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Biomedical subjects

G Kanel

Publications and source records attributed to G Kanel.

At least 19 recordsLinked to original sources
PubMed2001

Methionine adenosyltransferase 1A knockout mice are predisposed to liver injury and exhibit increased expression of genes involved in proliferation.

Liver-specific and nonliver-specific methionine adenosyltransferases (MATs) are products of two genes, MAT1A and MAT2A, respectively, that catalyze the formation of S-adenosylmethionine (AdoMet), the principal biological methyl donor. Mature liver expresses MAT1A, whereas MAT2A is expressed in extrahepatic tissues and is induced during liver growth and dedifferentiation. To examine the influence of MAT1A on hepatic growth, we studied the effects of a targeted disruption of the murine MAT1A gene. MAT1A mRNA and protein levels were absent in homozygous knockout mice. At 3 months, plasma methionine level increased 776% in knockouts. Hepatic AdoMet and glutathione levels were reduced by 74 and 40%, respectively, whereas S-adenosylhomocysteine, methylthioadenosine, and global DNA methylation were unchanged. The body weight of 3-month-old knockout mice was unchanged from wild-type littermates, but the liver weight was increased 40%. The Affymetrix genechip system and Northern and Western blot analyses were used to analyze differential expression of genes. The expression of many acute phase-response and inflammatory markers, including orosomucoid, amyloid, metallothionein, Fas antigen, and growth-related genes, including early growth response 1 and proliferating cell nuclear antigen, is increased in the knockout animal. At 3 months, knockout mice are more susceptible to choline-deficient diet-induced fatty liver. At 8 months, knockout mice developed spontaneous macrovesicular steatosis and predominantly periportal mononuclear cell infiltration. Thus, absence of MAT1A resulted in a liver that is more susceptible to injury, expresses markers of an acute phase response, and displays increased proliferation.

Animals↗
PubMed2000

Acute hepatitis induced by bupropion.

As an antidepressant, bupropion is considered to be a safe agent that usually causes infrequent and mild increase of serum liver enzymes. Asymptomatic elevation of serum transaminases was previously reported only in a single case. We describe a patient who developed typical acute hepatitis after receiving six weeks of bupropion for depression. His presentation was characterized with acute onset of symptoms associated with significantly elevated ALT, AST, and LDH and acute hepatic inflammation. The clinical course of our patient, including incubation period, pattern of liver enzyme elevation, and time of recovery, was similar to, but much more severe than, the case reported by Oslin and Duffy. Discontinuation of bupropion was followed by a rapid resolution of clinical symptoms and liver enzymes. The incidence of bupropion-induced hepatitis remains to be defined even though it appears to be relatively low. Since the clinical application of bupropion is broader, we must be aware of the clinical entity of bupropion-induced hepatitis.

Acute Disease↗
PubMed1999

Differential effect of thioacetamide on hepatic methionine adenosyltransferase expression in the rat.

Liver-specific and non-liver-specific methionine adenosyltransferase (MAT) are products of two genes, MAT1A and MAT2A, respectively, that catalyze the formation of S-adenosylmethionine (SAM), the principal methyl donor. Mature liver expresses mainly MAT1A. We showed a switch from MAT1A to MAT2A gene expression in human liver cancer cells that may offer a growth advantage. To gain a better understanding of the chronology and significance of the change in MAT expression, we examined changes in hepatic MAT expression after acute treatment of rats with a hepatocarcinogen, thioacetamide (TAA). TAA treatment for 3 weeks did not change the MAT1A mRNA level but reduced the liver-specific MAT protein level to below 30% of control. TAA also acutely reduced the activity of liver-specific MAT when added to normal liver homogenates. In contrast, both the mRNA and protein levels of non-liver-specific MAT were induced. Because liver-specific MAT exhibits a much higher Km for methionine (mmol/L) than non-liver-specific MAT ( approximately 10 micromol/L), MAT activity was decreased at 5 mmol/L but increased at 20 micromol/L methionine concentration. The SAM level, SAM-to-S-adenosylhomocysteine (SAH) ratio, and DNA methylation all fell during treatment. In summary, TAA treatment induced differential changes in hepatic MAT expression. The reduction in liver-specific MAT protein level represents a novel mechanism of inactivation of liver-specific MAT. This along with induction in MAT2A contributed to a fall in the SAM-to-SAH ratio. The resulting DNA hypomethylation may be important in the process of hepatocarcinogenesis.

Animals↗
PubMed1999

A novel, simple method of functional spleen volume calculation by liver-spleen scan.

UNLABELLED: Spleen enlargement is commonly associated with portal hypertension from cirrhosis and may cause thrombocytopenia. Thus, accurate assessment of spleen size may be helpful in the clinical evaluation. Spleen length is not a precise estimate of spleen size because of the variation in spleen configuration, and spleen volumes measured by edging techniques can be tedious. We present a new method of measuring the functional spleen volume by liver-spleen scan (LSSs), validation experiments and some clinical data. METHODS: The method involves measurement of the total spleen counts by SPECT and dividing by a representative voxel concentration on a single frame to obtain the organ volume. Validation included phantom studies and clinical evaluation in 443 consecutive patients, including 216 with histologic assessments of chronic liver disease (CLD) and 11 healthy volunteers. RESULTS: A calibration factor determined from phantoms was used to convert the calculated volume (CV) to the "true" volume (V): V = CV (0.956) - 66.5 (r = 0.9991; P < 0.001). The volume calculations were validated in a second group of phantoms (r= 0.981; P < 0.0001). Spleen volumes were expressed as volume (cm3) and as volume per pound ideal body weight (IBW) (cm3/lb) (the conversion factor to convert cm3/lb IBW to cm3/kg IBW is 2.2). Clinical studies of reproducibility included demonstration of a significant (P < 0.0001) linear correlation between volumes calculated from repeat LSSs within 9 mo of the initial LSS in 11 healthy volunteers and 32 patients with CLD: y = 1.02x - 25; r = 0.968. The correlation with spleen volumes from autopsy or splenectomy was significant: y = 0.766x + 57; r = 0.845; P < 0.001. The normal spleen volume in 11 patients was 201 +/- 77 cm3 and 1.43 +/- 0.68 cm3/lb IBW (upper limits of normal: 335 cm3 or 2.5 cm3/lb IBW). In 443 consecutive LSSs over 15 mo, half of the patients had spleen volumes above the upper limits of healthy volunteers, and CLD was present in 90.9% of these patients. In 216 patients with histologically proven liver disease, a progressive increase in the percentage of spleen volumes above the upper limits of normal was noted from no fibrosis (10%) to mild to moderate fibrosis (36.7%) to early cirrhosis (52%) to advanced liver disease (75%). The correlation of spleen volume with platelet count was excellent (r = 0.7635; P < 0.005). CONCLUSION: This novel spleen volume measurement detects serious liver disease and correlates with splenic hyperfunction.

Chronic Disease↗
PubMed1997

Low albumin gradient ascites complicating severe pseudomembranous colitis.

Pseudomembranous colitis (PMC) is a frequently severe, sometimes fatal iatrogenic disease that is antibiotic-associated in almost all cases. The most common clinical features of PMC include abdominal pain, watery diarrhea, fever, leukocytosis, hypoalbuminemia, and hypovolemia. Ascites, not considered a well-known feature of PMC, is fairly common, based on a review of the English language literature but has not been characterized fully. This case report describes 5 patients with PMC who presented with low serum-ascites albumin gradient (SAAG) and neutrocytic ascites, without evidence of infectious, malignant, or inflammatory peritoneal disease, which has not been reported previously. In 1 patient, massive low SAAG ascites was the presenting manifestation of PMC, a feature also not reported previously. Three of the 5 (60%) patients had acquired immunodeficiency syndrome. The characteristics of the fluid specimens in these 5 patients and the possible pathogenetic mechanisms are proposed. The findings suggest that PMC should be included in the differential diagnosis of low SAAG ascites, especially in patients with acquired immunodeficiency syndrome.

Acquired Immunodeficiency Syndrome↗
PubMed1997

Functional measurement of nonfibrotic hepatic mass in cirrhotic patients.

OBJECTIVES: We have postulated that the perfused hepatic mass (PHM) can be estimated by quantitative (volumetric) liver spleen scan (QLSS) using single photon emission computed tomography assessment of sulfur colloid distribution between liver, spleen, and bone marrow. Thus, this parameter should correlate with the amount of functioning tissue in the liver. As a "gold standard" estimate of the nonfibrotic functioning hepatic mass, the weight of the liver at autopsy or transplant was corrected for the amount of scar tissue present. QLSS parameters were correlated with functional hepatic mass in 13 patients with advanced liver disease with liver available at transplant (8 patients) or autopsy (5 patients) who had prior QLSS. METHODS: Greater than 1000 mm2 of a liver tissue was assessed histologically in all patients and from more than 2 regions of the liver in 9 of 13 patients. The total fibrosis score (TFS) (range, 0-17.5) was calculated as a semiquantitative estimate of hepatic fibrosis. The ratio of functioning tissue was calculated as (1 - TFS/20) and the amount of functioning tissue as the nonfibrotic weight (NFW): NFW = liver weight x (1--TFS/20). QLSS parameters were measured postprandially and 30 min after injection of 5 mCi of technetium Tc 99m sulfur colloid. Pixel and total counts from the liver, spleen, and bone marrow as well as organ length were measured. Liver/bone marrow index and liver/spleen index were calculated. The perfused hepatic mass (PHM) was defined as the mean of the liver/bone marrow index and liver/spleen index. RESULTS: All patients had cirrhosis: alcoholic (1 patient), alcoholic with alcoholic hepatitis (1 patient), hepatitis B (3 patients), hepatitis C (6 patients), hepatitis C with hepatocellular carcinoma (1 patient), and primary sclerosing cholangitis (n = 1). The ratio of functioning tissue was 0.54 +/- 0.07; liver weight 1215 +/- 317 g; and NFW = 658 +/- 193 g. The PHM = 55 +/- 14. The PHM calculated from the QLSS correlated strongly with the NFW (functioning tissue) at autopsy/transplant: NFW = 13 PHM - 55; r = 0.9505; p < 0.0001). CONCLUSIONS: In cirrhotic patients (a) we have confirmed that the sulfur colloid distribution by QLSS is determined by the perfused hepatic mass, and (b) the amount of functioning tissue can be precisely estimated by QLSS parameters.

Autopsy↗
PubMed1996

Duodenal and hepatic toxoplasmosis in a patient with HIV infection: review of the literature.

We report a case of watery diarrhea due to duodenal toxoplasmosis in a patient with the acquired immunodeficiency syndrome. Treatment with pyrimethamine, clindamycin, and folinic acid decreased the diarrhea as well as the duodenal toxoplasma cyst load. Hepatic toxoplasmosis was also present, associated with an elevated serum alkaline phosphatase activity and a minimally elevated lactate dehydrogenase level.

AIDS-Related Opportunistic Infections↗
PubMed1995

Perfused Kupffer cell mass. Correlation with histology and severity of chronic liver disease.

The perfused Kupffer cell mass determines sulfur colloid distribution by liver spleen scan (LSS) and is proportional to the perfused hepatocyte mass. This accounts for the correlation of sulfur colloid distribution with tests of hepatic function and raises the question of whether the LSS can be used as a quantitative test of hepatic function. The recent ability to precisely measure sulfur colloid distribution by single-photon-emission computerized tomography (SPECT) prompted us to evaluate the clinical value in 329 consecutive patients with adequate LSS and clinical information, of which 27 apparent normals and 220 patients with chronic liver disease (CLD) were included in this study. The liver-bone marrow index (LBI) indicated the distribution of counts between the liver and bone marrow. The liver-spleen index (LSI) indicated the distribution between liver and spleen adjusted for spleen size. The LBI and LSI correlated with each other (r = 0.753; P < 0.001). The arithmetic mean of LBI and LSI was defined as the severity score. Detailed clinical evaluation was available in these patients and included 109 who had liver biopsy. A severity score in 27 normals was 102 +/- 5 (mean +/- SD) with all values > 85. The severity score correlated with hepatic fibrosis (r = -0.694; P < 0.001) in 109 patients with benign liver disease who had recent biopsies and with the Child-Pugh classification (r = 0.78; P < 0.001) in 220 patients with CLD.(ABSTRACT TRUNCATED AT 250 WORDS)

Biopsy↗
PubMed1995

The liver-spleen scan as a quantitative liver function test: correlation with liver severity at peritoneoscopy.

Sulfur colloid distribution on liver-spleen scan is determined by the perfused Kupffer cell mass. The perfused Kupffer cell mass is proportional to the perfused hepatocyte mass, but is less affected by acute changes in hepatocyte function. Thus, sulfur colloid distribution parameters (precisely measured by quantitative liver-spleen scan [QLSS]) may be an excellent test of the perfused hepatic mass. Although no gold standard exists for confirmation, a close correlation should exist between liver disease severity assessed at peritoneoscopy and sulfur colloid distribution. Peritoneoscopy severity (scored as total peritoneoscopy score [PS]; range, 0-5) was assessed in 76 patients who also had QLSS. Multivariate equation were generated to estimate liver disease severity from the QLSS. These were then applied prospectively in 20 consecutive patients to validate these equations. In 76 patients, 62 were evaluated because of chronic liver disease (CLD) and included those with micronodular (20) and macronodular (20) cirrhosis with various degrees of severity (Child's A, 16; B, 29; C, 17). Multivariate analysis yielded a number of combinations of QLSS parameters that correlated with peritoneoscopic severity. These equations were used to estimate liver disease severity. Estimates of liver disease severity (estimated PS [EPS]) correlated well with the PS in these 76 patients (r = .9064; r2 = .8216; P < .0001). Adding histological fibrosis to the QLSS parameters yields an equation for estimating PS that was even more effective (r = .9462; r2 = .8953; P < .001). However, validation of multivariate equations requires confirmation of their value in a second population.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1991

A rodent model of cirrhosis, ascites, and bacterial peritonitis.

We sought to develop a rodent model of spontaneous bacterial peritonitis and report here the preliminary results of carbon tetrachloride-induced cirrhosis in which ascites and bacterial peritonitis predictably develop. Of 41 rats that survived the initial carbon tetrachloride toxicity, 38 (92.7%) developed cirrhosis with ascites. Of these 38, 21 (55.3%) developed 24 episodes of ascitic fluid infection without iatrogenic colonization. No surgically treatable source of infection was identified at autopsy in any rat; therefore, the infections were presumed to be "spontaneous." Eight (50%) of the 16 rats with culture-positive ascitic fluid at postmortem examination also had spontaneous pleural fluid infection with the same organism. Escherichia coli and Proteus sp. were the organisms most commonly isolated. This rodent model of cirrhosis with ascites appears to be the first high-yield animal model of spontaneous bacterial peritonitis. Ascitic fluid infection in these rats resembles ascitic fluid infection in humans. This model will allow further investigation of the mechanisms of pathogenesis of ascitic fluid infection and provide insight into the prevention and treatment of spontaneous bacterial peritonitis and pleural fluid infection in patients with cirrhosis.

Animals↗
PubMed1991

Fatty infiltration of the liver: quantification with phase-contrast MR imaging at 1.5 T vs biopsy.

Quantification of hepatic fat content by application of MR phase-contrast imaging (Dixon method) at 1.5 T was compared with results of biopsy in 16 patients with a variety of liver abnormalities. Motion artifact was suppressed by employing six or eight averages of short TR in-phase (echo offset, 0 msec), out-of-phase (echo offset, 1.1 msec), and in-phase (echo offset, 2.2 msec) spin-echo pulse sequences. The 360 degree out-of-phase sequence was used to assess the impact of T2* decay on this method of estimating fat fraction. A standard two-echo long TR sequence also was obtained in all patients. Histologic preparations from the biopsy specimens were examined by a pathologist who had no knowledge of the MR results and were graded according to overall visual assessment as belonging to one of four categories of fat fraction. Results of the MR-calculated apparent fat fraction were compared directly with biopsy category and were also placed in MR fat fraction categories, allowing estimation of the statistical correlation between the biopsy and MR grading systems. Eight of eight patients with biopsy categories indicating a fat fraction of less than 0.25 were computed by MR to have a fat fraction of less than 0.1. Seven of eight patients with biopsy categories indicating a fat fraction of greater than 0.25 were computed by MR to have a fat fraction of at least 0.24. The MR-calculated apparent fat fraction category correlated significantly with the histologic biopsy category (r = .86, p less than .01). When compared with the in-phase image, decreased signal from liver was visually apparent on the 180 degree out-of-phase images in all cases in which the fat fraction was at least 0.24, but there was no indication of fatty liver on the standard T1- or T2-weighted images. Calculated T2 also showed no correlation with degree of fatty deposition. Correction for T2* decay by using the 360 degree out-of-phase acquisition in addition to the standard 0 degree and 180 degree out-of-phase images had little effect on fat fraction computation. Phase-contrast MR is a promising noninvasive method for quantitative assessment of fatty deposition in the liver.

Adult↗
PubMed1990

Failure of colchicine to improve short-term survival in patients with alcoholic hepatitis.

Colchicine treatment was used in this randomized placebo-controlled trial in patients with severe acute alcoholic hepatitis [serum bilirubin greater than or equal to 5 mg/dL (85.5 mumol/L) mean, 17.5 +/- 7.5 mg/dL (299.25 +/- 128.25 mumol/L)]. Hospitalization mortality and morbidity and the effect on biochemical test results were the end points of the treatment. Patients in the two groups were evenly matched by demographics and laboratory test results. Mean time to study entry was less than 7 days from admission. The duration of the trial was 30 days. Thirty-six patients (24 men, 12 women) received colchicine (1 mg orally every morning) and 36 (25 men, 11 women) received an identical placebo. Seven (19%) colchicine-treated and six (17%) control patients died during the index hospitalization after a mean of 17.4 +/- 10.8 and 17.8 +/- 5.3 days, respectively (NS). During a 4-month follow-up period from entry into the trial, there were two additional deaths in each group. No differences between placebo- and colchicine-treated patients were observed in any of the laboratory parameters (serum bilirubin, aspartate transaminase, alanine transaminase, prothrombin activity, albumin, white blood cell count, hemoglobin, and creatinine) that were followed up over the 30-day treatment period. The frequency of complications did not differ statistically between the two groups. This study showed no effect of colchicine treatment on mortality and morbidity of severe alcoholic hepatitis. Colchicine cannot be recommended for the treatment of patients with alcoholic hepatitis.

Acute Disease↗
PubMed1989

Fibrinous pericarditis in alcoholic liver disease.

The autopsy data at the University of Southern California Liver Unit was studied during a 6-year period to investigate the relationship of fibrinous pericarditis with liver diseases. We found 18 cases of fibrinous pericarditis in 220 patients with alcoholic liver disease but none in 32 patients with fulminant and subacute hepatitis without alcoholism or in 39 patients with nonalcoholic cirrhosis. Although all the 18 patients with pericarditis had azotemia, 3 patients had pericarditis develop only in mild renal function impairment. These findings suggest that chronic alcoholism may precipitate pericarditis during the hepatorenal syndrome.

Adult↗
PubMed1988

In vivo acoustic attenuation in liver: correlations with blood tests and histology.

Results of in vivo attenuation measurements in the liver have been obtained in 26 normal controls and in 51 patients with chronic diffuse liver disease. A modified real-time sector scanner was used for narrow-band amplitude attenuation examination. In the control group (people without apparent liver disease), a statistically significant correlation was found between acoustic attenuation in liver and two blood tests reflecting liver function: serum albumin (n = 24, r = 0.67, p = 0.002) and prothrombin time (n = 23, r = 0.63, p = 0.019). There was a statistically significant positive correlation between attenuation and fat for all biopsied patients (n = 51, r = 0.32, p = 0.023) and for patients with minimal fibrosis (n = 25, r = 0.45, p = 0.027). Although no correlation with fibrosis was found for all patients, in the group of patients with minimal fat there was a correlation with portal fibrosis (n = 33, r = 0.37, p = 0.035). This double blind prospective study shows that in the liver: (1) attenuation estimates appear correlated with clinical parameters (blood tests) in normal volunteers, and (2) large changes in fat affect narrow-band acoustic attenuation estimates to a greater degree than severe portal fibrosis in patients with chronic diffuse liver disease. Further research is needed before these estimates can become a clinical tool.

Fatty Liver↗