Liver[JOURNAL]
Sun
200 papers
Molecular Adsorbent Recirculating System: clinical experience in patients with liver failure based on hepatitis B in China.
Chen S, Zhang L, Shi Y … +2 more , Yang X, Wang M
Liver · 2002 · PMID 12220304 · Publisher ↗
The aim of this study is to evaluate the effect of treatment with the Molecular Adsorbent Recirculating System (MARS) on liver failure based on HBV. In 25 patients (median age, 36.3 years, range, 22-67 years, bilirubin l...
The aim of this study is to evaluate the effect of treatment with the Molecular Adsorbent Recirculating System (MARS) on liver failure based on HBV. In 25 patients (median age, 36.3 years, range, 22-67 years, bilirubin level > 255 micro mol/l) admitted with liver failure based on HBV, the 6-8h MARS intermittent treatments were performed without any adverse events, A significant decrease in bilirubin, ammonia and urea levels were observed (P < 0.05). All patients achieved a remarkable neurologic recovery, particularly 2 HE-III and 3 HE-IV patients regained normal consciousness, respectively. The survival rate for the patients whose treatments kept to the MARS art strategy was 76.9% (10/13), while the others only had the survival rate of 16.7% (2/12) due to their giving up sequential MARS treatments after the first time. The rebounding rate of the bilirubin level in the patients after a single MARS treatment was significantly lower than that of patients, who underwent a single plasma-exchange treatment (P < 0.01). It is concluded that MARS method can contribute to the optimistic treatment of liver failure patients based on HBV which being the major epidemic liver disease in China.
MARS (Molecular Adsorbent Recirculating System): experience in 34 cases of acute liver failure.
Novelli G, Rossi M, Pretagostini R … +6 more , Poli L, Novelli L, Berloco P, Ferretti G, Iappelli M, Cortesini R
Liver · 2002 · PMID 12220303 · Publisher ↗
As reported in the literature, the mortality rates for patients with Acute Hepatic Failure (AHF) approaches 80% in cases in which liver transplantation is not possible. Post-transplant mortality mostly depends on the sev...
As reported in the literature, the mortality rates for patients with Acute Hepatic Failure (AHF) approaches 80% in cases in which liver transplantation is not possible. Post-transplant mortality mostly depends on the severity of the neurological condition at the time of the operation (20% in I-II degree coma patients and 44% in III degree coma patients). The primary indications for liver transplantation in AHF are Fulminant Hepatitis (FH)(93%), Subfulminant Hepatitis (5%) and other indications (2%). Other causes of AHF are Primary Non-Function (PNF) and Delayed Function (DF), which occur in 7-10%. Therefore it becomes necessary to monitor the patients with a Liver Support Device to be able to improve the clinical condition of the patients before liver transplantation (LT). In our experience we used the Molecular Adsorbent Recirculating System (MARS) (MARS Monitor; Teraklin AG, Rostock Germany), which enables the selective removal of albumin-bound substances accumulating in liver failure by the use of albumin-enriched dialysate. The system is used as a bridging device to orthotopic liver transplantation (OLT) of patients with FHF. We studied 34 patients, including 16 males and 18 females: 9 were affected by Primary-Non-Function (PNF), nine by Fulminant Hepatitis (FH), six by Delayed-Non-Function (DNF), and ten by Acute on Chronic Hepatic Failure (AOCHF). The average age of the patients was 41.8 years and the average number of applications was 6.4; the median length of application was about eight hours. The parameters that we monitored, before and after each treatment, were neurological status (EEG, cerebral CT, Glasgow Coma Score), haemodynamic parameters, acid base equilibrium, and blood gas analysis. We also monitored hepatic and renal function. In addition, the clinical conditions of the patients were monitored using kidney and liver ultrasound/ultrasonography (US). Inclusion criteria were bilirubin > 15 mg/dL, ammonia > 160 micro g/dL and a Glasgow Coma Score between 6 and 11. The reduction of bilirubin and ammonia were very significant (P < 0.01), whereas the changes of International Normalized Ratio (INR) were not significant. Also the modifications of albumin, total protein, sodium, potassium and calcium were not significant. In conclusion, four out of nine patients with PNF are alive without a second transplantation and were discharged after about 48 days; four out of nine underwent OLT, while one out of nine died; five out of six patients with DF are alive without a second transplantation, and they were discharged after an average time of 55.5 days, one out of six died; six out of nine patients with fulminant hepatitis underwent OLT and four of these are alive, while two died due to sepsis; three patients are alive without OLT. Four patients with AOCHF underwent OLT and are alive, three patients are alive and on a waiting list, two died while on a waiting list and one patient who experienced reactivation of HBV infection during chemotherapy for non-Hodgkin's lymphoma is alive. In spite of the limited number of cases of our study, we believe that MARS can be applied with high tolerance for a very long period of time. In addition, its repeatability allows it to be used in patients with DNF and FH as a bridge to transplant. In patients with DNF, it is used while waiting for complete recovery of the transplanted organ.
Albumin dialysis: single pass vs. recirculation (MARS).
Peszynski P, Klammt S, Peters E … +3 more , Mitzner S, Stange J, Schmidt R
Liver · 2002 · PMID 12220302 · Publisher ↗
The single pass albumin dialysis (SPAD) was reported to be an alternative to the Molecular Adsorbent Recirculating System (MARS) for the effective removal of protein bound substances in liver failure. Three SPAD experime...
The single pass albumin dialysis (SPAD) was reported to be an alternative to the Molecular Adsorbent Recirculating System (MARS) for the effective removal of protein bound substances in liver failure. Three SPAD experiments using different albumin concentrations and dialysate flow rates were performed. In each experiment, 1000 ml human donor plasma, spiked with 250 mg unconjugated bilirubin, 200 mg sulfobromophthalein (BSP) and 115 mg glycocholic acid (N-[3alpha,7alpha,12alpha-trihydroxy-24-oxycholan-24-yl]glycine) - a conjugated bile acid (BA), circulated in a closed loop with 150 ml/min and was dialysed against albumin solution. These substances are bound to the different binding sites of albumin and have different association constants. For the comparison, the standard MARS experiment was performed using the same plasma flow rate of 150 ml/min. Moreover, the clearances of bilirubin for MARS and SPAD during clinical treatments were calculated using own data and those reported by Seige, Kreymann, Jeschke, et al. in Transplant Proc 1999; 31: 1371-5. The concentrations of bilirubin, BSP and BA were measured in plasma and dialysate and for these substances clearances (Cl) were calculated. It is known that the elimination rate of bilirubin is not very high during albumin dialysis in comparison to other substances, like bile acids, due to the high association constant. An increase of albumin concentration or the flow rate improved the efficacy but also raised the costs substantially. In this study, we have shown that MARS is the more effective kind of albumin dialysis for the important substances like bile acids. By SPAD an improvement of efficacy can be reached only by dramatic increase of the costs. Also, the earlier experiments showed that MARS is safer because of the removal of the stabilizers, which are normally included in the commercial albumin solutions.
Amino acid dysbalance in liver failure is favourably influenced by recirculating albumin dialysis (MARS).
Loock J, Mitzner SR, Peters E … +2 more , Schmidt R, Stange J
Liver · 2002 · PMID 12220301 · Publisher ↗
INTRODUCTION: Dysbalance between branched chain (BCAA) and aromatic amino acids (AAA), which can be quantified by a low Fischer's Index (SigmaBCAA/SigmaAAA), as well as elevated levels of free tryptophan in plasma are co...
INTRODUCTION: Dysbalance between branched chain (BCAA) and aromatic amino acids (AAA), which can be quantified by a low Fischer's Index (SigmaBCAA/SigmaAAA), as well as elevated levels of free tryptophan in plasma are common in hepatic failure and may contribute to the development of hepatic encephalopathy. AIM: To evaluate the influence of a new extracorporeal detoxification system for liver failure (Molecular Adsorbents Recirculating System, MARS(R), i.e. dialysis against a recirculating albumin solution cleaned online by charcoal and an anion exchange resin) on plasma tryptophan and Fischer's Index. METHODS: Plasma samples were taken before, during and after MARS treatments (n = 11, mean blood flow 135 ml/min, mean dialysate flow 120 ml/min, high flux polysulfone membrane). Simultaneous to blood sampling, aliquots of the albumin dialysate were taken between the elements of the dialysate circuit. RESULTS: Fischer's Index in systemic blood increased during MARS by 24% (from 1.44 to 1.79, P < 0.001; mean treatment duration, 5.5 h). Systemic tryptophan level was significantly reduced at the same time (-25%, n = 8). Amino acid removal rates from plasma during a single dialyser passage ranged from 10 to 53%. In particular, AAA were preferentially removed (42-44% throughout treatment), while BCAA removal was 28-46% initially and later declined to 24-28%. A maximum concentration gradient between plasma and dialysate was maintained for the AAA throughout treatment through their apparently complete removal by the charcoal adsorber. Conversely, BCAA removal at both adsorbers was only minor. As a result, Fischer's Index showed a significant increase in the processed plasma, which became even more pronounced with increasing treatment duration. CONCLUSIONS: MARS enables an elevation of a pathologically decreased Fischer's Index as well as a reduction of systemic tryptophan levels in patients with liver failure. The effects of MARS on plasma amino acid dysbalance may contribute to an improvement of hepatic encephalopathy.
Extracorporeal liver support by recirculating albumin dialysis: analysing the effect of the first clinically used generation of the MARSystem.
Klammt S, Stange J, Mitzner SR … +3 more , Peszynski P, Peters E, Liebe S
Liver · 2002 · PMID 12220300 · Publisher ↗
UNLABELLED: Albumin dialysis with the MARSystem is used in many hospitals to support excretory hepatic function in acute or acute on chronic liver failure. Potential pathogenic albumin bound substances accumulated in exc...
UNLABELLED: Albumin dialysis with the MARSystem is used in many hospitals to support excretory hepatic function in acute or acute on chronic liver failure. Potential pathogenic albumin bound substances accumulated in excretory liver insufficiency can be removed from patients blood by dialysis against albumin solution. A specific membrane enables the selective transport of albumin bound metabolites to the albumin containing dialysate compartment, where the loaded transport albumin is cleared and regenerated at the same time by adsorption columns and a second dialyser. Between 1993 and 1995 different membranes, set-ups and components in albumin dialysis were tested and led finally to the recirculating MARSystem with a modified polysulphone based membrane (P3/5S Gambro, Hechingen) and two adsorption columns (N350 and BR 350, ASAHI Medical Ltd.), which showed the best performance at this time. This first generation of MARSystems was used clinically between 1995 and 1998 with only minor changes in 15 patients with acute (n = 1) or acute deterioration of chronic liver disease in our department until the improved next generation of MARSystems has been available (MARS set and monitor, Teraklin AG, Rostock, Germany). Changes in blood tests pre/post during 95 single MARS treatments and in clinical status over treatment period were evaluated retrospectively. RESULTS: A significant decrease of albumin bound substances (average reduction during single MARS treatments: bilirubin -18%, bile acids -43.7%) as well as of water soluble metabolites (creatinine -32%, urea -31%) was observed. During extracorporeal therapy also a significant drop in platelets (- 15.4%) and a prolongation of activated prothrombin time (- 21%) was documented, whereas haemoglobin, WBC, electrolytes as well as transaminases and albumin were not affected significantly. CONCLUSION: Albumin dialysis with the first generation of MARS enables the removal of albumin bound and water soluble toxins. Unwanted side-effects and changes in laboratory tests are comparable to conventional haemodialysis (drop of platelets and prolongation of coagulation tests). The elimination of albumin bound and water soluble substances was accompanied by an improvement of clinical status.
Economic evaluation of MARS--preliminary results on survival and quality of life.
Hessel FP, Mitzner SR, Rief J … +3 more , Gress S, Guellstorff B, Wasem J
Liver · 2002 · PMID 12220299 · Publisher ↗
OBJECTIVES: The short-term medical benefit of the liver dialysis system MARS in patients with severe acute liver disease has clearly been demonstrated. An economic analysis of MARS has not been presented previously. Obje...
OBJECTIVES: The short-term medical benefit of the liver dialysis system MARS in patients with severe acute liver disease has clearly been demonstrated. An economic analysis of MARS has not been presented previously. Objective of the study is to calculate the costs per life saved and life year gained and to measure health related quality of life in patients who survived acute liver failure. First results on survival and HRQL are presented here. STUDY DESIGN: Cost effectiveness and cost utility analysis of MARS are performed. All patients since 1993 with chronic liver failure (Bilirubin > 300 micro mol/l) of the university hospital Rostock are included in the original sample (n = 141). Survival data are calculated. Surviving patients were contacted personally, thus quality of life data (EQ 5D and SF12) determined. Patients were compared in case control study design. In a later stage inpatient hospital costs, direct and indirect outpatients costs are included in the analysis. PRELIMINARY RESULTS: MARS-Patients show a higher survival: Kaplan-Meier cumulative survival after 100 days: 0.59 after MARS, 0.39 without (P <0.05). There was no significant difference in health related quality of life (SF12 and EQ-D). Calculations of quality adjusted life years (QALYs) result in 0.116 QALYs gained by treatment of one patient with MARS in one year. DISCUSSION: First preliminary results suggest that 1 year after therapy MARS seems to have a positive effect concerning survival rate, survival time and QALYs gained. Final results of cost-effectiveness and cost-utility analysis will soon be presented.
Experiences with MARS liver support therapy in liver failure: analysis of 176 patients of the International MARS Registry.
Steiner C, Mitzner S
Liver · 2002 · PMID 12220298 · Publisher ↗
Extracorporeal liver support using the MARS recently has shown remarkable results in several trials. This study aims to extend the basis for analyses by making available the worldwide data with help of an international r...
Extracorporeal liver support using the MARS recently has shown remarkable results in several trials. This study aims to extend the basis for analyses by making available the worldwide data with help of an international registry. One hundred and seventy six patients were analysed, main indications are acute-on-chronic liver failure (56%), acute liver failure (22%), primary graft dysfunction (15%), liver failure post liver surgery (4%) and miscellaneous (3%). The predicted survival within the first group based on a mean MELD score of 30.4 pts. and a mean Child score of 12.6 pts. was quite limited. The data suggest an improved survival accompanied by significant improvements of hepatic encephalopathy, mean arterial pressure, serum bilirubin level, creatinine, urea, albumin, INR, ammonia and MELD score. The results are confirming observations of other trials before which have shown MARS therapy to be an effective and safe extracorporeal liver support in liver failure.
Cholestatic liver disease: pathophysiology and therapeutic options.
Hofmann AF
Liver · 2002 · PMID 12220297 · Publisher ↗
Cholestasis results from defective canalicular secretion of bile or obstruction to bile flow distal to the canaliculus. In early primary biliary cirrhosis, bile secretion continues, because of the secretory pressure of b...
Cholestasis results from defective canalicular secretion of bile or obstruction to bile flow distal to the canaliculus. In early primary biliary cirrhosis, bile secretion continues, because of the secretory pressure of bile or because some ductules are not obstructed. With complete cholestasis, a bile acid deficiency occurs in the small intestinal lumen leading to lipid maldigestion and fat-soluble vitamin malabsorption. Bacterial proliferation, bacterial translocation to lymph nodes and endotoxemia may also occur leading to an acute phase reaction. Retention of bile acids in the hepatocyte leads to apoptosis. Accumulation of bile acids in the systemic circulation leads to pruritus, and may contribute to endothelial injury in the lungs and kidney. Early attempts to mimic hepatic excretory function by hemoperfusion over adsorbent columns were unsuccessful for a variety of reasons. Extracorporeal dialysis against albumin offers promise of a realistic albeit partial simulation of hepatic excretory function.
The pathophysiological basis of acute-on-chronic liver failure.
Sen S, Williams R, Jalan R
Liver · 2002 · PMID 12220296 · Publisher ↗
The vast majority of patients that are referred to a specialist hepatological centre suffer from acute deterioration of their chronic liver disease. Yet, this entity of acute-on-chronic liver failure remains poorly defin...
The vast majority of patients that are referred to a specialist hepatological centre suffer from acute deterioration of their chronic liver disease. Yet, this entity of acute-on-chronic liver failure remains poorly defined. With the emergence of newer liver support strategies, it has become necessary to define this entity, its pathophysiology and the short and long-term prognosis. This review focuses upon how a precipitant such as an episode of gastrointestinal bleeding or sepsis may start a cascade of events that culminate in end-organ dysfunction and liver failure. We briefly review the pathophysiological basis of the therapeutic modalities that are available. Our current strategy for the management of liver failure involves supportive therapy for the end-organs with the hope that the liver function would recover if sufficient time for such a recovery is allowed. Because liver failure, whether of the acute or acute-on-chronic variety, is potentially reversible, the stage is set for the application of newer liver support strategies to enhance the recovery process.
Heterogeneous hepatic enhancement on CT angiography in idiopathic portal hypertension.
Waguri N, Suda T, Kamura T … +1 more , Aoyagi Y
Liver · 2002 Jun · PMID 12100579 · Publisher ↗
BACKGROUND: Idiopathic portal hypertension is an uncommon condition characterized by presinusoidal portal perfusion disturbance without known causes. METHODS: In the present study, portal and arterial perfusion dynamics...
BACKGROUND: Idiopathic portal hypertension is an uncommon condition characterized by presinusoidal portal perfusion disturbance without known causes. METHODS: In the present study, portal and arterial perfusion dynamics were evaluated in two cases with idiopathic portal hypertension using computed tomography during arterial portography and hepatic arteriography. Ten cases with liver cirrhosis were also studied as a reference. RESULTS: In cases with idiopathic portal hypertension, portal perfusion was conspicuously heterogeneous and decreased especially at the periphery of the liver where arterial perfusion was reciprocally increased. When the spatial heterogeneity of an enhancement of the liver was quantified using a densitometric analysis of computed tomography during hepatic arteriography images, the densities at the periphery were higher and varied more than those of the inner areas in cases with idiopathic portal hypertension. In contrast, the densities did not vary between the periphery and the inner areas at the cases with liver cirrhosis. CONCLUSIONS: The heterogeneous increase of arterial perfusion in periphery of the liver may be an important feature of idiopathic portal hypertension.
Raised serum ferritin predicts non-response to interferon and ribavirin treatment in patients with chronic hepatitis C infection.
Distante S, Bjøro K, Hellum KB … +5 more , Myrvang B, Berg JP, Skaug K, Raknerud N, Bell H
Liver · 2002 Jun · PMID 12100578 · Publisher ↗
BACKGROUND/AIM: Previous studies have indicated that response to interferon therapy is inversely proportional to the amount of body iron stores. We have studied the relationship between serum ferritin, transferrin satura...
BACKGROUND/AIM: Previous studies have indicated that response to interferon therapy is inversely proportional to the amount of body iron stores. We have studied the relationship between serum ferritin, transferrin saturation, liver iron, presence of HFE-C282Y gene mutation and response to treatment in patients with chronic hepatitis C infection. METHODS: Two hundred and fifty-six naive, HCV-RNA positive patients (60% males, median age 38 years, range 21-70) were treated with interferon and ribavirin for 6 months. Iron indices and the presence of the C282Y mutation were measured. In 242 (94%) patients iron deposition were determined by Perls staining method. Patients with negative HCV-RNA at 6 months after the end of treatment were defined as sustained viral responders. RESULTS: Non-responders (n = 127) had significantly higher median s-ferritin values compared with sustained viral responders (130 microg/L vs. 75 microg/L P < 0.001). There was no difference in transferrin saturation among the two response groups. Only 23% (4/7) of patients with Perls grade 1 in liver biopsies responded to treatment vs. 54% (122/225) patients without iron deposition (P = 0.02), however, 10/13-non-responders had HCV genotype one. Two patients (0.8%) were homozygous for the C282Y mutation, 36 patients were heterozygous (14%). Among mutation carriers 26/38 achieved sustained response compared with 102/216 non-carriers (68% vs. 48%, P = 0.02). In a multivariate analysis s-ferritin (P = 0.030) and C282Y carrier status (P = 0.012) remained independent predict of sustained response. CONCLUSIONS: Raised s-ferritin values predicate non-response to interferon-ribavirin therapy in hepatitis C patients. Response rate in C282Y mutation carriers seems greater than in non-carriers.
Activation of cyclin-dependent kinases CDC2 and CDK2 in hepatocellular carcinoma.
Li KK, Ng IO, Fan ST … +3 more , Albrecht JH, Yamashita K, Poon RY
Liver · 2002 Jun · PMID 12100577 · Publisher ↗
BACKGROUND: The cyclin-dependent kinases (CDKs) CDC2 and CDK2 are key regulators of the cell cycle. The expression of the CDK alone does not necessary reflect their true activities because they are highly regulated by po...
BACKGROUND: The cyclin-dependent kinases (CDKs) CDC2 and CDK2 are key regulators of the cell cycle. The expression of the CDK alone does not necessary reflect their true activities because they are highly regulated by post-translational mechanisms. Human hepatocellular carcinoma (HCC) is one of the most common cancers in the world, but the kinase activities of CDKs in HCC have not been examined. METHODS: Here we examined the protein expression and kinase activities associated with CDC2 and CDK2 in HCC and the corresponding non-tumorous liver tissues. RESULTS: CDC2 and CDK2 are activated in HCC in over 70% and 80% of the cases, respectively, but have little correlation with clinical parameters and PCNA expression. Interestingly, PCNA was readily detectable in extracts from non-tumorous liver, but more than 60% of samples contain higher concentration of PCNA in HCC than the corresponding non-tumorous tissues. CDC2 and CDK2 are generally activated in the same HCC samples, but the extent of their activation varied significantly, suggesting that the pathways leading to the activation of CDC2 and CDK2 can be regulated independently. Both positive regulators of CDK activity like cyclins and CDKs, and negative regulators of CDK activity like p21(CIP1/WAF1) and Thr14/Tyr15 phosphorylation were up-regulated in HCC. CONCLUSION: CDC2 and CDK2 are activated in HCC, and this may be due to a complex interplay between the level of the cyclin, CDK, CDK inhibitors, and inhibitory phosphorylation.
The correlation between portal myofibroblasts and development of intrahepatic bile ducts and arterial branches in human liver.
Libbrecht L, Cassiman D, Desmet V … +1 more , Roskams T
Liver · 2002 Jun · PMID 12100576 · Publisher ↗
BACKGROUND/AIMS: The development of the intrahepatic bile ducts most likely requires interactions between epithelial and mesenchymal cells. In view of the epithelial-mesenchymal interactions between portal myofibroblasts...
BACKGROUND/AIMS: The development of the intrahepatic bile ducts most likely requires interactions between epithelial and mesenchymal cells. In view of the epithelial-mesenchymal interactions between portal myofibroblasts (pMFs) and biliary epithelial cells in adult diseases of the bile ducts, we investigated the presence and function of pMFs during the development of intrahepatic bile ducts, as well as the development of intrahepatic branches of the hepatic artery. METHODS: We performed haematoxylin-eosin-stainings and immunohistochemistry for alpha-smooth-muscle actin, cytokeratin 19 and vimentin on serial sections of 45 fetal and postnatal liver biopsies. RESULTS: The mesenchyme of portal tracts in the ductal plate stage devoid of a hepatic artery branch, contained numerous and diffusely scattered pMFs. Portal tracts with a hepatic artery branch were always larger than those without and showed a decreasing number of pMFs. In the remodeling stage, all portal tracts contained a hepatic artery branch, and pMFs were restricted to the periductal mesenchyme. These periductal pMFs disappeared after full incorporation of the bile duct. CONCLUSION: Our findings strongly suggest interactions between pMFs and epithelial cells of the developing bile ducts. The development of the intrahepatic arterial branches always precedes the incorporation of the tubular segments of the ductal plate.
Single nucleotide polymorphisms and microsatellite alleles of tumor necrosis factor alpha and interleukin-10 genes and the risk of advanced chronic alcoholic liver disease.
Ladero JM, Fernández-Arquero M, Tudela JI … +4 more , Agúndez JA, Díaz-Rubio M, Benítez J, de la Concha EG
Liver · 2002 Jun · PMID 12100575 · Publisher ↗
BACKGROUND: Only a minority of ethanol abusers develop advanced chronic alcoholic liver disease (CALD). In CALD there is a imbalance between TNF alpha and IL-10, which may be modulated by several polymorphisms at both ge...
BACKGROUND: Only a minority of ethanol abusers develop advanced chronic alcoholic liver disease (CALD). In CALD there is a imbalance between TNF alpha and IL-10, which may be modulated by several polymorphisms at both genetic loci. Our aim has been to elucidate the possible relation between these polymorphisms and the risk of CALD. PATIENTS AND METHODS: 147 patients with advanced CALD and 355 healthy controls (all white Spaniards) were included. TNF alpha biallelic single nucleotide polymorphisms (SNP) at positions -238, -308, and -376 and IL-10 biallelic SNP at positions -597, - 824, and - 1087 were investigated by polymerase chain reaction (PCR) amplification and dot blot hybridization. Moreover, polymorphic microsatellites TNFa, TNFb, IL-10.R and IL-10.G were investigated in a multiplex PCR and alleles were estimated in an automatic sequencer. RESULTS: No differences were found in the distribution of any of the studied polymorphisms, except by an excess of the haplotype formed by the allele 11 of the microsatellite IL-10.G and the GCC arrangement of the SNPs at the promoter of IL-10 gene in patients (15.7 vs. 8.24%, odds ratio: 2.08, 95% C.I. = 1.31-3.31). CONCLUSIONS: The studied polymorphisms at TNF alpha and IL-10 genetic loci are not clearly related to the risk of CALD. The excess of G11-GCC haplotype found in CALD patients needs independent confirmation.
An electron microscopic and morphometric study of ursodeoxycholic effect in primary biliary cirrhosis.
Neuman MG, Cameron RG, Haber JA … +2 more , Katz GG, Blendis LM
Liver · 2002 Jun · PMID 12100574 · Publisher ↗
BACKGROUND/AIMS: Primary biliary cirrhosis (PBC) is a chronic liver disease that results in cholestasis and bile duct loss. Ursodeoxycholic acid (UDCA) has been shown to reduce hepatocellular damage in PBC. The study att...
BACKGROUND/AIMS: Primary biliary cirrhosis (PBC) is a chronic liver disease that results in cholestasis and bile duct loss. Ursodeoxycholic acid (UDCA) has been shown to reduce hepatocellular damage in PBC. The study attempted to quantify perisinusoidal collagenization and the number of apoptotic bodies in PBC liver biopsies from patients in a randomized control trial treated with UDCA compared to those who received placebo. METHODS: Twenty-eight patients with PBC (10 cirrhotic, 18 non-cirrhotic; 13 treated with UDCA, 15 treated with placebo) were compared with 32 controls with normal hepatic histology on light microscopy. Liver biopsies were examined for degree of perisinusoidal fibrosis and apoptotic activity using electron microscopy. RESULTS: The degree of perisinusoidal fibrosis and apoptotic activity was similar in pretreatment biopsies of UDCA and placebo-treated patients. After two years of placebo, patients showed a significant increase in fibrosis (P < 0.001). In contrast, there were no changes in non-cirrhotic and a decrease in fibrosis in cirrhotic patients given UDCA. At baseline, PBC patients had higher numbers (apoptotic cells/100 hepatocytes +/- SE) of apoptotic cells (7 +/- 3), than controls (2 +/- 0.5) (P < 0.05), with no difference between cirrhotic and non-cirrhotic patients in the two groups of patients. After two years, the numbers of apoptotic cells in UDCA-treated patients decreased significantly compared to baseline (3 +/- 2) (P < 0.05); with placebo patients the number of apoptotic cells increased (12 +/- 5) (P < 0.05). CONCLUSION: Treatment with UDCA prevents the deposition of perisinusoidal collagen and reduces the apoptotic activity in PBC patients after 2 years of therapy.
Apoptosis of biliary epithelial cells in primary biliary cirrhosis and primary sclerosing cholangitis.
Tinmouth J, Lee M, Wanless IR … +3 more , Tsui FW, Inman R, Heathcote EJ
Liver · 2002 Jun · PMID 12100573 · Publisher ↗
BACKGROUND/AIMS: Primary biliary cirrhosis (PBC) is an autoimmune disease characterized by inflammatory destruction of small bile ducts. Primary sclerosing cholangitis (PSC) is a different, presumed autoimmune cholestati...
BACKGROUND/AIMS: Primary biliary cirrhosis (PBC) is an autoimmune disease characterized by inflammatory destruction of small bile ducts. Primary sclerosing cholangitis (PSC) is a different, presumed autoimmune cholestatic liver disease where the bile ducts are also destroyed. In this study, apoptosis and portal triad inflammation in liver tissue from patients with PBC is examined and compared to that from patients with PSC and patients with normal liver. METHODS: Explanted liver tissue from patients with PBC and PSC and normal liver from patients with metastases to liver were examined. The liver samples were stained for apoptosis using the terminal deoxynucleotidyl triphosphate (TdT)-mediated deoxyuridine triphosphate nick end labelling (TUNEL) assay. The biliary epithelial cells (BEC) were then scored on the basis of their TUNEL stain and the degree of periductal inflammation. RESULTS: In PBC, apoptosis of BEC, as detected by the TUNEL assay, was significantly increased in the presence of inflammation. Regardless of the presence or absence of inflammation, the small bile ducts in PBC liver tissue exhibited greater evidence of apoptosis than did similar ducts from PSC or control livers. CONCLUSION: These findings suggest that in PBC, unlike PSC, the apoptosis of BEC in PBC is secondary to the invasion of inflammatory cells.
Tropoelastin expression is up-regulated during activation of hepatic stellate cells and in the livers of CCl(4)-cirrhotic rats.
Kanta J, Dooley S, Delvoux B … +3 more , Breuer S, D'Amico T, Gressner AM
Liver · 2002 Jun · PMID 12100572 · Publisher ↗
BACKGROUND/AIMS: Activated hepatic stellate cells (HSC) are regarded as the principal cells synthesizing extracellular matrix components in fibrotic liver. Elastin content is increased in cirrhotic livers, but the cellul...
BACKGROUND/AIMS: Activated hepatic stellate cells (HSC) are regarded as the principal cells synthesizing extracellular matrix components in fibrotic liver. Elastin content is increased in cirrhotic livers, but the cellular source is not known. Contribution of HSC to the production of elastin was investigated. METHODS: Expression of elastin in CCl(4)-cirrhotic rat liver was studied by immunohistochemistry and in situ hybridization, liver myofibroblasts were identified in histological sections by alpha-smooth muscle actin (alpha-SMA) staining. LightCycler PCR and Northern blotting were used to detect tropoelastin mRNA in isolated HSC; tropoelastin protein was detected in the cells and in cell-conditioned medium by Western blotting. RESULTS: HSC, isolated from normal rat liver, displayed increasing tropoelastin mRNA expression during transdifferentiation in culture. Expression of tropoelastin mRNA was accompanied by the production of tropoelastin protein in vitro. Increased levels of tropoelastin transcripts were found in the connective tissue septa of CCl(4)-cirrhotic rats and co-localized with alpha-SMA positive cells. Immunohistochemistry demonstrated elastin presence in the septa. CONCLUSION: HSC express tropoelastin and its expression increases during transdifferentiation to myofibroblast-like cells.
HLA and cytokine gene polymorphisms in biliary atresia.
Donaldson PT, Clare M, Constantini PK … +4 more , Hadzic N, Mieli-Vergani G, Howard E, Kelley D
Liver · 2002 Jun · PMID 12100571 · Publisher ↗
BACKGROUND/AIMS: Extrahepatic biliary atresia remains one of the major hepatic causes of death in early childhood. Though a number of hypotheses have been developed to account for this disease, its aetiopathogenesis is p...
BACKGROUND/AIMS: Extrahepatic biliary atresia remains one of the major hepatic causes of death in early childhood. Though a number of hypotheses have been developed to account for this disease, its aetiopathogenesis is poorly understood. One possibility is that this is an immune mediated disease which occurs following either toxic or infectious insult in a genetically susceptible host. Earlier studies suggested weak HLA associations but these remain unconfirmed. More recently studies of viral and autoimmune liver disease have begun to investigate non-MHC immunoregulatory gene polymorphisms. METHODS: In the present study we used molecular genotyping to investigate selected HLA A, B, DRB1, DQA1, DQB1 and DPB1 alleles as well as polymorphisms in the interleukin-1 gene family, interleukin-10 promoter sequence and tumour necrosis factor alpha promoter genes in 101 children referred for surgical assessment with extra hepatic biliary atresia. Genotyping data were compared with those of 134 racially and geographically matched healthy adult health care workers. RESULTS AND CONCLUSIONS: Overall there were no statistically significant differences in the distribution of any of the genes tested comparing patients and controls. These data suggest that biliary atresia is not an HLA-associated disease and that polymorphisms in both the interleukin-1 and interleukin-10 genes are not risk factors for this disease.
Quantification of hepatic thrombopoietin mRNA transcripts in patients with chronic liver diseases shows maintained gene expression in different etiologies of liver cirrhosis.
Tacke F, Trautwein C, Zhao S … +4 more , Andreeff M, Manns MP, Ganser A, Schöffski P
Liver · 2002 Jun · PMID 12100570 · Publisher ↗
BACKGROUND/AIMS: Platelet production is regulated by thrombopoietin (TPO), which is primarily synthesized in the liver. The TPO in patients with liver diseases could possibly be owing to impaired hepatic TPO production....
BACKGROUND/AIMS: Platelet production is regulated by thrombopoietin (TPO), which is primarily synthesized in the liver. The TPO in patients with liver diseases could possibly be owing to impaired hepatic TPO production. As we reported previously, TPO serum levels are not decreased in patients with liver diseases compared with healthy controls and do not depend on the stage of cirrhosis or platelet count, but are highly elevated in patients with chronic virus hepatitis. METHODS: To study possible mechanisms, we measured hepatic TPO mRNA levels in liver tissue samples from 31 liver cirrhosis patients by quantitative TaqMan real-time RT-PCR and corresponding serum TPO concentrations by ELISA. RESULTS: Median TPO serum levels were elevated in patients with viral hepatitis (n = 12) compared with patients with a biliary (n = 10), alcoholic (n = 6) or other (n = 3) disease etiology, while hepatic TPO mRNA levels did not differ. The TPO mRNA levels in patients with chronic liver diseases were not different from normal liver tissue sample. The TPO mRNA and TPO serum level did not correlate. CONCLUSIONS: We conclude that hepatic TPO gene expression appears to be maintained on a constitutive transcriptional level in patients with liver diseases and does not change dependent on disease etiology.
In situ expression of Granzyme B and Fas-ligand in the liver of viral hepatitis.
Ibuki N, Yamamoto K, Yabushita K … +7 more , Okano N, Okamoto R, Shimada N, Hakoda T, Mizuno M, Higashi T, Tsuji T
Liver · 2002 Jun · PMID 12100569 · Publisher ↗
BACKGROUND/AIMS: The molecular mechanism involved in hepatocellular injury in viral hepatitis remains to be clarified. METHODS: We investigated the in situ expression of effector molecules of cytotoxic T lymphocytes such...
BACKGROUND/AIMS: The molecular mechanism involved in hepatocellular injury in viral hepatitis remains to be clarified. METHODS: We investigated the in situ expression of effector molecules of cytotoxic T lymphocytes such as Fas-ligand (Fas-L), perforin and Granzyme B (Gr-B) immunohistochemically in liver tissues from 20 patients with chronic hepatitis B (CHB) and C (CHC). The degree of cell infiltration was analysed semi-quantitatively and compared with the histological activity index (HAI). Fas-L was expressed in both CD4 and CD8 T-cells in the portal tract as well as in the parenchyma. RESULTS: Immunostaining of serial sections demonstrated that mononuclear cells at interface hepatitis and focal necrosis were mainly Fas-L positive CD8 T-cells. On the other hand, the expression of perforin or Gr-B was limited to a few mononuclear cells in the portal tract and parenchyma. Semi-quantitative analysis showed a positive correlation between HAI and the grade of infiltration of CD8 T-cells or Fas-L-positive cells, while the correlation was not apparent between HAI and the number of Gr-B positive cells. The expression of these molecules was not different between types of viruses. CONCLUSIONS: These results suggest that Fas-L-positive CD8 T-cells play a major role in the pathogenesis of liver cell injury in chronic hepatitis.
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