leukocyte antigen DR loci were 2 and 9. In the woman, a 6-month course of interferon therapy in 1992 failed to eradicate the infection. Cholangiography in 1999 revealed multiple narrowings and dilatations of intra- and extrahepatic bile ducts. Ultrasound guided biopsy of the liver in 1992 had revealed onionskin lesions around the bile duct epithelium in the portal tract. The human leukocyte antigen DR locus was 2. From these findings, the 2 cases were diagnosed as primary sclerosing cholangitis. Further studies may provide insights into the relation between the pathogenesis of the disease and the infection.

Multiple hypervascular liver nodules in a heavy drinker of alcohol.

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.

Development of multicentric hepatocellular carcinoma after completion of interferon therapy.

We report a case of multicentric hepatocellular carcinoma that developed in a 74-year-old man 3 and 6 years after interferon (IFN) treatment for chronic hepatitis C, despite sustained virologic, biochemical, and histological improvement. Initially, serum hepatitis C virus RNA was positive and the patients' serum level of alanine aminotransferase (ALT; 82 IU/ml) was abnormal. Hepatitis B virus (HBV) in the serum was negative for surface antigen, surface antibody, core antibody, and DNA. The patient was started on 10 x 10(6) international units (IU) of IFNalpha, 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.

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.

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.