Examination Of Liver Biopsy Specimens Research Articles

Th1/Th2 balance: an important indicator of efficacy for intra-arterial chemotherapy

It has been reported that Th2 cytokines down-regulate antitumor immunity, while activation of type 1 T cells promotes antitumor immunity. However, the immunological features of liver cirrhosis (LC) patients with advanced hepatocellular carcinoma (aHCC) treated by intra-arterial chemotherapy are still unclear. The aim of this study was to assess the influence of intra-arterial combination chemotherapy on the Th1/Th2 balance in LC patients with aHCC. Twenty-one adult Japanese LC patients with aHCC were treated by intra-arterial combination chemotherapy. The control group was composed of 20 adult Japanese patients with chronic hepatitis C diagnosed from examination of liver biopsy specimens. All control patients were over 55 years old and were stage 1 according to the fibrosis score of Desment. Thirteen of the 21 aHCC patients (group R) showed an objective response, but the other 8 patients (group N) showed no response. There were no significant differences of Th1 cells between group R and group N either before or after chemotherapy. Although there was no significant difference from group R, group N had a significantly higher percentage of Th2 cells than the control group both before and after chemotherapy (p < 0.05 by Tukey's test). These results indicate that the Th1/Th2 balance might be a useful indicator of the effect of intra-arterial combination chemotherapy in LC patients with aHCC. Inhibition of an increase of Th2 cells might be important for the efficacy of intra-arterial chemotherapy in such patients.

Relationship of peripheral blood CD4-positive T cells to carcinogenesis in patients with HCV-related chronic hepatitis and liver cirrhosis

It has been reported that Th2 cytokines down-regulate antitumor immunity, while activation of type 1 T cell responses promotes antitumor immunity. However, detailed information on the immunological background of patients with HCC is still unknown. The objectives of this study were to evaluate the Th1/Th2 balance and to investigate the relation between carcinogenesis and host immunity in patients with chronic hepatitis C, HCV-related liver cirrhosis (LC), or HCC. The study population was 117 patients who had chronic inflammation due to HCV infection diagnosed from pathological examination of liver biopsy specimens, including 32 patients who had HCV-related LC with HCC. Apart from the patients with HCC, they were divided into the four subgroups based on the fibrosis score of Desment (stages 1-4). Blood samples were collected in the early morning before treatment. Flow cytometry was used to assess cytoplasmic IFN-gamma and IL-4 expression by peripheral blood CD4+ T cells, and the percentage of IFN-gamma+ and IL4- T cells (Th1) or IFN-gamma- and IL4+ T cells (Th2) was calculated before the start of each therapy. There were 20 patients in F1, 25 patients in F2, 19 patients in F3, 21 patients in F4, and 32 patients with HCC. In the F4 and HCC groups, Th1 cells tended to increase depending on the extent of fibrosis, although there were no significant differences between these groups and the other groups. In the HCC group, Th2 cells showed a significantly higher percentage than in the F1 or F3 groups. These results suggest that Th1 dominance is lost due to an increase of Th2 cells in HCC patients and that carcinogenesis might occur in patients with chronic HCV infection and increased level of Th2 cells.

Nodular Regenerative Hyperplasia and Severe Portal Hypertension in Cystinosis

Cystinosis is a rare autosomal-recessive disorder characterized by the intralysosomal accumulation of cystine, which is responsible for widespread tissue destruction. Liver biopsy specimens of patients with cystinosis show cystine crystal formation in Kupffer cells. However, significant liver disease and portal hypertension is not a common complication of cystinosis. We report the case histories of 2 young men with poorly treated nephropathic cystinosis who developed noncirrhotic portal hypertension with evidence of nodular regenerative hyperplasia (NRH). Liver biopsy examinations, upper and lower endoscopy with biopsy examination, imaging studies, venous pressure measurements, and laboratory investigations were used to evaluate the causes of the liver disease and portal hypertension. Histologic examination of liver biopsy specimens from both patients showed changes characteristic of NRH with portal hypertension documented by measurement of pressure gradients. In addition, endoscopy in the first patient showed varices and portal hypertensive gastropathy. NRH was confirmed by histologic examination of the liver in both patients and is the likely cause of their portal hypertension. NRH may represent a rare, late complication of cystinosis, although the mechanism remains undefined.

Copper-Associated Chronic Hepatitis in Labrador Retrievers

This study summarizes the clinical and pathologic findings in 15 Labrador Retrievers with copper-associated chronic hepatitis (CACH). Our hypothesis was that this form of hepatitis is caused by a defect in hepatic copper metabolism, which most likely originates from a genetic defect. Affected Labradors consisted of 11 female and 4 male Labrador Retrievers. Eight family members of 2 of these patients were examined prospectively, as were 6 unrelated healthy Labrador Retrievers. All dogs were registered at the breed club. The average age at clinical presentation was 7 years (range, 2.5-10.5 years). All dogs were presented for anorexia, which was associated with vomiting in 8 patients. The diagnosis of CACH was based on histologic examination of liver biopsy specimens in all dogs, including semiquantitation of copper. A disproportionate increase in alanine aminotransferase (ALT) activity relative to alkaline phosphatase (ALP) activity, as well as the centrolobular localization of copper and the association of copper accumulation with hepatic lesions, suggested a primary copper storage disease rather than primary cholestatic liver disease causing copper accumulation. Mean hepatic copper concentration measured in related Labradors was 1,317 microg/g dry weight liver (range, 402-2,576 microg/g). Mean hepatic copper concentration of unrelated normal Labradors was 233 microg/g dry weight liver (range, 120-304 microg/g). Our findings support the hypothesis that a hereditary form of hepatitis occurs in Labrador retrievers and is caused by a defect in hepatic copper metabolism.

Non-alcoholic Fatty Liver Disease and Non-alcoholic Steatohepatits in Patients with Childhood-Onset Adult Growth Hormone Deficiency

Patients with growth hormone deficiency (GHD) often have obesity, hyperlipidemia, fatty liver and diabetes mellitus which are similar to metabolic syndrome. Recently, it has been reported that non-alcoholic fatty liver disease (NAFLD), especially with non-alcoholic steatohepatits (NASH) are associated with metabolic syndrome. Therefore, it is interesting to know the relationship between GHD and NASH/NAFLD. In the present study, we investigated NASH/NAFLD in patients with childhood-onset adult GHD. A retrospective chart analysis was performed on 38 patients (M/F 19/19, age 35 ± 11, range 18-62) with childhood-onset GHD who visited our outpatient clinic. Clinical course, symptoms and laboratory data were reviewed in these patients. The average body mass index (BMI) and the value of HOMA-R of the patients were 24.9 ± 3.8 kg/m2 and 3.09 ± 2.9, respectively. Liver dysfunction was found in 17 patients. We performed abdominal ultrasonography on 7 of 17 patients with liver dysfunction, and observed fatty liver change in all patients. The majority of these patients had impaired glucose tolerance and dyslipidemia by the time of diagnosis of NAFLD. Moreover, microscopic examination of liver biopsy specimens from one patient revealed NASH with fibrosis. In conclusion, patients with GHD are at risk of excessive weight gain, impaired glucose tolerance, and dyslipidemia with subsequent development of NAFLD. As NAFLD is related to the occurrence of NASH and cirrhosis, this novel evidence that GHD may be accompanied by progressive NAFLD has important implications for follow-up and management of patients with GHD.

Serum markers detect the presence of liver fibrosis: A cohort study

Histologic examination of a liver biopsy specimen is regarded as the reference standard for detecting liver fibrosis. Biopsy can be painful and hazardous, and assessment is subjective and prone to sampling error. We developed a panel of sensitive automated immunoassays to detect matrix constituents and mediators of matrix remodeling in serum to evaluate their performance in the detection of liver fibrosis. In an international multicenter cohort study, serum levels of 9 surrogate markers of liver fibrosis were compared with fibrosis stage in liver biopsy specimens obtained from 1021 subjects with chronic liver disease. Discriminant analysis of a test set of samples was used to identify an algorithm combining age, hyaluronic acid, amino-terminal propeptide of type III collagen, and tissue inhibitor of matrix metalloproteinase 1 that was subsequently evaluated using a validation set of biopsy specimens and serum samples. The algorithm detected fibrosis (sensitivity, 90%) and accurately detected the absence of fibrosis (negative predictive value for significant fibrosis, 92%; area under the curve of a receiver operating characteristic plot, .804; standard error, .02; P < .0001; 95% confidence interval, .758-.851). Performance was excellent for alcoholic liver disease and nonalcoholic fatty liver disease. The algorithm performed equally well in comparison with each of the pathologists. In contrast, pathologists' agreement over histologic scores ranged from very good to moderate (kappa = .97-.46). Assessment of liver fibrosis with multiple serum markers used in combination is sensitive, specific, and reproducible, suggesting they may be used in conjunction with liver biopsy to assess a range of chronic liver diseases.

Hepatic hyper-vitaminosis A

We report the case of a 32-year-old man with portal hypertension without cirrhosis due to chronic vitamin A intoxication. Portal hypertension revealed by oesophageal varice rupture progressively worsened and ascites occurred 5 years after the patient stopped vitamin A intake. Initially, serum retinyl palmitate concentration was increased whereas serum retinol concentration was normal. There was no hepatic fibrosis on light microscopic examination of liver biopsy specimens. Five years after the patient stopped excessive vitamin A intake, serum retinol and retinol-binding protein concentrations were below the normal range even though there was an increased hepatic retinyl ester content. This was attributed to the late development of peri-sinusoidal fibrosis. This case mainly shows the importance of retinyl ester level determination: serum retinyl palmitate should be measured immediately after intoxication and hepatic retinyl esters should be measured initially and particularly later. Indeed, later serum and hepatic retinol levels in chronic hyper-vitaminosis A may be normal and lead to under-estimation of liver vitamin A overload.

Ultrasonographic findings in three cows with chronic ragwort (Senecio alpinus) poisoning

Three cows with ragwort (Senecio alpinus) poisoning were examined clinically, haematologically and ultrasonographically, and biopsy specimens of the liver were examined histologically. At the end of the study, the cows...

Surgical correction of patent ductus venosus in three brothers.

We report the presence of a patent ductus venosus in three brothers who underwent surgical correction. Patent ductus venosus was demonstrated by ultrasonography. Portosystemic venous shunt ratios as evaluated by [123I]iodoamphetamine per rectal portal scintigraphy were 67%, 50%, and 77%, respectively. Histologic examination of liver biopsy specimens revealed fatty degeneration in all cases. Portal vein pressure before and after temporarily occluding the patent ductus venosus was estimated by an Anthron P-U catheter introduced into the portal vein via the ligament teres hepatis. Portal venous pressure increased from 10 to 17 cm H2O, 16 to 23 cm H2O, and 14 to 27 cm H2O, respectively. Therefore, banding of the ductus venosus with Teflon tape was attempted to prevent portal hypertension following complete ligation. As a result, portal venous pressures after stricture of the ductus venosus were 12, 21, and 20 cm H2), respectively. Bile acid and liver enzymes decreased and returned to normal within 14 days after surgery. Interestingly, serum concentrations of hepatocyte growth factor (HGF) increased significantly after restoration of the portal blood flow and then gradually decreased, but remained persistently elevated for at least two weeks in two cases measured after surgical correction. One month after correction, liver function returned to normal as assessed by serological and histological parameters in all cases. These results suggest that it is important to determine whether stricture or complete ligation is indicated for a patent ductus venosus during surgical correction, based on the portal venous pressure after temporal test occlusion of the duct. In addition, HGF may be a useful marker for normalization of hepatic microcirculation after surgery.

Chronic hepatitis C associated with anti-liver/kidney microsome-1 antibody is not a subgroup of autoimmune hepatitis.

To determine whether "autoimmune hepatitis type IIb" should be categorized as a subgroup of autoimmune hepatitis, we conducted a clinicopathological study of 25 adult Japanese patients who were positive for anti-liver/kidney microsome-1 (anti-LKM-1) anti-body and infected with the hepatitis C virus (HCV). Anti-LKM-1 was determined by indirect immunofluorescence and by the double immunodiffusion assays we have developed. Twenty-two patients did not present any unusual symptoms or any associated diseases during the course of their chronic HCV infection. The spectrum of HCV genotypes of these patients did not significantly differ from that of anti-LKM-1-negative Japanese patients with chronic hepatitis C. Histological examination of liver biopsy specimens showed the usual characteristics of chronic hepatitis C and lack of characteristics of autoimmune hepatitis type I. No disease-specific HLA haplotypes were noted, and HLA-DR4, which is detectable in 88.7% of Japanese patients with autoimmune hepatitis type I, was detected in only 50.0% of our group, the same rate as the background frequency. Prednisolone was effective in none of the six patients treated, but interferon was effective in six of ten treated patients (60%). From these results, we conclude that "autoimmune hepatitis type IIb" should not be categorized as autoimmune hepatitis, and that this subgroup is essentially chronic hepatitis C in which an autoantibody has been produced during the course of chronic HCV infection.

Volunteer blood donors with antibody to hepatitis C virus: clinical, biochemical, virologic, and histologic features. The Hepatitis C Study Group.

To assess the clinical significance of antibody to hepatitis C virus (anti-HCV) in volunteer blood donors. Prospective cohort study. National Institutes of Health Clinical Center, a tertiary referral research hospital. 60 anti-HCV-positive blood donors, divided into three groups of 20 persons each: Group I had normal alanine aminotransferase levels, group II had levels elevated to values less than twice the normal range, and group III had levels elevated to values greater than twice the normal range. Medical history, results of laboratory and virologic testing, and percutaneous liver biopsy findings. Participants with normal alanine aminotransferase levels were older and more often female than those with abnormal levels. The source of infection, duration of disease, symptom score, and amount of alcohol consumed were similar in the three groups. Hepatitis C virus RNA was detectable in 85% of participants, more commonly in the groups with elevated alanine aminotransferase levels (95%) than in the group with normal levels (65%); however, titers were similar in all groups. Examination of liver biopsy specimens showed chronic hepatitis in 54 participants (90%) and cirrhosis in 1 participant. The only normal liver biopsy specimens (n = 3) were those from participants who were HCV RNA negative and had normal alanine aminotransferase levels. Most blood donors with anti-HCV have chronic hepatitis C regardless of their serum alanine aminotransferase levels. Donors with normal alanine aminotransferase levels and no HCV RNA in their serum generally have normal liver histologic findings or minimal changes and have probably recovered from HCV infection.

Preliminary evidence that a trpE‐HEV fusion protein protects cynomolgus macaques against challenge with wild‐type hepatitis e virus (HEV)

Immunization of two cynomolgus macaques (cynos) with trpE-C2 protein, a trpE-HEV fusion protein that represents the carboxyl two thirds of the putative capsid protein, prevented development of biochemical evidence of viral hepatitis in these primates after challenge by wild-type HEV from either a Burmese or Mexican stool isolate. Neither of the immunized animals showed any elevation of alanine aminotransferase activity after challenge with wild-type HEV in marked contrast with the unimmunized (control) cynos. In the case of the Burmese HEV challenged cyno, the protective effect was complete with the animal failing to demonstrate any evidence of HEV infection. The immunized cyno challenged with Burmese HEV did not exhibit any HEV RNA in its stools or HEV antigen in its liver. The immunized cyno (#8902) challenged with Mexican virus exhibited HEV RNA in its stools and HEV antigen in its liver; however, microscopic examination of liver biopsy specimens from this cyno failed to detect histopathologic evidence of viral hepatitis. All of the animals (naive and immunized) developed anti-HEV IgM and IgG responses after HEV challenge. Our preliminary studies indicate that the trpE-C2 protein is a promising candidate HEV vaccine.

Serum lipoprotein concentrations and hepatic lesions in obese cats undergoing weight loss

Summary Serum lipoprotein concentrations, routine serum biochemical values, and morphologic changes of the liver were evaluated in cats undergoing weight loss. Food was witheld from 6 obese and 6 control cats for 3 days (days 0 to 2), followed by feeding 50% of previous food intake for 26 days (days 3 to 28). Percutaneous liver biopsy specimens were obtained from all cats on days 0, 7, 14, and 28. Blood samples for serum biochemical analysis and lipoprotein profiles were obtained on days 0, 3, 7, 14, and 28. All cats lost weight throughout the study, and none developed signs of clinical illness, including those of idiopathic hepatic lipidosis syndrome. Serum total cholesterol concentrations decreased initially in all cats, but rapidly returned to normal after day 3 in obese cats, suggesting altered cholesterol metabolism during dietary restriction. Low-density lipoprotein concentrations decreased throughout the study in control cats, but were unchanged in obese cats. Examination of liver biopsy specimens from each cat revealed minimal lipid accumulation in all specimens, although some specimens contained hydropic degeneration.

Cholesteryl Ester Storage Disease: Hepatopathology and Effects of Therapy With Lovastatin

We describe three patients with cholesteryl ester storage disease. Diagnosis was confirmed by demonstrating a deficiency in lysosomal acid cholesteryl hydrolase activity in cultured skin fibroblasts from each of these patients. All had hepatomegaly, elevated serum aminotransferase activities and hyperlipoproteinemia. Histological examination of liver biopsy specimens before treatment revealed accumulation of fat within hepatocytes, bile duct epithelium and endothelial and Kupffer cells. Cholesterol crystals were recognized by their birefringence in frozen sections. A striking feature was the presence of markedly hypertrophied Kupffer cells and portal macrophages with foamy, tan-colored cytoplasm that stained readily with the periodic acid-Schiff reagent and aldehyde fuchsin. Periportal fibrosis was noted in all cases; incomplete cirrhosis was present in one case. Distinctive and hitherto undescribed lysosomal accumulations of triglyceride and cholesterol crystals were noted. The patients were treated with lovastatin, a cholesterol-lowering agent, for at least 12 mo. No significant changes were seen in serum lipoprotein concentrations or liver histopathology after therapy. Thus lovastatin did not have an obviously beneficial effect on abnormal lipid metabolism in these patients.

Primary sclerosing cholangitis: a long-term follow-up study.

During the 10-year period from 1 January 1975 to 31 December 1984, primary sclerosing cholangitis (PSC) was diagnosed in 45 patients. Twelve of the patients have died (26.7%), 10 of them of causes related to PSC. Inflammatory bowel disease was found in all patients; ulcerative colitis was found in 37, Crohn's disease in 6, and unclassified colitis in 2 patients. Of the patients alive, 27 were submitted to a follow-up study in 1985. At the follow-up examination no general progression of the liver disease, as measured on the basis of clinical examination and levels of transaminases, alkaline phosphatases, and bilirubin, was found. Cholangiographic evaluation in 24 patients showed that the stage of ductal changes progressed from mild to moderate in 3 patients; in the other patients the stage was not altered. Morphologic examination of liver biopsy specimens in patients with a benign clinical course usually showed portal inflammation, fibrosis, and minor signs of piecemeal necrosis, whereas widespread piecemeal necrosis was found in patients who deteriorated and died. The 50% survival since diagnosis of liver disease was calculated to be 17 years in patients with PSC and 50 years in a comparable group among the general population. The estimated survival curve in PSC was displaced to the left, indicating a reduced life expectancy of about 30 years.

LIVER FUNCTION TESTS IN CLINICAL MEDICINE

Knowledge of the functional status of the liver, gained by the use of tests, is growing in importance in medicine and surgery. Such tests are particularly helpful (1) in patients with jaundice and (2) in some without jaundice as in (a) cirrhosis of the liver, (b) gallbladder disease, (c) controlling the therapy with hepatotoxic drugs and (d) hyperthyroidism. Our object is to give the indications and uses of liver function tests based on our experience gained from examination and study of 563 jaundiced and 112 nonjaundiced patients. In 111 of these cases which came to operation our studies were supplemented by histologic and fluorescence microscopic examination of liver biopsy specimens. WHICH LIVER FUNCTION TESTS ARE USEFUL? The answer to the question Which liver function tests are useful? depends first on whether or not the patient is jaundiced. In jaundice, the usual problem is to decide