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PubMed2002

Spontaneous acceptance of liver transplants in rodents: evidence that liver leucocytes induce recipient T-cell death by neglect.

In many animal models transplanted livers are not rejected, even when there is a complete MHC mismatch between the donor and recipient and the recipient is not immunosuppressed. This distinguishes liver transplants from other organs, such as kidneys and hearts, which are rapidly rejected in mismatched individuals. Acceptance of transplanted livers in a rat model is not due to the absence of an immune response to the liver and there is a rapid, abortive response that is ultimately exhausted. Donor leucocytes transferred with the liver appear to be responsible for both liver acceptance and the abortive activation of the recipient's T cells. The immune mechanism of liver transplant acceptance appears to be due to 'death by neglect' in which T cells are activated to express IL-2 and IFN-gamma mRNA in the recipient lymphoid tissues, but not at adequate levels within the graft. Subsequently the activated T cells die leading to specific clonal deletion of liver donor-reactive T cells. These findings have important implications for liver transplant patients as immunosuppressive drugs that are given to prevent rejection can also interfere with this form of tolerance. In addition, it might be possible to modify the immunosuppressive drug treatment of transplant patients to promote the process of death by neglect of recipient alloreactive T cells.

Animals↗
PubMed2002

Cold ischemia decreases liver regeneration after partial liver transplantation in the rat: A TNF-alpha/IL-6-dependent mechanism.

New strategies of partial liver transplantation such as cadaveric split or living related liver transplantation have been developed to overcome organ shortage. Thus, studies on the ability of small partial grafts to regenerate to normal size while maintaining adequate function have become important. Here, we evaluated the effects of cold preservation on hepatocyte proliferation and function in a novel model of partial liver transplantation in rats. Lewis rats subjected to 70% liver resection (control) were compared with rats that underwent total hepatectomy and 30% partial liver transplantation (recipient). Livers were preserved at 4 degrees C for 30 minutes, 10 hours, or 16 hours in University of Wisconsin solution. Seventy percent liver resection was associated with 100% survival, whereas 30-minute, 10-hour, and 16-hour preservation before 30% transplantation resulted in 80%, 40%, and 20% animal survival, respectively. Prolonged time of cold preservation (10 and 16 hours) was associated with a dramatic decrease of all markers of regeneration (P <.05). Tumor necrosis factor alpha (TNF-alpha) and interleukin 6 (IL-6) levels were also significantly decreased in recipient rats compared with the control group. Finally, pretreatment of recipients with recombinant IL-6 (rIL-6) normalized all markers of regeneration and significantly improved survival in the 10-hour group (90% vs. 40%; P <.05). In conclusion, sustained periods of cold preservation significantly impaired TNF-alpha and IL-6 production, the regenerative ability of the liver, and animal survival. rIL-6 reversed impaired regeneration in the 10-hour cold ischemia group and suggests a primary role of nonparenchymal cells in modulating hepatocyte proliferation in the ischemic liver.

Animals↗
PubMed2004

Influence of hepatocyte-rich liver cell mixture and liver fibroblasts on prolonging graft islet survival in rats without immunosuppressive drugs.

BACKGROUND: We noted that a liver cell suspension, made up of a mixture of several kinds of hepatic cells, affected allogenic islet survival when it was transplanted into the liver, mixed with the islets or separately. AIM: To study if this effect was related to a liver cell mixture rich in hepatocytes (hp) or to liver fibroblasts (fb). METHODS: We studied 14 groups of rats: (A) a sham group with saline; (B) a group receiving transplantation with hepatic cells alone; (C) a control group, with islets alone via the portal vein, without hepatic cells (hp or fb). For the other groups, we used a different ratio of cells/islets (100 : 1, 150 : 1 and 200 : 1) and different co-transplantation techniques with both types of cells. For the D, E, J groups, a mixture of hepatocytes (hepatocyte-rich liver cell mixture) or fibroblasts with islets was injected into the portal vein. For the other groups, we used a sequential procedure with a 15 minute interval between a first injection of hp or fb into the portal vein or into the vena cava, and a second injection of islets always into the portal vein; thus, it was a sequential portal/portal procedure with hepatocyte-rich liver cell mixture (hp) (F, G) or fibroblasts (K, L) and a sequential cava/portal with hp (H, I) or fibroblasts (M, N). RESULTS: Most of the co-transplantation groups showed functional islets (blood glucose < 250 mg/dl) on the first or second day of transplantation; after several days they once again had high glucose levels, though not as high as pre-transplantation. There was statistical significance (p < 0.001) between the presence or not of hepatic cells to obtain prolongation of graft survival (blood glucose < 250 mg/dl). Statistical significance (p < 0.001) was found for several sequential groups with hp (F, I) and fb (K, L). It was also remarkable that 3 rats (37.5 %) from the I group (sequential cava/portal with hp/islets 200 : 1) were euglycemic (blood glucose < 150 mg/dl) for more than 3 months. ANOVA showed a large interaction between the type of transplant performed and the cellular ratio used, with a significance of p < 0.001. Histological studies in rats with prolonged euglycemia, showed insulin-producing cell aggregates in the liver, while there was a remarkable decrease in insulin-producing cells in the remaining islets of pancreatic tissue. CONCLUSION: The results showed a marginal prolongation of islet graft survival when they are co-transplanted with a hepatocyte-rich liver cell mixture or with liver fibroblasts. The mechanism does not seem to be a cellular interaction between different hepatic cells and islets, but some kind of cellular interaction or released factor from either two cell types on the immune system, blocking or modulating it, at least temporarily.

Analysis of Variance↗
PubMed1998

[Progress of acute liver failure and indications for liver transplantation].

OBJECTIVE: To analyse the course of acute liver failure and the indications for liver transplantation. PATIENTS AND METHODS: In 16 patients who developed acute liver failure between July 1992 and July 1997 the indications for liver transplantation and total survival time were analysed retrospectively. RESULTS: Intensive medical care (ventilation, dialysis) was necessary in 60% of the patients to bridge organ failure until liver transplantation. In 14 patients liver transplantation was indicated. Eleven of the patients, with a minimal Quick value of less than 10%, presented with the prognostically poorest London criteria. In two patients the combination of three additional criteria of the London classification led to liver transplantation being indicated. In one patient with Wilson's disease the transplantation was undertaken despite good clotting factor synthesis, because an encephalopathy occurred. In two patients liver transplantation was not undertaken even though indicated, in one because liver functions improved, in the other because necrotizing pancreatitis had occurred. In another patient, who had been poisoned by eating the mushroom Amanita phalloides, the attempted transplantation was cut short, because intestinal necrosis had developed, and the patient died during the operation. Nine of the eleven patients who had a transplantation and three of the four treated conservatively survived. CONCLUSION: The 60-day survival rate in this series, achieved in a recently established transplantation programme, is high (12 of 16; 75%), being comparable to those in larger transplantation centres.

Adult↗
PubMed2003

Mouse liver CYP2C39 is a novel retinoic acid 4-hydroxylase. Its down-regulation offers a molecular basis for liver retinoid accumulation and fibrosis in aryl hydrocarbon receptor-null mice.

Livers of aryl hydrocarbon receptor (AHR)-null mice have high levels of retinoic acid (RA), retinol, and retinyl palmitate. Hepatic accumulation of RA in these mice may be responsible in part for the hepatic phenotype characterized by small liver size and fibrosis. The increased levels of hepatic RA may be due to decreased metabolism of RA to 4-hydroxyretinoic acid. To identify the P450 isoform(s) involved in RA metabolism, liver microsomes from AHR-null and wild-type mice were subjected to Western blotting and probed with antibodies to rat P450s that cross-react with murine forms. Signal intensity in Western blots probed with anti-rat CYP2C6 antibodies correlated with levels of RA 4-hydroxylation. Furthermore, this anti-rat CYP2C6 antibody inhibited RA 4-hydroxylase activity of wild-type mouse liver microsomes to the levels of AHR-null mouse liver. When used to screen a mouse liver cDNA expression library, this antibody exclusively recognized the murine P450 CYP2C39. Catalytic assays of five recombinant mouse CYP2Cs expressed in Escherichia coli revealed that only CYP2C39 was competent for RA 4-hydroxylation (K(m) = 812.3 nm and V(max) 47.85 (fmol/min/pmol P450)). Real time reverse transcriptase-PCR used to assess the Cyp2C39 mRNA expression showed decreased levels (30%) of this transcript in AHR-null compared with wild-type liver, consistent with decreased protein levels observed by Western blot analysis using an antibody to a CYP2C39-specific peptide. These data show that CYP2C39 catalyzes RA catabolism and thus possibly controls RA levels in mouse liver. Down-regulation of Cyp2C39 is hypothesized to be responsible for the liver phenotype in the AHR-null mouse.

Animals↗
PubMed1978

Biotin deficiency and liver metabolism in relation to fatty liver and kidney syndrome.

Varying degrees of biotin deficiency were induced by adding freeze-dried, raw egg white to the diet of broiler chicks. Aspects of liver metabolism were studied with reference to fatty liver and kidney syndrome. Mortality was low with 11.8 g egg white/kg diet, or less, but with 17.7 g/kg or more, mortality was very high. High mortality was observed with less than 0.33 microgram biotin/g liver. Associated with low concentrations of liver biotin were substantial increases in liver weight and lipid content in starved birds. The increased liver lipid content was not observed in birds fed ad libitum. The increased liver lipid content in biotin-deficient, starved birds was not reflected in the specific activities of hepatic lipogenic enzymes or hepatic lipogenesis in vivo measured by the incorporation of tritium from 3H-labelled water into liver lipid. Biotin deficiency affected the specific activities of the biotin-requiring enzymes, pyruvate carboxylase and acetyl CoA carboxylase, differently; the latter was unaffected whereas the former decreased concomitantly with liver biotin concentration.

Animals↗
PubMed1985

Histochemical characteristics of fat-storing cells in alcoholic liver disease: a study by the gold chloride method using needle biopsy specimens of the liver.

To evaluate the relationship between fat-storing cells and fibrosis of the liver in alcoholic liver disease, the characteristics of fat-storing cells were studied by light microscopy with a modification of Kupffer's gold chloride method. Liver biopsy specimens were obtained at laparoscopy with a Trucut needle from 59 patients with alcoholic liver disease, 10 with no hepatic fibrosis, 18 with mild fibrosis, 18 with moderate fibrosis, and 13 with liver cirrhosis. These specimens were divided into three classes (weak, moderate, and strong) with respect to the response of fat-storing cells to the gold chloride reaction, which indicates the amount of vitamin A contained in fat-storing cells. It was found that in alcoholic liver disease the gold chloride reaction became weaker as hepatic fibrosis progressed (P less than 0.001). By contrast, no significant association was observed between the gold chloride reaction and the degree of hepatic fibrosis in 74 specimens from patients with nonalcoholic liver disease. These results show that in alcoholic liver disease hepatic fibrosis is characterized histochemically by the reduced response of fat-storing cells to the gold chloride reaction. The role of the change in fat-storing cells in alcoholic liver disease remains to be elucidated.

Biopsy, Needle↗
PubMed2002

Rocuronium plasma concentrations during three phases of liver transplantation: relationship with early postoperative graft liver function.

BACKGROUND: Previous studies have suggested that neuromuscular blocking agents might be used to assess liver function during liver transplantation. This study examines changes in rocuronium plasma concentration during liver transplantation, to assess graft function. METHODS: A constant-rate infusion of rocuronium was administered to 17 adult patients undergoing liver transplantation. Blood samples were taken at 30-min intervals throughout the procedure, which was divided into three phases: paleo-, an-, and neohepatic. Assay of plasma concentrations of rocuronium was by a gas chromatographic-mass spectrometry technique. Postoperative liver function was followed for up to five days by measuring plasma aminotransferases. RESULTS: In 14 of the 15 patients who survived the transplantation procedure, there was a 7-50% decrease in rocuronium concentration during the neohepatic phase compared with the anhepatic phase. In contrast, rocuronium concentrations increased in the two patients who died after surgery, one as a result of primary non-function and one from massive bleeding. In one patient who survived there was no change in rocuronium concentration. The increase in plasma rocuronium concentration during the neohepatic phase in the two patients who died was consistent with high levels of plasma aminotransferases. CONCLUSIONS: Comparison of changes in plasma rocuronium concentration during the neohepatic phase with early postoperative liver function tests suggests the potential use of rocuronium as a pharmacokinetic probe for predicting liver function during liver transplantation. Further study of rocuronium's potential as an intraoperative pharmacodynamic probe of liver function by measuring neuromuscular paralysis is suggested.

Adult↗
PubMed1987

Induction of alkoxyresorufin O-dealkylases, epoxide hydrolase, and liver weight gain: correlation with liver tumor-promoting potential in a series of barbiturates.

The effects of a series of barbiturates, of known and varying liver tumor-promoting ability, on several short-term endpoints including liver weight and liver-to-body weight ratio increases and induction of cytochromes(s) P-450 and epoxide hydrolase activities were examined. Male F344 rats (3 months of age) were administered barbiturates in the drinking water for 12 days. At the end of the treatment period they were killed, body and liver weights were taken, microsomal p-nitroanisole O-demethylation and epoxide hydration, and liver S-9 O-dealkylation of ethoxy-, pentoxy- and benzyloxyresorufin were measured. The latter two substrates have been shown to be preferentially metabolized by the major phenobarbital-inducible form of cytochrome(s) P-450 (P-450b), and were employed since they offered a means of differentiating more clearly varying levels of P-450 induction. Exposure to sodium barbital (SB) and sodium phenobarbital (PB) resulted in significant increases in liver weight and liver-to-body weight ratios. Induction of cytochrome(s) P-450 and epoxide hydrolase activities by the various barbiturates depended on the functional groups on C5. When ranked in terms of decreasing induction potency, the following order was obtained for each enzyme activity quantitated: PB, SB, sodium pentobarbital, amobarbital, hexobarbital and the C5-unsubstituted parent compound (barbituric acid). Thus, the barbiturates were found to exhibit a spectrum of induction potencies, with PB and SB, the most potent liver tumor promoters, yielding the greatest degree of liver weight increase and induction of cytochrome(s) P-450 and epoxide hydrolase activities.

7-Alkoxycoumarin O-Dealkylase↗
PubMed1995

Combined liver and kidney transplantation in patients with chronic nephritis associated with end-stage liver disease.

A variety of renal diseases can be associated with end-stage liver diseases requiring orthotopic liver transplantation (OLT), including cirrhosis-associated glomerulonephritis (GN), and nephropathy unrelated to the liver disease. A retrospective survey showed that nine patients undergoing liver transplantation in our centre had histologically proven GN or interstitial nephritis with renal failure and/or nephrotic-range proteinuria, and experienced severe complications post-OLT since nephrotoxic immunosuppressive drugs (CsA and FK506) could not be adequately given. Four of the nine patients died. Therefore, combined liver-kidney transplantation has been suggested as first choice treatment in such patients. From January 1990 to February 1994, in patients with end-stage liver disease referred for OLT, and who presented with unexplained renal function impairment and/or significant proteinuria, severe nephropathy was confirmed by renal biopsy in nine: four mesangiocapillary GN with immune deposits, one membranous nephropathy, two diabetic glomerulosclerosis and two interstitial nephritis. All underwent liver transplantation immediately followed by kidney transplantation. The postoperative period was uneventful, and neither death nor renal failure were recorded. Combined transplantation resulted in all patients in the normalization of renal function, and in the disappearance of proteinuria within the first postoperative month. From 6 months to 4 years post-transplant, the renal function remained within normal ranges in all patients. Routine renal transplant biopsy was performed in two patients with pre-transplant cirrhosis-associated GN, and showed no evidence of recurrence of the original nephropathy. We conclude that combined liver-kidney transplantation is an adequate therapeutic option in patients with end-stage liver disease associated with advanced kidney disease.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1996

Rapid en bloc technique for pancreas-liver procurement. Improved early liver function.

It is our experience that warm dissection in the porta hepatis as well as extensive organ mobilization during combined pancreas-liver procurements may cause posttransplant dysfunction of the liver. To avoid this, we recently utilized a rapid en bloc procurement technique with minimal warm dissection and division of the liver and pancreas ex vivo. Fifteen procurements were performed using this rapid en bloc technique; seventeen procurements involved extensive dissection followed by sequential in situ procurement of the liver and pancreas grafts. The control group consisted of 15 age-matched patients who received livers when no pancreas was harvested. Dissection time was 157 +/- 13 min (mean +/- SEM) in the in situ group, 78 +/- 3 min in the en bloc group (P<0.02), and 51 +/- 6 min in the liver only group (P<0.02). There was no difference in donor age, cold ischemia time, or recipient United Network for Organ Sharing status. Pancreata obtained using the en bloc technique all had immediate function and there were no episodes of acute pancreatitis. Early liver graft function, as assessed by lactate dehydrogenase, serum glutamic oxaloacetic transaminase, serum glutamic pyruvic transaminase, and total bilirubin levels, was significantly lower in the en bloc and liver only group when compared with the in situ group. The total hospital stay was also significantly lower in these groups. We conclude that the rapid en bloc technique decreases operative time during the donor operation. Procurement-related injury to the liver graft is minimized without compromising pancreas graft function.

Adult↗
PubMed1997

Heterotopic auxiliary liver transplantation in a 3-year-old boy with acute liver failure and aplastic anemia.

BACKGROUND: Auxiliary liver transplantation offers an alternative method to conventional transplantation in acute liver failure. It is especially challenging for children because lifelong immunosuppression may be avoided. However, experience with this procedure is rare and there is controversy about whether to place the graft orthotopically or heterotopically. METHODS: We present the case of a 3-year-old boy with acute liver failure due to non-ABC hepatitis complicated by aplastic anemia who underwent auxiliary liver transplantation. Segments 2 and 3 of the graft were implanted heterotopically in the right lower abdomen. RESULTS: Good liver function was immediately restored. Aplastic anemia resolved 3 weeks after transplantation. Immunosuppressive therapy was discontinued after 14 months, and the graft was left to atrophy. Thirty-nine months after transplantation the boy is alive and well with normal liver function tests and normal blood cell counts. CONCLUSIONS: Heterotopic auxiliary liver transplantation allowed recovery of the native liver in a child with acute liver failure and aplastic anemia due to non-ABC hepatitis.

Abdomen↗
PubMed2006

Use of extended criteria livers decreases wait time for liver transplantation without adversely impacting posttransplant survival.

INTRODUCTION: The use of extended criteria donors (ECDs) could minimize shortage of suitable donor livers for transplantation. In 3 years, the aggressive use of ECD livers has reduced the wait list at our center from 257 to 30 patients with a median wait time of 18 days without using living donors. This study compares the graft/patient survival from standard (SD) and ECD for our transplant population between 2001 and 2005. METHODS: Records of all adult liver transplant recipients over 4 years were reviewed (n = 571). ECD criteria included: age >59 years, BMI >34.9, maximum AST/ALT >500, maximum bilirubin >2.0, peak serum sodium >170, HBV/HCV/HTLV reactive, donation after cardiac death, cold ischemia time >12 hours, ICU stay >5 days, 3 or more pressors simultaneously, extensive alcohol abuse, cancer history (nonskin), active meningitis/bacteremia, or significant donor liver trauma. Outcomes included graft and patient survival at 90 days, 1 year, and 2 years. RESULTS: Sixty-eight percent of recipients (n = 388) received ECD livers. Primary factors accounting for ECD-liver status included: elevated liver function tests (20%), hypernatremia (12.6%), and extensive alcohol abuse (11.4%). Graft survival was (SD, ECD): 90-day 91%, 88%; 1-year 84%, 80%; 2-year 78%, 77%; patient survival was: 90-day 93%, 90%; 1-year 87%, 82%; 2-year 83%, 79%. Kaplan-Meier survival analysis failed to demonstrate an overall difference in graft or patient survival at any time point. Only donor age >60 years was associated with decreased graft and patient survival. CONCLUSIONS: Liver grafts from ECD can be used to dramatically reduce wait list time with outcomes comparable to those for SD without resorting to living donor liver transplantation.

Age Factors↗
PubMed2004

Treatment of Budd-Chiari syndrome in a liver transplant unit, the role of transjugular intrahepatic porto-systemic shunt and liver transplantation.

BACKGROUND: Budd-Chiari syndrome is an uncommon cause of liver failure usually associated with an underlying hypercoagulable state. AIM: To evaluate current trends in management of Budd-Chiari syndrome at our institution. METHODS: Twenty-two patients with Budd-Chiari syndrome underwent transjugular intrahepatic porto-systemic shunt, liver transplantation, or both in between 1992 and 2001. We analysed underlying diagnosis, medical therapy, complications, follow-up and overall outcomes. RESULTS: Five patients (17%) presented with fulminant liver failure and 17 patients (83%) with new-onset ascites or chronic liver disease. Seventeen patients (74%) underwent transjugular intrahepatic porto-systemic shunt: improvement or stabilization occurred initially in 14 (82%), whereas the other three patients died within a month. At a mean 3 years follow-up eight patients (47%) continued to do well clinically and four have died (23.5%); seven have required transjugular intrahepatic porto-systemic shunt revisions (mean 2.3 interventions), five have experienced transjugular intrahepatic porto-systemic shunt occlusion managed with new transjugular intrahepatic porto-systemic shunt placement and five patients underwent subsequent transplantation. Of the 10 patients who underwent liver transplantation, patient and graft survival are 80% at a mean 5.7 years of follow-up. No patient developed post-transplant Budd-Chiari syndrome. CONCLUSIONS: Transjugular intrahepatic porto-systemic shunt is usually feasible in patients with Budd-Chiari syndrome, and is best suited as a bridge to more timely liver transplantation. Long-term success of transjugular intrahepatic porto-systemic shunt is limited and usually requires revision, placement of a new shunt or liver transplantation. Liver transplantation with chronic anticoagulation offers excellent short- and medium-term patient and graft survival. In our series, there was no recurrence of Budd-Chiari syndrome after liver transplantation.

Adolescent↗
PubMed2006

Interferon gamma-secreting HCV-specific CD8+ T cells in the liver of patients with chronic C hepatitis: relation to liver fibrosis--ANRS HC EP07 study.

Little is known about the role of specific hepatitis C virus (HCV) CD8+ T cells in liver damage, especially for the progression of fibrosis, during the highly variable course of chronic C hepatitis. The aim of this study was to investigate the presence of HCV-specific CD8+ T cells in the liver of patients with chronic C hepatitis and to examine their clinical significance by relating the response to liver fibrosis and progression rate, serum viral load, serum aminotransferase levels, inflammatory activity and in situ characteristics of the intrahepatic infiltrate. Fifteen patients were prospectively included in the study. Intrahepatic lymphocytes were tested for interferon gamma (IFNg) production in response to HCV class I-restricted epitopic peptides using enzyme-linked immunospot analysis. Liver biopsy samples were evaluated for fibrosis, fibrosis progression rate, activity, and in situ number of CD8+ cytotoxic lymphocytes and apoptotic cells. An IFNg-specific CD8+ T-cell response was detected in the liver samples of 47% of patients which was significantly related to a lower stage of fibrosis (P = 0.02) and a lower progression rate of fibrosis (P = 0.01). It was neither related to the number of cytotoxic lymphocytes infiltrating the liver nor to hepatocyte apoptosis. In conclusion, our results indicate that the presence of HCV-specific IFNg-secreting T cells in the liver of patients with chronic C hepatitis is associated with low liver fibrosis and fibrosis progression rate, suggesting that these IFNg-secreting T cells might limit the progression of liver damage.

Adult↗
PubMed1984

Modification of the intramolecular turnover of terminal carbohydrates of dipeptidylaminopeptidase IV isolated from rat-liver plasma membrane during liver regeneration.

An intramolecular turnover of the terminal carbohydrates L-fucose, N-acetylneuraminic acid and D-galactose is a characteristic property of several liver plasma membrane glycoproteins, first demonstrated for dipeptidylaminopeptidase IV (EC 3.4.14.5., DPP IV). The core carbohydrates D-mannose and N-acetyl-D-glucosamine turn over like the polypeptide chain. The ratio of apparent half-lives of L-fucose and L-methionine of DPP IV is shifted from 0.17 in normal liver to 0.60 in regenerating liver. The ratio of half-lives of N-acetylneuraminic acid and L-methionine is only slightly changed from 0.43 in normal liver to 0.61 in regenerating liver. The ratio of apparent half-lives of D-mannose and L-methionine amounts to 0.80 in normal liver and 0.71 after partial hepatectomy. From this a drastic reduction of the intramolecular turnover of L-fucose on plasma membrane DPP IV in regenerating liver can be derived. The intramolecular N-acetylneuraminic acid turnover is affected to only a minor extent. D-Mannose turns over like the polypeptide in both normal and regenerating liver. The intramolecular L-fucose turnover may be involved in membrane glycoprotein recycling, which presumably is altered in regenerating liver. Additionally, L-fucose could regulate the rate of degradation of DPP IV, since core-fucosylated glycoproteins appear to be resistant to mammalian endo-N-acetylglucosaminidase.

Animals↗
PubMed2006

Liver regeneration in acute severe liver impairment: a clinicopathological correlation study.

BACKGROUND: Although normally quiescent, the adult mammalian liver possesses a great capacity to regenerate after different types of injury. Major players in the regeneration process are mature residual cells, including hepatocytes, cholangiocytes and stromal cells. However, if the regenerative capacity of mature cells is impaired, hepatic progenitor cells (HPCs) are activated and expand into the liver parenchyma. Upon transit amplification, the progenitor cells generate new hepatocytes and biliary cells to restore liver homeostasis. AIMS/METHODS: To study the relationship between different histopathological parameters as well as their correlations with clinical parameters and outcome, we examined liver specimens from 74 patients with acute or subacute severe liver impairment by immunohistochemistry for CK7/CK19 (evaluation of HPCs activation/differentiation), Mib1(Ki 67)/P21 (evaluation of proliferative activity/proliferation arrest of hepatocytes) and hematoxylin and eosin (evaluation of hepatocyte loss). RESULTS: Of the 74 patients, 32% survived without transplantation, 14% died without transplantation and 54% were transplanted. Our results show that a threshold of 50% loss of hepatocytes, associated with significant decrease in the proliferative activity of remaining mature hepatocytes, is needed for extensive hepatic progenitor cell activation. Such activation is a sign of disease severity and occurs early (within 1 week) in the disease course. However, development of intermediate hepatocytes, suggesting HPCs differentiation towards mature hepatocytes, takes at least 1 week's time. We found a positive correlation between histopathological parameters (percentage hepatocyte loss, number of proliferating hepatocytes and number of HPCs) and clinical parameters of liver impairment such as model for end stage liver diseases (MELD). Surviving patients compared with those who either died or were transplanted had significantly less hepatocyte loss, less HPCs activation and more mature hepatocyte proliferative activity. Hepatocyte proliferative activity and degree of hepatocyte loss were the most important independent histopathological parameters in predicting outcome. CONCLUSION: Liver biopsy can provide important additional information in a patient with severe acute liver impairment.

Adult↗
PubMed2003

Relationship between thrombopoietin serum levels and liver function in patients with chronic liver disease related to hepatitis C virus infection.

OBJECTIVES: Thrombopoietin (Tpo) is an important regulator of megakaryocyte maturation and platelet production, and is mainly produced by the liver. A decrease in Tpo production is partly responsible for the thrombocytopenia observed in patients with chronic liver disease (CLD). The aim of this study was to evaluate the relationship between Tpo serum levels and liver function in patients with CLD related to hepatitis C virus (HCV) infection. METHODS: We studied 37 patients with various degrees of HCV-related CLD. Of the patients, 17 had chronic hepatitis and 20 liver cirrhosis. Liver function was evaluated in all patients by the following hepatic blood flow dependent and independent tests that explore various hepatic metabolic functions: carbon-13 (13C)-aminopyrine breath test (13C-ABT), 13C-galactose breath test (13C-GBT), and monoethylglycinexylidide (MEGX) test. Liver function tests results were correlated with Tpo serum levels. RESULTS: Tpo serum levels were significantly lower in patients with liver cirrhosis (88 +/- 23 pg/ml) as compared to those in patients with chronic hepatitis (128 +/- 55 pg/ml, p=0.0031). However, they did not correlate with serum albumin, bilirubin, or prothrombin activity. Tpo serum levels showed a significant positive correlation with 13C-ABT results (hourly dose at 30 min, rs=0.489, p=0.002; cumulative dose at 120 min, rs=0.425, p=0.008). Moreover, they showed a fair, positive correlation with 13C-GBT hourly dose at 30 min (rs=0.366, p=0.028), and a trend toward a positive correlation with the various MEGX test sampling times (MEGX15, rs=0.314, p=0.059; MEGX30, rs=0.284, p=0.088; and MEGX60, rs=0.320, p=0.059). CONCLUSIONS: In this study we have shown that a progressive decline in liver function in patients with HCV-related CLD is paralleled by a decrease in Tpo production. The different correlations observed between Tpo and the various liver function tests suggests that this finding is mainly the result of a decrease in hepatic functional mass rather than dependent on alteration in splanchnic hemodynamic.

Adult↗