Trimethadione tolerance tests for the assessment of feasible size of hepatic resection in patients with hepatocellular carcinoma

Pre-operative evaluation of the quantity of functional remnant hepatic parenchyma after hepatectomy was carried out to predict the optimal amount of hepatic resection using the trimethadione (TMO) tolerance test. This test is an estimate based on serum diamethadione (DMO)/TMO ratio (DMO is the only metabolite of TMO) 4 h after oral administration of TMO, and computed tomography (CT) scans of the liver in patients with hepatocellular carcinoma (HCC). The percentage of remnant hepatic parenchyma was calculated pre-operatively from the remaining non-cancerous portion and the whole hepatic parenchyma, excluding the HCC portion, using the CT scans. Presumptive remnant DMO/TMO ratio was calculated by multiplying the percentage of remnant hepatic parenchyma and pre-operative serum DMO/TMO ratio in 45 patients with HCC undergoing resection. The presumptive remnant DMO/TMO ratios were 0.31 ± 0.10 (mean ±s.d.) in 42 patients who survived hepatectomy and 0.13 ± 0.02 (below 0.15) in the three patients who died from postoperative hepatic failure. Of these surviving patients, two patients who had the presumptive remnant DMO/TMO ratios under 0.15 developed postoperative severe complications. Thus, hepatectomy may not be indicated in patients where presumptive remnant DMO/TMO ratio is 0.15 and lower. These findings suggest that pre-operative measurement of presumptive remnant DMO/TMO ratio, when obtained with the CT of the liver and TMO tolerance test, is useful for prediction of the quantity of functional remnant hepatic parenchyma after hepatectomy in patients with chronic liver disease.     

Trimethadione tolerance test for the quantitative assessment of liver function in rats

The quantitative estimation of the hepatic functional volume in rats was attempted using the serum dimethadione (DMO)/trimethadione (TMO) ratio in a single blood sampling after oral administration of TMO, which we call the TMO tolerance test, in order to develop a means of pre-operatively assessing hepatic resectability. Serum DMO/TMO ratios correlated well with the total amount of the hepatic microsomal TMO-N-demethylase activity (enzyme activity) and with the remnant liver weight after 37% and 68% partial hepatectomy. These ratios increased after partial hepatectomy in parallel with the changes in the enzyme activity and the remnant liver weight. The results suggest that the quantitative functional changes of the remnant liver after hepatectomy in both CCl4-treated and untreated rats can be estimated pre-operatively by the TMO tolerance test.     

肝活检对82例肝病诊断的临床价值

本文对82例肝病患者做肝活检，并以病理诊断与临床诊断进行对比。结果临床与病理诊断符合者49例，占59．8％，不符合33例占40．2％，其中肝硬化患者临床与病理诊断符合率69．7％，慢性活动性肝炎诊断符合率60％，慢性迁延性肝炎符合率66．7％，肝脓疡及亚急性重症肝炎符合率50％。慢性无症状乙肝病毒携带者8例，病理确诊为慢性迁延性肝炎5例，慢性活动性肝炎1例，肝轻微病变2例。以上资料表明，对肝病患者做肝活检是非常必要的，既可明确诊断，又可早期预防和治疗。     

慢性肝病60例血浆内毒素与生化、病理和中医证型关系的研究

目的 探讨慢性病毒性肝炎、肝硬化血浆内毒素的变化与肝脏病理、生化、中医证型的关系及其临床意义。 方法 1993年3月至12月对慢性肝病60例采用基质显色法鲎试验定量检测血浆内毒素。 结果 CAH重型血浆内毒素均值明显高于CPH及CAH轻型(P<0.05);与Bil呈正相关,与PA呈负相关。血瘀血热型内毒素均值明显高于肝郁脾虚型(P<0.05)。 结论 检测血浆内毒素含量可以作为判断肝病病情轻重的指标之一,并为中医辨证提供了客观依据。     

Pancreatic excretion of dimethadione and trimethadione by repeated oral administration of trimethadione in dogs

To examine pancreatic excretion of dimethadione (DMO), a weak organic acid, as well as of its precursor trimethadione (TMO), TMO was given orally to dogs with pancreatic fistulae at a dose of 10-160 mg/kg/day over a period of 14 days. Blood samples were taken once a day during the administration of TMO and for 7 days after discontinuation of the drug. On the 15th day, pancreatic juice was collected under stimulation by secretin (2 Crick-Haper-Raper units/kg/h). DMO concentration in plasma reached a maximal plateau around the 10th day after starting TMO administration, and depended directly on the dose of TMO. Pancreatic excretion of DMO at a steady state closely depended on both the dose of TMO and the DMO concentration in plasma. The pancreatic juice/plasma concentration ratio for DMO exceeded 1.0 at a steady rate and decreased with the increased flow rate. Pancreatic DMO clearance (DMO output/DMO concentration in plasma) increased, depending on the flow rate, the bicarbonate concentration, and pH of pancreatic juice. Pancreatic excretion of TMO was zero or extremely low.     

A comparison between previous and present histologic assessments of chronic hepatitis C viral infections in humans

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Virus replication and liver disease in chronic hepatitis B virus infection

Recent studies on the natural history of chronic hepatitis B virus infection have provided evidence for a close temporal relationship between the phase of active virus replication and development of liver lesions. To assess the role that virus replication plays in this phase in determining the severity of the liver disease, we studied serum levels of virus-specific DNA-polymerase activity and hepatitis B_e antigen/antibody status in 48 chronic carriers of the hepatitis B surface antigen found positive for the hepatitis B core antigen in the liver. There was a remarkably evident inverse correlation between virus replication activity and liver disease activity, patients with minimal histological changes having the highest DNA-polymerase levels (mean±sd: 3879±2557 cpm) and those with severe chronic active hepatitis the lowest enzyme levels (419±246 cpm), while cases of chronic persistent hepatitis and of mild chronic active hepatitis had intermediate levels. Serum hepatitis B_e antigen was detected in 31/32 patients with milder liver lesions and in 11/16 with severe liver lesions; the remaining five cases were anti-HB_e-positive despite the presence of the core antigen in the liver. Serum levels of virus replication markers closely correlated with the distribution pattern of the core antigen in the liver. These findings indicate that in chronic hepatitis B the severity of liver disease is not directly related to levels of virus replication, thus suggesting a predominant role of host immune mechanisms.     

Presence of Active Hepatitis Associated with Liver Cirrhosis Is a Risk Factor for Mortality Caused by Posthepatectomy Liver Failure

The histologic activity of associated hepatitis was examined in 285 patients who underwent hepatectomy for hepatocellular carcinoma (HCC), to determine if the histologic activity is an independent risk factor for postoperative mortality due to liver failure. The proportion of patients with liver cirrhosis who died due to liver failure (6/180, 3.3%) was not different from that of patients with chronic hepatitis (2/68, 2.9%). However, mortality was higher in patients with liver cirrhosis and active hepatitis (4/46, 8.7%) than in those with cirrhosis and inactive hepatitis (2/134, 1.5%, P < 0.05). Such difference was not observed in the chronic hepatitis group. Multivariate analysis showed that clearance of indocyanine green at 15 min (ICGR15) and activity of hepatitis were two independent risk factors for postoperative mortality due to liver failure. In conclusion, histologic activity of associated hepatitis should be taken into account in hepatic resection of HCC in cirrhotic liver, in addition to the functional reserve of the liver.     

Mallory-Denk Bodies in chronic hepatitis

Mallory-Denk Bodies(MDB) are important as investigators,suggesting MDB as an indicator of the histologic severity of chronic hepatitis,causes of which include hepatitis C,primary biliary cirrhosis(PBC),and nonalcoholic fatty liver disease(NAFLD).Matteoni et al scored MDB in patients with NAFLD as none,rare and many,and reported that MDB plays a prominent role in this classification scheme in an earlier classification system.In this study,we evaluated 258 patients with chronic hepatitis due to metabolic,auto...     

慢性乙型肝炎患者肝组织炎症与肝功能和乙型肝炎病毒标志物的关系

目的：探讨慢性乙型肝炎（乙肝）和活动性肝硬变肝组织病变与乙肝病毒标志物（HBVM）和肝功能的关系。方法：在Knodell的乙肝肝组织炎性活性指标（HAI）分类上采用3次密码读片。用常规的方法检测血清胆红素（SB）、丙氨酸转氨酶（ALT）、天冬氨酸转氨酶（AST）、白蛋白／球蛋白（A／G）比率，肝内HBsAg,HBcAg检测用PAP法。结果：SB、ALT、AST值随HAI记分值的增高而增高，慢性肝炎，活动肝硬变患者血清A、G的含量及A／G随HAI记分值的增高而变化，结论：HAI能客观定量的反映肝组织病变的程度，为疾病的诊断，治疗和预后判断提供一种实用的病理指标，并有利于微机图像阅片和统计学分析。     

慢性肝病141例与微量元素关系的研究

本文对141例慢性肝病(慢活肝30例,肝硬化111例)患者血、肝组织中微量元素锌、铜、铁的含量测定,并测定肝硬化患者血清铜兰蛋白含量及尿锌的排出量。结果血清中锌值均明显低于对照组(P<0.05),肝硬化较慢活肝更低,而铜与铜兰蛋白含量均明显高于对照组(P<0.01)。其中19例肝硬化患者作肝组织锌、铜测定,锌含量特别低,其均值比对照组低3倍(P<0.05),而铜含量则高于对照组1倍以上(P<0.05)。肝硬化患者24h尿锌排出量明显高于对照组(P<0.001)。通过对这些微量元素代谢变化的探讨,为慢性肝病治疗中纠正其代谢障碍提供了科学依据。     

Liver eosinophilic infiltrate is a significant finding in patients with chronic hepatitis C

Summary.  Eosinophilic infiltrate of liver tissue is described in primary cholestatic diseases, hepatic allograft rejection and drug-induced liver injury, but its significance and its implications in chronic hepatitis C are unknown. The aim of this study was to investigate the clinical significance of eosinophilic liver infiltrate in patients with chronic hepatitis C. We retrospectively evaluated 147 patients with chronic hepatitis C. The presence of eosinophilic infiltrate was investigated in liver biopsies, and a numeric count of eosinophilic leucocytes in every portal tract was assessed. An eosinophilic infiltrate of liver tissue (≥3 cells evaluated in the portal / periportal spaces) was observed in 46 patients (31%), and patients who consumed drugs had an odds ratio (OR) of 4.02 (95% CI: 1.62–9.96) to have an eosinophilic infiltrate in liver biopsy. By logistic regression analysis, the presence of steatosis was independently associated with eosinophilic infiltrate (OR 5.86; 95% CI: 2.46–13.96) and homeostasis model assessment-score (OR 1.18; 95% CI: 1.00–1.39). Logistic regression analysis also showed that fibrosis staging ≥ 2 by Scheuer score was associated with grading >1 by Scheuer score (OR 6.82; 95% CI 2.46–18.80) and eosinophilic infiltrate (OR 4.00; 95% CI 1.23–12.91). In conclusion, we observed that the eosinophilic infiltrate of liver tissue was significantly more frequent in patients who assumed drugs, and found a significant association between eosinophilic infiltrate, liver steatosis and liver fibrosis. These preliminary data could lead to a constant assumption of drugs as a co-factor of eosinophils-mediated liver injury in chronic hepatitis C.     

Ornithine decarboxylase activity in the non-cancerous hepatic tissue of patients with hepatocellular carcinoma

BACKGROUND/AIMS: Hepatocellular carcinoma may develop in patients with chronic hepatitis and cirrhosis. Active hepatitis is an important etiologic factor in the development of hepatocellular carcinoma. We measured ornithine decarboxylase activity, an important enzyme during cell proliferation, in non-cancerous hepatic tissue in patients with hepatocellular carcinoma. METHODOLOGY: Thirty-four patients who underwent liver resection for hepatocellular carcinoma were the subjects of this study. Hepatitis B surface antigen was detected in 7 patients (HBV group) and hepatitis C virus antibody was detected in 27 patients (HCV group). Tissue ornithine decarboxylase activity was measured. Histologic severity in active hepatitis (activity score) and degree of fibrosis (staging score) were determined. RESULTS: Ornithine decarboxylase activity was significantly higher in the HCV group than in the HBV and control groups. In all patients, ornithine decarboxylase activity correlated directly with the histologic activity score and the histologic staging score. In the HCV group, ornithine decarboxylase activity correlated with the histologic activity score. CONCLUSIONS: Ornithine decarboxylase activity in non-cancerous hepatic tissue correlated with the severity of active hepatitis and degree of fibrosis. In patients with hepatitis C virus, active hepatitis with increased ornithine decarboxylase activity is an important factor in the development of hepatocellular carcinoma.     

HBsAg-negative Chronic Active Hepatitis and Mixed Connective Tissue Disease Syndrome

ABSTRACT Two patients are described who suffered from both HB_sAg-negative chronic active hepatitis and mixed connective tissue disease syndrome. The diagnosis of liver disease was made prior to the diagnosis of collagenosis in one of the patients, whereas the opposite was the case in the other. In spite of the fact that symptoms and laboratory data suggesting both diagnoses were present from the moment of presentation, there was a considerable delay in establishing the second diagnosis in both patients. To our knowledge, this is the first report on an association between chronic active hepatitis and mixed connective tissue disease syndrome. It illustrates the difficulties when diagnosing overlap conditions.     

Phenotypic characterization of mononuclear infiltrate present in liver of biliary atresia

The liver tissue of 26 chidren with biliary atresia was compared to that of 20 adults with autoimmune chronic active hepatitis, 20 adults with chronic hepatitis due to hepatitis B infection, and 5 children with ₁-antitrypsin deficiency in terms of the number and type of mononuclear cells in portal and lobular areas of each using a panel of specific monoclonal antibodies that recognize different cell surface epitopes. All of the tissues studied were obtained at time of liver transplantation. In addition the livers of 5 adults biopsied for hepatomegaly but found to have no histologic liver disease were used as normal controls for this study. The results demonstrate that liver tissue obtained from children with end-stage biliary atresia is more like normal liver in terms of the number and type of mononuclear cells present than in either of the two types of adult liver diseases. Moreover although the liver of children with end-stage ₁-antitrypsin deficiency is more like that of normal liver than either of the two adult liver diseases studied in terms of the number and type of mononuclear cells within the liver, it is less similar to that of normal adult liver than is liver tissue obtained from children with biliary atresia. These findings suggest that as a morphologic basis biliary atresia is unlikely to be due to either a viral or an autoimmune attack upon the liver.This work was supported in part by grants AA04425-07 and NIDDK DK32556-05.     

Comparative pharmacokinetic study of trimethadione and dimethadione for lysis of pancreatic stones

In order to investigate the biological equivalence of dimethadione (DMO) and its precursor trimethadione (TMO), comparative pharmacokinetic studies were performed in 6 beagle dogs. DMO and TMO power was given orally at the same molar dose of 1.0 g and 1.11 g (7.7 mM), respectively. Plasma concentration of DMO and TMO was determined at an appropriate interval. Four pharmacokinetic parameters were calculated from the plasma concentration-time curves of DMO and TMO; the peak plasma concentration (Cmax), the time to the peak concentration of Cmax (Tmax), the area under the plasma concentration-time curve (AUC), and the biological half-life (t 1/2). In the plasma concentration-time curve of DMO, Tmax after oral administration of TMO was longer than that after administration of DMO. This resulted from the presence of the conversion process of TMO to DMO in the body, because of the very short Tmax observed in the plasma concentration-time curve of TMO. Cmax, AUC and t 1/2 did not differ significantly between the drugs. The results obtained indicate that TMO is biologically equivalent to DMO in regard to plasma concentration of DMO.     

Serum matrix metalloproteinase-1 in patients with chronic viral hepatitis

BACKGROUND AND AIMS: Previously we found that serum matrix metalloproteinase (MMP)-1 activity decreased with progression of chronic liver disease. Our objectives in the present study were to observe the change in the serum MMP-1 protein concentration using recently developed specific enzyme immunoassays for MMP-1 and MMP-1 complexed with tissue inhibitor of metalloproteinases (TIMP)-1 and to elucidate the clinical usefulness of the serum MMP-1 test in chronic viral hepatitis. We measured the serum concentrations of MMP-1 and MMP-1/TIMP-1 complex using these immunoassays in 64 patients with histologically characterized chronic viral hepatitis. RESULTS: Serum MMP-1 concentration was inversely related to the histological severity of chronic hepatitis (P< 0.0001). It was closely associated with the histological degree of periportal necrosis (P< 0.0001), intralobular necrosis (P< 0.005), portal inflammation (P<0.0001) and liver fibrosis (P< 0.05). The serum concentration of MMP-1/TIMP-1 complex was also related to the histological severity of chronic hepatitis (P< 0.0001). It was associated with the degree of portal inflammation (P< 0.05), but not with the degree of periportal necrosis, intralobular necrosis or liver fibrosis. As serum MMP-1 level was closely associated with the histological degree of necroinflammation, we examined the ability of the serum MMP-1 test to differentiate active and inactive forms of hepatitis with a receiver operating curve. The results were compared with those of serum procollagen type III N-peptide (PIIINP) test. We found that the serum MMP-1 test was superior to the serum PIIINP test in assessing liver necroinflammation. CONCLUSIONS: In addition to the previously reported changes in enzyme activity, MMP-1 proteins in serum decreased during histological progression of chronic hepatitis. The serum MMP-1 test may be useful clinically to differentiate active and inactive types of hepatitis in patients with chronic viral hepatitis.     

Chronic hepatitis C is mild in menstruating women

BACKGROUND AND AIMS: Women with chronic hepatitis C may have a slower rate of disease progression than men. We have previously demonstrated a relationship between hepatic iron concentration and liver fibrosis in patients with chronic hepatitis C. Our aim was to compare hepatic histologic findings, iron status and other factors putatively capable of determining the severity of chronic hepatitis between menstruating women and men of comparable age. METHODS: We studied 21 consecutive hepatitis C virus (HCV)-RNA positive menstruating women and 24 consecutive HCV-RNA positive men of comparable age, who underwent liver biopsy for chronic hepatitis C. Alcohol intake was recorded and blood tests, HCV genotyping, serum iron, unsaturated iron binding capacity, serum ferritin, hepatic iron concentration, and liver histology were evaluated. RESULTS: Menstruating women showed lower grading (2.7 +/- 1.5 vs 3.6 +/- 2, P = 0.09) and significantly lower staging (1.38 +/- 1.11 vs 2.42 +/- 1.64, P = 0.037) scores than men of comparable age. Among the factors putatively capable of determining the severity of chronic hepatitis, only the hepatic iron concentration correlated with the hepatic histologic staging in a multivariate analysis. Iron-depleted women (transferrin saturation < 20% and/or serum ferritin < 9 micrograms/L) showed significant lower hepatic histologic grading (1.75 +/- 0.7 vs 3.23 +/- 1.55, P = 0.027) and staging (0.75 +/- 1.03 vs 1.77 +/- 1.01, P = 0.026) scores than women with normal iron status. CONCLUSIONS: Menstruating women with chronic hepatitis C may have a milder disease compared to men of comparable age, possibly because of menstrual blood loss and lower hepatic iron concentration. Women with chronic hepatitis C and iron deficiency have a milder disease compared to women with normal iron status, suggesting that iron deficiency results in a slower rate of disease progression.     

Prognostic significance of cholestatic alcoholic hepatitis

Tissue cholestasis is a histologic feature in some patients with alcoholic liver disease, but its significance is unknown. We studied prospectively the clinical, laboratory, and histologic findings of 306 chronic male alcoholics in whom liver tissue was available. Tissue cholestasis permitted identification of two groups: group I, absent or mild cholestasis (239 patients), and group II, moderate to severe cholestasis (67 patients). Statistical evaluation was performed by Student's ttest and regression analyses. In patients with tissue cholestasis, 97% had elevated serum cholylglycine levels, while only 61% had significant jaundice (serum bilirubin > 5 mg/dl). In patients without tissue cholestasis, 66% had elevated serum cholylglycine and 13.5% jaundice. Highly significant statistical correlations (P <0.0001) were found between cholestasis and malnutrition, prothrombin time, AST, alkaline phosphatase, bilirubin, Maddrey's discriminant function, serum cholylglycine level, albumin, and histologic severity score. In group I, 54% survived 60 months versus 22% in group II (P <0.0001). Highly significant statistical correlations (P <0.0001) were noted between serum cholylglycine levels and the parameters enumerated earlier, but not with survival. We conclude that tissue cholestasis is a highly significant prognostic indicator of outcome in alcoholic hepatitis and is more consistently associated with bile salt retention than jaundice.