Masao Takatori

Accurate prediction of fulminant hepatic failure in severe acute viral hepatitis: multicenter study.

Background: We have attempted to predict the development of fulminant hepatic failure at the stage of severe acute hepatitis before the onset of coma. This prediction is valuable because it may be used to block the development of fulminant hepatic failure with appropriate medical treatment. Methods: To establish a discrimination formula, we retrospectively compared 13 clinical and laboratory variables in 36 patients with acute viral hepatitis and prothrombin levels of 40% or less of the control value who later developed fulminant hepatic failure with these variables in 12 patients who recovered spontaneously. A prospective study of 58 patients who developed fulminant hepatic failure and 18 who spontaneously recovered confirmed the validity of this formula. Results: In the retrospective study, we established the following discrimination equation: Z = −0.89 + 1.74 × (causal viruses, 1 point for type A or type B in acute hepatitis B virus [HBV] infection, 2 points for others) + 0.056 × (total bilirubin, mg/dl) −0.014 × (cholinesterase, U/ml). A positive Z value indicates that fulminant hepatic failure will develop. In the prospective study, the specificity, sensitivity, predictive accuracy, and positive and negative predictive values were 0.833, 0.983, 0.947, 0.950, and 0.938, respectively. Conclusions: The present study indicated that fulminant hepatic failure can be predicted, by a simple discrimination equation, at the stage of severe acute hepatitis.

Increased serum levels and sinusoidal expression of thrombomodulin in acute liver damage

Thrombomodulin (TM) is a surface glycoprotein of endothelial cells involved in both anticoagulation and antifibrinolysis. In this study, we assessed the clinical significance of TM in acute liver damage by using a rat model induced by intraperitoneal injection of D-galactosamine (Gal-N). Serum TM levels were measured with enzyme immunoassay utilizing rabbit anti-rat TM antibody. Simultaneously, immunohistochemical examination was performed using the same antibody. Serum TM levels increased significantly after the injection of Gal-N compared with preinjection levels, peaking from 48 to 72 hours after injection and normalizing by 168 hours. Changes in parenchymal damage were synchronized with changes of TM, and changes of TM levels mirrored changes of liver weight. In immunohistochemical examination, TM immunoreactivity was observed only on the endothelial surfaces of both the artery and portal vein within Glissons sheath in controls. After injection of Gal-N, TM immunoreactivity was gradually intensified, especially around the necrotic area and the central veins. These findings disappeared with improvement of parenchymal damage. Both the increase of serum TM levels and intensified TM immunoreactivity in the liver were synchronized with acute liver parenchymal damage induced by Gal-N. These findings on TM are related to endothelial damage with parenchymal necrosis and liver regeneration interacting with both homeostasis of microcirculation and healing of parenchymal damage.

Plasma thrombomodulin in liver diseases

Thrombomodulin (TM) is an endothelial cell surface membrane protein that binds to thrombin and acts as both a cofactor for protein C activation and an inhibitor of fibrinogenolysis (I). Since TM was discovered in plasma (2), the clinical significance of plasma TM (p-TM) has lately attracted attention. However, alteration of p-TM in liver disease has not yet been reported. Levels of p-TM in liver diseases were measured using a newly developed EIA (3). The levels of p-TM were significantly higher in patients with fulminant hepatitis, decompensated liver cirrhosis, hepatocellular carcinoma (p<0.01) and chronic active hepatitis (p/0.05) than healthy controls, while there was no significant increase in acute hepatitis and compensated liver cirrhosis. (Fig.) Thus the levels of p-TM might be considered to increase as a progression of liver damage, whereas they could be correlated statistically with neither liver function tests nor conventional coagulation-fibrinolytic parameters. The metabolism of p-TMremains obscure. Recently it has been suggested that the levels of p-TMmay increase in patients with collagen disease which involve destruction of vascular endothelial cells. The levels of p-TMare also said to increase in cases of chronic renal failure, in which p-TM is correlated with serum creatinin level. In liver disease, however, no correlation was found between the levels of p-TM and serum creatinin levels. These results indicate that a possible mechanism of increase in p-TM is present in liver disease, which may vascular endothelial cells TM (ng/ml} in damaged liver. ,20

Amino acid mutations in the interferon sensitivity determining region and serum virus load in hepatitis C virus carriers with long-term normal ALT levels.

The amino acid mutations in a part of the non-structural region 5A (NS5A) of the hepatitis C virus (HCV) genome, called the interferon sensitivity determining region (ISDR), can affect the response to interferon (IFN) treatment. We analyzed the serial changes of the amino acid substitutions in the ISDR during the natural course of patients with sustained long-term normal alanine aminotransferase (ALT) levels in relation to the changes in virus load, and assessed the clinical significance of ISDR in the natural course and IFN treatment. The subjects were nine patients infected with HCV (genotype 1b) who had been examined for serum ALT levels every month for more than 1 year and had well-sustained normal levels. The amino acid sequence of the ISDR was determined by the direct sequencing method, and the number of amino acid mutations was evaluated in comparison with the prototype (HCV-J). Quantitation of serum HCV RNA levels was conducted by the Amplicor-monitor method (Nihon Roche). On the initial analysis of the ISDR, six patients were determined to have no mutations, and three patients had one or two mutations. However, an increased number in amino acid mutations compared with the wild type during the follow-up period was confirmed in only one patient, and that increase was limited to within two amino acids. Virus load changed regardless of the changes in amino acid substitutions in the ISDR. The ISDR was therefore inferred to be a stable region unrelated to the virus load in patients with well-sustained normal ALT levels. Additional changes of amino acid sequence in this region were not a sensitive marker for determining whether IFN treatment is indicated.

Mutations in the non-structural protein 5A gene in patients with chronic hepatitis C virus 1b infection during repeated interferon treatment.

It has been previously reported that the non-structural region 5A (NS5A) of the hepatitis C virus (HCV) includes an interferon sensitivity determining region (ISDR) and that amino acid substitutions in this region are closely associated with the response to interferon (IFN) treatment. We assessed the clinical significance of serial changes of amino acid sequences in the ISDR during repeated IFN treatment in patients with chronic hepatitis C (genotype 1b), related to serum HCV RNA load. During treatment, additional amino acid substitutions in the ISDR were observed in four of eight patients (50% 2/5 of complete responders (CR); 2/3 of non-responders (NR). However, comparing these amino acid substitutions to wild-type ISDR, the number of amino acid mutations was limited to only one amino acid identified in two CRs. The virus load changed regardless of the amino acid substitutions in the ISDR during treatment, and the wild-type and intermediate type (with less than three amino acid substitutions) showed wide variations in virus load. These data indicate that amino acid mutations in the ISDR, which indicate the switch to mutant-type do not occur easily even during repeated IFN treatment, and the additional amino acid substitutions in the ISDR are not a sensitive marker during repeated IFN treatment. In cases where virus load is used as a marker of response to repeated UN treatment, serial examinations are necessary to determine the precise virus load levels.

A case of complete necrosis of well-differentiated early hepatocellular carcinoma by percutaneous transhepatic portal embolization

The patient was a 49-year-old male under observation for chronic hepatitis B. In July 1997, abdominal ultrasonography showed multiple hyperechoic nodules in the right lobe, the largest with a diameter of 3.5 cm. Abdominal computed tomography did not reveal enhanced nodules, and the patient was hospitalized for suspected multiple liver tumors. All biochemical tests were normal, except for a slight decrease in platelets. The patient was positive for HBs antigen, negative for HBe antigen and positive for anti-HBe antibody. Hepatocellular carcinoma (HCC) with patent portal blood flow was strongly suspected based on the results of various imaging techniques. A tumor biopsy was conducted, and findings of multiple early hepatocellular carcinoma of a well-differentiated type were observed. Based on the HCC stage and liver function, an extensive right hepatectomy was indicated. Before the surgical resection, a percutaneous transhepatic portal embolization (PTPE) was performed using gerfoam sponzel in the right portal vein. Complete necrosis of the tumor lesions was observed in the resected liver. Early HCC thought to have developed multifocally concurrently with chronic inactive hepatitis was observed. It is highly possible that complete necrosis of these tumors occurred due to PTPE, suggesting that they are supplied by the portal blood flow.