Various scoring systems evaluating histologic features of chronic hepatitis C treated with interferon.

Various scoring systems for chronic hepatitis have been proposed; however, there is no standard scoring system for studies of interferon (IFN) therapy in patients with chronic hepatitis C. The aims of this study were to determine the most useful system reflecting histologic changes in biopsy specimens from complete responders and predicting the efficacy of IFN therapy. Patients with chronic hepatitis C were administered IFN-alpha for 6 months. Forty-six patients were included in this study and categorized as complete responders (n = 15), partial responders (n = 24), and nonresponders (n = 7) according to viral and biochemical responses to the therapy. Biopsy specimens obtained from each patient before and after treatment were evaluated under 3 different systems: Histological Activity Index (HAI), modified HAI, and Scheuer classification. Complete responders showed considerable improvement in both grade and stage on the modified HAI and Scheuer classifications. On the HAI, a considerable improvement was observed in grade but not in stage. No significant change was observed in partial responders or nonresponders on any system. Prediction of complete response was not possible under any system, but the pretreatment score reflecting piecemeal necrosis on any 1 of the 3 classifications and the fibrosis score on Scheuer classification were predictors of nonresponse. The modified HAI system and Scheuer classification were amply useful in evaluating histologic changes in complete responders. Scores higher than 4 of the categories reflecting piecemeal necrosis on any system and fibrosis scores of 3 or 4 on Scheuer classification predicted nonresponse to IFN therapy.

Significance of serum matrix metalloproteinases and their inhibitors on the antifibrogenetic effect of interferon-alfa in chronic hepatitis C patients.

OBJECTIVE AND METHODS: The imbalance between matrix metalloproteinases (MMPs) and tissue inhibitors of matrix metalloproteinases (TIMPs) is considered to be an important determination of deposition and breakdown of the extracellular matrix. To investigate the antifibrogenetic effect of interferon-alpha (IFN-alpha) treatment on factors regulating hepatic fibrosis, serum MMP-1, MMP-2, TIMP-1 and TIMP-2 levels were measured by the one-step sandwich enzyme immunoassay in 27 patients with chronic hepatitis C and compared with the histological status of the patients before and at the end of treatment. RESULTS: After 6 months of IFN-alpha treatment, the histological status of liver fibrosis showed improvement in 9 patients (IF group) and no change or a worsening in 18 patients (NIF group). Compared with pretreatment levels, in the IF group, IFN treatment caused a significant increase in the MMP-1/TIMP-1 ratio. In the NIF group, however, the MMP-1/TIMP-1 ratio tended towards a decrease; moreover, there was not only a significant increase in TIMP-2 levels but also a tendency towards an increase in TIMP-1 levels. CONCLUSION: These results suggested that an elevated MMP-1/TIMP-1 ratio may ameliorate liver fibrosis by interferon in cases of chronic hepatitis C, whereas elevated levels of TIMP-1 and TIMP-2 might impede improvement.

Histological study of PIVKA-II expression in hepatocellular carcinoma and adenomatous hyperplasia.

Although serum concentration of protein induced vitamin K absence or antagonist II (PIVKA-II) has been widely used for diagnosing hepatocellular carcinoma (HCC), little information is available concerning tissue PIVKA-II as an immunohistochemical marker for liver histology. In this study, we examined the expression of PIVKA-II in precancerous nodules (adenomatous hyperplasia) and various differentiation grades of HCC by immunohistochemical study using the monoclonal anti-PIVKA-II antibody (MU-3). We examined the relationship between tissue PIVKA-II staining and serum PIVKA-II level, tumor histology and tumor size. PIVKA-II was mainly detected in the cytoplasm of the HCC cells. The positive rates of PIVKA-II were as follows: adenomatous hyperplasia (AH), 0% (0/9); well-differentiated HCC, 65% (15/23); moderately differentiated HCC, 85% (22/26); poorly differentiated HCC, 54% (7/13). The expression of tissue PIVKA-II staining in moderately differentiated HCC was significantly higher than in well- or poorly differentiated HCC, whereas the serum PIVKA-II level in poorly differentiated HCC was higher than well- or moderately differentiated HCC. There was no relationship between the expression of PIVKA-II in cancer tissues and serum levels of PIVKA-II. Immunohistochemical studies revealed that PIVKA-II was expressed even in small-sized or well-differentiated HCC cells, but expression was not detected in AH. It was concluded that PIVKA-II is a useful immunohistochemical marker, even in small-sized or well-differentiated HCC.

[A case of hepatitis B virus carrier complicated with nephrotic syndrome].

We report a patient, a 23-year-old man, who was a hepatitis B virus(HBV) carrier complicated with nephrotic syndrome. He was admitted to our hospital because of generalized edema and massive ascites. Laboratory data on admission were as follows: proteinuria 9,850 mg/day, Cr 2.7 mg/dl, BUN 73 mg/dl, albumin 1.9 g/dl, cholesterol 501 mg/dl, GOT 23 IU/l, GPT 19 IU/l, HBsAg(+), and HBeAg(222.7). Since his nephrotic symptoms were seriously complicated with renal failure, we selected steroid therapy for nephrosis preference. His renal function was improved and the urinary protein decreased immediately, but his liver function deteriorated. The renal biopsy revealed focal mesangial proliferative glomerulonephritis. Immunofluorescent examination revealed slight deposits of IgG, IgM, and C3 along the glomerular basement membrane and mesangial matrix. He was not compliant and often stopped taking the steroid therapy, thereby causing nephrosis to recur each time. After all, nephrotic symptoms have been well-controlled with cyclosporin and steroid. In spite of the seroconversion of HB virus by formation of HBe antibody, mutant HBV infection continued. The fact that liver biopsy revealed severe lymphoid infiltration at the portal area suggested chronic active hepatitis. His clinicopathologic course suggests that HBV-associated nephropathy does not always remit as there are some cases in whom hepatitis remains in an active state even after seroconversion, due to its mutant status. In these cases, the long-term prognosis of HBV nephropathy has not been defined. Further study is necessary to establish the optimal treatment for HB nephropathy in adults.

[A case of hepatitis C virus-associated glomerulonephropathy presenting with MPO-ANCA-positive rapidly progressive glomerulonephritis].

We report a case of hepatitis C virus-associated glomerulonephropathy presenting with MPO-ANCA-positive, rapidly progressive glomerulonephritis(RPGN). A 60-year-old woman was admitted to our hospital for evaluation of RPGN. Laboratory evaluation revealed microhematuria, proteinuria(800 mg/day), anemia, renal failure(blood urea nitrogen 27 mg/dl, serum creatinine 2.2 mg/dl), cryoglobulinemia, hypocomplementemia, positive MPO-ANCA(232 EU), and hepatitis C virus infection(GOT 58 IU/l, GPT 38IU/l, HCV-RNA(PCR) 1,200 kcopy/ml, serotype 1). After admission, the patient's renal function and anemia deteriorated rapidly, then prednisolone(30 mg/day) was started. After treatment her renal function gradually improved, then a renal and liver biopsy was performed. The renal biopsy revealed six sclerosing fibrous crescentic glomeruli in twelve glomeruli. Immunofluorescent examination revealed granular deposits of IgG, C3, and fibrinogen along the glomerular basement membrane and mesangial matrix. The pathogenesis of RPGN in this case may relate to the deposition of immune complexes in the glomeruli because immunofluorescent examination was revealed to be the immune-complex type, but not pauci immune type nephritis. Liver histology revealed chronic active hepatitis with mild piecemeal necrosis and did not reveal vasculitis. Although her renal function was improved after treatment with prednisolone, she suffered from pulmonary manifestations(dry cough etc.) on the 120th hospital day. Suddenly she died because of pulmonary hemorrhage on the 180th hospital day. These findings suggest that various HCV-induced immunological abnormalities, such as positive MPO-ANCA, cryoglobulinemia and hypocomplementemia, play an important role in the pathogenesis of this RPGN, although we could not demonstrate deposition within glomeruli of immune complexes containing HCV. The effect of interferon therapy on such immunological abnormalities remains to be documented. Since interferon is known to have immunomodulatory effects, we selected corticosteroid therapy. Future studies need to focus on the optimal treatment strategy for hepatitis C virus-associated glomerulonephritis.

[Clinical study of imipenem/cilastatin sodium in serious infections in critical care medical center].

Patients with severe trauma and illness were treated at our critical care medical center. Many of these patients have diabetes, anemia and other underlying conditions which sometimes lead to serious infections caused by methicillin-resistant Staphylococcus aureus (MRSA) or Pseudomonas aeruginosa. A clinical study imipenem/cilastatin sodium (IPM/CS) was performed at our Medical Center. IPM/CS was administered to 30 patients with serious infections. Clinical results were excellent in 11, good in 5, fair in 9 and poor in 5 patients, thus an overall efficacy rate of 53.3% was obtained. Bacteriological efficacy rate was 50% with eradications in 11 cases and decreases in 3 cases out of 28 cases examined. No side effects were observed in any patients.

Cognitive development of severely and profoundly mentally retarded individuals.

Corman and Escalona's scales for Object Permanence and Spatial Relationships were readministered to 71 severely and profoundly mentally retarded individuals five years after the last previous administration of the scales. Gains in mean scores were small but statistically significant for both scales. In addition, significantly more subjects gained than lost on Spatial Relationships, though not on Object Permanence. These findings provide evidence that the cognitive development of at least some severely and profoundly retarded individuals continues into early adulthood, even in the absence of special programs designed to promote such development.