Biomedical subjects
M J Bahr
Publications and source records attributed to M J Bahr.
Transcriptional activity of the human tissue inhibitor of metalloproteinases 1 (TIMP-1) gene in fibroblasts involves elements in the promoter, exon 1 and intron 1.
The active forms of all of the matrix metalloproteinases (MMPs) are inhibited by a family of specific inhibitors, the tissue inhibitors of metalloproteinases (TIMPs). Inhibition represents a major level of control of MMP activity. A detailed knowledge of the mechanisms controlling TIMP gene expression is therefore important. We have isolated a genomic clone of the human TIMP-1 gene. A 3 kbp XbaI fragment has been sequenced; this fragment contains 1718 bp 5' flanking sequences, exon 1, a 929 bp intron 1 and part of exon 2. Computer analysis reveals 10 consensus sequences for Sp1, six for activating protein 1 (AP-1), six for polyoma enhancer A3 (PEA3), 12 for AP-2 and five CCAAT boxes. The region hybridizing with a murine TIMP-1 promoter fragment has been subcloned and analysed further. RNase protection identifies six transcription start points, making exon 1 up to 48 bp in length. Transient transfection of promoter-chloramphenicol O-acetyltransferase reporter constructs into primary human connective tissue fibroblasts shows that a 904 bp fragment that hybridizes to a murine TIMP-1 promoter fragment contains a functional promoter. Constructs of -738/+95 to -194/+21 are inducible with serum or phorbol ester to a similar extent to the endogenous TIMP-1 gene. These results and further mapping with 5' deletion mutants from the -738/+95 region have demonstrated that an AP-1 site at -92/-86 is essential for basal expression of the gene. Point mutations within this region have further confirmed the role of this site, along with a more minor role for a neighbouring PEA3 site, in basal expression. Deletions from the 3' end also implicate a region across the exon 1/intron 1 boundary and especially +21 to +58 in basal expression. The +21/+58 region contains a putative binding site for the transcription factor leader-binding protein 1 (LBP-1). Gel-shift analysis shows that protein binds specifically to this region, but competition studies suggest that it is unlikely to be LBP-1.
Long-term outcome of hepatitis C virus infection after liver transplantation.
We analyzed the long-term clinical course of 71 patients with RNA-positive hepatitis C virus (HCV) infection after liver transplantation. Patients with reinfection after transplantation for HCV-related liver disease, or de novo infection at transplantation were followed for up to 12 years. Cumulative survival for patients with HCV infection at 2, 5, and 10 years after transplantation was 67%, 62%, and 62%, respectively. It was not significantly different from that in patients transplanted for other nonmalignant diseases without HCV infection. The main factor determining long-term survival was the presence or absence of hepatocellular carcinoma (HCC) at transplantation. The 5-year survival rate for HCV patients with or without HCC was 35% versus 73%, respectively (P < .05). No deaths because of viral hepatitis of the graft were observed. Deaths in the first year after transplantation were caused by infectious complications, cardiovascular problems, or rejection; deaths after more than 12 months were exclusively because of recurrence of HCC. Biochemical and histological evidence of hepatitis was found in the majority of the patients, only 16% had normal alanine aminotransferase (ALT) values throughout. Twenty-two percent of patients complained of symptoms, with hepatitis C being the cause in 82% of these. Two patients lost their HCV-RNA for prolonged, ongoing periods of time. The severity of the posttransplantation hepatitis was unrelated to age, sex, severity of liver disease before transplantation, cold ischemic time of the graft, duration of the operation, transfusions, the number of rejection episodes, or the long-term immunosuppressive regime. Only initial short-term therapy with interleukin 2 (IL2) receptor antibodies adversely influenced inflammatory activity. Viral genotype did not influence the course of the graft hepatitis in our series. Histology showed inflammation in 88% of the biopsies and signs of fibrosis in 24%. Mean ALT values correlated with inflammation but not with fibrosis in the biopsies. Porto-portal bridging was observed in six patients, one patient developed cirrhosis within 2 years after orthotopic liver transplantation (OLT). We conclude that chronic hepatitis develops in the majority of patients with HCV infection after liver transplantation. Carrier states without significant laboratory abnormalities are observed in approximately 16%, biochemical abnormalities without symptoms are seen in 60%, and symptomatic disease develops in a quarter of the patients. The disease course closely resembles that seen in nontransplanted hepatitis C patients. It is generally mild but little over 10% of patients develop signs of fibrosis of the graft during the first decade.
Detection of a soluble form of the human adhesion receptor lymphocyte function-associated antigen-3 (LFA-3) in patients with chronic liver disease.
BACKGROUND/AIMS: Multiple immune functions, such as cytotoxic reactions, B cell differentiation, and monocyte activation, are mediated via the adhesion receptor/ligand pairs CD2/lymphocyte function-associated antigen(LFA)-3 and LFA-1/ intercellular adhesion molecule(ICAM)-1. Since soluble forms of LFA-3 (sLFA-3) and ICAM-1 (sICAM-1) can interfere with these functions, we asked whether increased levels of sLFA-3 can be found in patients with different forms of chronic liver disease and/or hepatocellular carcinoma. METHODS: sLFA-3 was measured in sera from 84 patients with chronic liver disease (39 with chronic viral liver disease, 30 with autoimmune liver disease, 12 with alcoholic cirrhosis, 3 with other causes of cirrhosis), 24 patients with hepatocellular carcinoma (15 with and 9 without cirrhosis), and 61 normal controls. From 36 of the patients with liver cirrhosis, arterial and hepatic venous serum samples were simultaneously obtained and tested for sLFA-3 and sICAM-1. RESULTS: In comparison to controls, sLFA-3 levels were elevated in patients with liver cirrhosis due to autoimmune liver disease (p < 0.0001) and viral liver disease (p = 0.001), but not in patients with alcoholic cirrhosis. Increased sLFA-3 levels were also found in patients with hepatocellular carcinoma and liver cirrhosis. However, sLFA-3 was not significantly elevated in sera from patients with autoimmune liver disease, viral liver disease, and hepatocellular carcinoma without concomitant liver cirrhosis. No difference was found between arterial and hepatic venous serum levels of sLFA-3 and sICAM-1. sLFA-3 levels correlated positively with aspartate transaminase, alkaline phosphatase, bilirubin, sICAM-1, and inversely with albumin and cholinesterase. CONCLUSIONS: Taken together, sLFA-3 serum concentrations of patients with liver cirrhosis due to autoimmune liver disease or viral liver disease and of patients with hepatocellular carcinoma and cirrhosis are significantly increased compared to controls. Elevated sLFA-3 and sICAM-1 levels might reflect the generalized inflammation in cirrhosis and by interference with cell-cell interactions sICAM-1 and sLFA-3 may limit the extent of inflammation.
Successful hepatitis B reinfection prophylaxis with lamivudine and hepatitis B immune globulin in patients with positive HBV-DNA at time of liver transplantation.
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Serum laminin P1 levels do not reflect critically elevated portal pressure in patients with liver cirrhosis.
BACKGROUND/AIMS: Laminin P1 serum levels run parallel to the accumulation of hepatic extracellular matrix in patients with liver cirrhosis. Recent studies reported a correlation between laminin P1 and portal pressure, leading to the proposal that laminin P1 may be used to identify patients with critically elevated portal pressure in liver cirrhosis. So far, most of the data has been obtained from patients with alcoholic liver disease. METHODOLOGY: We studied the relationship between laminin P1 serum levels and portal hypertension in 34 patients with liver cirrhosis, mostly of non-alcoholic etiology. Using hepatic venous catheterisation the hepatic venous pressure gradient (HVPG), an estimate of portal hypertension, was measured. Laminin P1 was compared to the HVPG and the size of esophageal varices. RESULTS: Serum laminin P1 was elevated in all samples. However, laminin P1 did not significantly correlate with either portal hypertension or the size of esophageal varices. Furthermore, laminin P1 measurement did not identify patients with critically elevated portal pressure using a HVPG of either 12 mmHg or 16 mmHg as cut-off points. CONCLUSION: The use of laminin P1 serum levels to diagnose critically elevated portal pressure in liver cirrhosis cannot be supported for etiologies other than alcoholic liver disease.
Lipid parameters predicting liver function in patients with cirrhosis and after liver transplantation.
BACKGROUND/AIMS: The liver plays a central role in the production and metabolism of lipoproteins, regulating their synthesis and degradation. The protein content of the lipoproteins are the so-called apolipoproteins. Some of the apolipoproteins serve as cofactors for enzymatic reactions, as ligands for interaction with specific receptors, and as structural proteins. Apolipoprotein B (apoB) is the primary structural component of the atherogenic low density lipoprotein (LDL) particles and has a specific binding region for interacting with the LDL-receptor. In contrast, apolipoprotein A-I (apoA-I) represents the primary protein content of the high density lipoprotein (HDL) particles, which interacts with the putative HDL-receptor, and stimulates the enzymatic reaction of lecithin-cholesterol acyltransferase (LCAT) resulting in esterified cholesterol, which is the essential step in the process of reverse cholesterol transport. METHODOLOGY: We studied lipid parameters in arterial and hepatic venous serum samples from 52 patients with cirrhosis and from 16 patients in the clinically stable long-term course after liver transplantation. Splanchnic blood flow was measured (indocyanine-green steady-state infusion) and hepatic extraction/production rates were calculated. To assess the influence of the clinical stage of established cirrhosis, the quantitated parameters were statistically analyzed. RESULTS: In cirrhosis, apolipoprotein A-I levels are decreased depending on the clinical stage (p<0.01). This parameter showed excellent correlations to liver function tests. Triglycerides (TG) (p<0.05) and cholesterol (Chol) (p<0.05) were reduced as well, whereas apolipoprotein B levels did not change. In cirrhosis, hepatic production of both cholesterol and triglycerides were decreased (p<0.05 each), as well as hepatic extraction of free fatty acids (FFA) (p<0.01). Except for cholestatic liver disease with raised serum cholesterol (p<0.05) and apolipoprotein B levels (p<0.001), the etiology of cirrhosis had no impact on the observed serum lipid alterations. CONCLUSIONS: The serum concentrations of the determined lipid parameters depend primarily on liver function. Decreased liver function was associated with reduced extraction of free fatty acids and reduced cholesterol and triglyceride synthesis. Liver transplantation restored the lipid abnormalities to normal. Finally, apolipoprotein A-I served as an excellent parameter for predicting liver function in the studied patients.