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Activated sub-populations of lymphocytes and natural killer cells in normal liver and liver grafts before transplantation.

AIMS/BACKGROUND: The anatomic structure of the liver suggests that it is a place of intense trafficking between intra-hepatic and peripheral blood compartment leukocytes. Furthermore, the liver contains a large number of passenger leukocytes that may play a role in the appearance of donor-type microchimerism after transplantation. In this study, we aimed to define the principal lymphocyte sub-populations contained in donor peripheral blood and liver grafts and in normal liver removed during minimally invasive surgery. METHODS: Liver biopsies were taken at the time of vascular clampage during liver extraction from donors in a brain dead state (GI: n=14). Normal liver biopsies were removed during minimaly invasive surgery (GII: n= 10). RESULTS: We observed evidence of the presence of lymphocytic activation associated with the two major CD8+ lymphocyte and natural killer (NK) cell populations in the two groups, with a significant increase in TCRgammadelta-bearing lymphocyte receptors between normal liver and the liver graft. CONCLUSIONS: The presence of activated leukocytes in the graft could have a fundamental role in induction of peripheral tolerance. This activation could be the result of a basic immunological response linked to the interaction of T cells and NK cells, and of secondary activation due to stress and the conditions necessary for organ removal from donors in a brain dead state.

Adult↗

Impact of adult living donor liver transplantation on waiting time survival in candidates listed for liver transplantation.

Studies comparing adult living donor liver transplantation to deceased donor liver transplantation have focused on post-transplant survival. Our aim was to focus on the impact of living donor liver transplant on waiting time mortality and overall mortality. We analyzed the affect of living donor liver transplantation on waiting time mortality and overall mortality (from listing until last follow up) in a cohort of 116 transplant candidates. Fifty-eight candidates who had individuals present as potential living donors (volunteer group) were matched by MELD score to 58 liver transplant candidates who did not have individuals present as a potential living donor (no volunteer group). Twenty-seven percent of candidates in the no volunteer group and 62% of candidates in the volunteer group underwent liver transplantation, p = 0.0003. One-year waiting list mortality for the volunteer group and no volunteer group was 10% and 20%, respectively, p = 0.03. Patient survival from the time of listing to last follow up was similar between the two groups. In our study group, living donor liver transplantation is associated with a higher rate of liver transplantation and lower waiting time mortality. In the era of living donor liver transplantation, estimates of patient survival should incorporate waiting time mortality.

Female↗

Treatment of severe liver failure with a bioartificial liver.

Orthotopic liver transplantation (OLT) is the definitive therapy for severe liver failure. However, many patients die before an organ becomes available, mostly from cerebral edema. To provide temporary liver support, we developed a bioartificial liver (BAL) based on porcine hepatocytes and a charcoal column. Fifty-four consecutive BAL treatments were carried out in three groups of patients: Group I (n = 15) patients presented with FHF were listed for emergent OLT, Group II (n = 3) patients with primary non-function (PNF) of their liver grafts required urgent re-transplantation and Group III (n = 10) patients with acute exacerbation of chronic liver disease were not candidates for OLT. Patients were managed in a critical care unit receiving maximal standard support. Each BAL treatment was conducted for 6 hours. In Group I, all patients showed significant neurologic improvement, intracranial pressure (ICP) decreased and cerebral perfusion pressure (CPP) increased; other significant improvements, included lowered plasma ammonia and liver enzymes and increased glucose. One patient recovered spontaneously without OLT, all other patients were "bridged" to OLT, and recovered. Group II: PNF patients showed similar benefits. Group III: Chronic liver patients demonstrated transient beneficial effects after BAL treatment(s), however, most (n = 8) eventually succumbed to sepsis and multiple organ failure as they were not candidates for OLT; two patients, recovered, later were successfully transplanted and survived. Our clinical experience demonstrates that the BAL can serve as a bridge to OLT in patients with acute liver failure.

Adult↗

Primary human liver cells as source for modular extracorporeal liver support--a preliminary report.

Cell-based extracorporeal liver support is an option to assist or replace the failing organ until regeneration or until transplantation can be performed. The use of porcine cells or tumor cell lines is controversial. Primary human liver cells, obtained from explanted organs found to be unsuitable for transplantation, are a desirable cell source as they perform human metabolism and regulation. The Modular Extracorporeal Liver Support (MELS) concept combines different extracorporeal therapy units, tailored to suit the individual and intra-individual clinical needs of the patient. A multi-compartment bioreactor (CellModule) is loaded with human liver cells obtained by 5-step collagenase liver perfusion. A cell mass of 400 g - 600 g enables the clinical application of a liver lobe equivalent hybrid organ. A detoxification module enables single pass albumin-dialysis via a standard high-flux dialysis filter, and continuous veno-venuous hemodiafiltration may be included if required. Cells from 54 human livers have been isolated (donor age: 56 +/- 13 years, liver weight: 1862 +/- 556 g resulting in a viability of 55.0 +/- 15.9%). These grafts were not suitable for LTx, due to steatosis (54%), cirrhosis (15%), fibrosis (9%), and other reasons (22%). Out of 36 prepared bioreactors, 10 were clinically used to treat 8 patients with liver failure. The overall treatment time was 7-144 hours. No adverse events were observed. Initial clinical applications of the bioreactor evidenced the technical feasibility and safety of the system.

Bioreactors↗

Cholangiocyte marker-positive and -negative fetal liver cells differ significantly in their ability to regenerate the livers of adult rats exposed to retrorsine.

We have used monoclonal antibodies against cell-surface developmental epitopes in combination with micromagnetic beads to isolate phenotypically defined subpopulations of cholangiocyte marker-positive fetal liver epithelial cells (CMP-FLEC). Differentiation potential was evaluated by injecting cell isolates from dipeptidyl peptidase IV (DPPIV) positive (DPPIV+) Fischer donor rats into the spleen of partially hepatectomized, DPPIV negative (DPPIV-) Fischer host rats exposed to retrorsine. At various time points, liver tissue was harvested and cells in DPPIV+ colonies were phenotyped by immunofluorescence and histochemical protocols. Functional differentiation and liver replacement were determined by comparing donor and host hepatocyte protein expression patterns and DPPIV enzyme activity in extracts from livers of host rats receiving CMP-FLEC. Our results showed that bipotentiality was retained during differentiation and maturation of CMP-FLEC, indicating that the acquisition of ductal morphology and phenotype were not indicative of lineage commitment. CMP-FLEC transplanted into the adult rat liver lost ductal and gained hepatocyte markers, and acquired protein expression patterns in 2D gels with a close similarity (>75% spot match) to host hepatocytes but differing significantly from the transplanted CMP-FLEC cell isolate (<25% spot match). The average size of donor hepatocyte colonies increased with time so that by 1 year, up to 70% of the host rat liver was replaced by CMP-FLEC derived DPPIV+ hepatocytes. Depletion of CMP-FLEC from fetal liver isolates resulted in a marked decrease in adult liver colonization, suggesting that a high percentage of the hepatocyte colonies in animals receiving total fetal liver isolates are derived from CMP-FLEC.

Animals↗

Pathological changes in the liver of a senescence accelerated mouse strain (SAMP8): a mouse model for the study of liver diseases.

Liver disease is characterized by fatty liver, hepatitis, fibrosis and cirrhosis and is a major cause of illness and death worldwide. The prevalence of liver diseases highlights the need for animal models for research on the mechanism of disease pathogenesis and efficient and cost-effective treatments. Here we show that a senescence-accelerated mouse strain (SAMP8 mice), displays severe liver pathology, which is not seen in senescence-resistant mice (SAMR1). The livers of SAMP8 mice show fatty degeneration, hepatocyte death, fibrosis, cirrhotic changes, inflammatory mononuclear cell infiltration and sporadic neoplastic changes. SAMP8 mice also show abnormal liver function tests: significantly increased levels of alanine amino-transferase (ALT) and aspartate aminotransferase (AST). Furthermore, titers of murine leukemia virus are higher in livers of SAMP8 than in those of SAMR1 mice. Our observations suggest that SAMP8 mouse strain is a valuable animal model for the study of liver diseases. The possible mechanisms of liver damage in SAMP8 mice are also discussed.

Alanine Transaminase↗

The neonatal liver part II: Assessment and diagnosis of liver dysfunction.

The liver, the largest organ in the body, performs many essential functions, including the storage and filtration of blood, production of bile, regulation of plasma proteins and glucose, and biotransformation of drugs and toxins. Many neonates display signs of hepatic dysfunction such as hyperbilirubinemia, hepatomegaly, or elevated liver enzymes. Primary liver disease in neonates is rare; much of the liver dysfunction seen in the neonatal period is secondary to systemic illness such as sepsis or hypoxic injury. It is important for the clinician to have the skills and knowledge necessary to distinguish intrinsic liver disease from liver dysfunction resulting from extrahepatic causes. Early intervention to address the cause of dysfunction is critical to successful management of liver disease. This article reviews the assessment of liver function in neonates and examines the techniques used to diagnose liver dysfunction.

Diagnostic Tests, Routine↗

A comparative study of precision cut liver slices, hepatocytes, and liver microsomes from the Wistar rat using metronidazole as a model substance.

1. Metronidazole is metabolized by rat liver in vitro models to form a hydroxy metabolite, an acetic acid metabolite, a glucuronic acid conjugate, and a sulphate conjugate. 2. Four different in vitro systems for investigation of drug metabolism based on liver preparations from the male Wistar rat have been investigated. 3. An incubation system where liver slices are incubated in 12-well culture plates was evaluated with respect to metabolism of metronidazole. Optimal viability was observed for a time period of up to 24 h. The Michaelis-Menten parameters for the metabolism of metronidazole in liver slices were calculated and the intrinsic clearance values compared with the values determined in hepatocytes incubated in suspension. It was found that the intrinsic clearance with respect to formation of oxidative metabolites, the hydroxy metabolite, and the acetic acid metabolite correlated, whereas the intrinsic clearance with respect to formation of the glucuronic acid conjugate was lower in slices compared with hepatocytes. 4. The metabolism of metronidazole in liver slices, in hepatocytes in primary monolayer culture, in hepatocytes incubated in suspension, and in liver microsomes was compared. All the incubations were performed under identical incubation conditions including the same incubation medium. The trend observed was that the initial metabolic rates of the production of the hydroxy metabolite, the glucuronic acid metabolite, and the acetic acid metabolite of metronidazole were higher in microsomes than in the other liver preparations. The metabolic rates in hepatocytes in primary culture and in suspension with respect to the oxidative metabolites were higher than in liver slices. The metabolic turnover observed in liver slices was predicted to correlate with in vivo data earlier obtained for rat.

Acetic Acid↗

A marked increase in free copper levels in the plasma and liver of LEC rats: an animal model for Wilson disease and liver cancer.

Most of copper present in rat plasma and liver binds to caeruloplasmin and metallothionein, respectively, and is not redox active. However, free forms of copper including loosely bound forms to other molecules are redox active. We assessed the free copper in Long-Evans rats with a cinnamon-like coat color (LEC rats), an animal model of Wilson disease and liver cancer. Compared to those of control rats, the liver and plasma of LEC rats showed a marked elevation of free copper, especially at the stage of acute hepatitis, in parallel with an increase of total copper levels in the livers and a decrease of plasma caeruloplasmin (ferroxidase I) activity. At the onset of jaundice, the total copper levels, however, decreased in liver, but increased in plasma, while free copper levels in both liver and plasma remained higher. Free iron levels in both liver and plasma were also determined and did not change significantly, except for the case of plasma in jaundiced rats. The data are consistent with a proposal in which increased levels of redox active free copper in the liver of LEC rats catalyze Fenton-type reactions, producing a large flux of hydroxyl radicals that would play an important role in the observed liver dysfunction, leading to acute hepatitis, and finally, hepatocarcinoma. This is the first demonstration that the free copper may participate in the pathophysiology of the LEC rats and Wilson disease.

Animals↗

Correlation between TIMP-1 expression and liver fibrosis in two rat liver fibrosis models.

AIM: To evaluate serum TIMP-1 level and the correlation between TIMP-1 expression and liver fibrosis in immune-induced and CCL4-induced liver fibrosis models in rats. METHODS: Immune-induced and CCL4-induced liver fibrosis models were established by dexamethasone (0.01 mg) and CCL4 respectively. Serum TIMP-1 level was detected with ELISA, while histopathological grade of liver biopsy was evaluated. Spearman rank-correlation test was used to analyse the difference of the correlation between the TIMP-1 expression and hepatic fibrosis in the two fibrosis models. Furthermore, in situ hybridization was used to determine the expression difference of TIMP-1 mRNA in the two models. RESULTS: Positive correlation existed between serum TIMP-1 level of immune induced group and the histopathological stages of fibrosis liver of corresponding rats (Spearman rank-correlation test, r(s) = 0.812, P < 0.05), and the positive in situ hybridization signal of TIMP-1 mRNA was strong. In CCL4-induced liver fibrosis model, the correlation between the serum TIMP-1 level and the severity of hepatic fibrosis was not statistically significant(Spearman rank-correlation test, r(s) = 0.229, P > 0.05). And compared with immune-induced model, the positive in situ hybridization signal of TIMP-1 mRNA was weaker, while the expression variation was higher in hepatic fibrosis of the same severity. CONCLUSION: The correlations between TIMP-1 expression and liver fibrosis in two rat liver fibrosis models are different. In immune-induced model, serum TIMP-1 level could reflect the severity of liver fibrosis, while in CCL4-induced model, the correlation between the serum TIMP-1 level and the severity of hepatic fibrosis was not statistically significant.

Animals↗

Can low volume liver transplant centers be successful? The Regional Transplant Center of Willis-Knighton & Louisiana State University Medical Center. The first 120 liver transplants.

The development of orthotopic liver transplantation represents this century's most significant advance in the management of liver disease. In the 1980s the vast majority of liver transplants were performed at several large centers; however, in this decade, improvements in techniques and success rates have allowed live transplantation to expand to regional centers across the country, particularly in the southeast. This proliferation of regional centers and the widening disparity between organ availability and numbers of recipients have created tremendous controversy at the national level regarding the allocation scheme used to distribute livers to recipients. The large programs today are advocating change to a national waiting list which would eliminate local priority and jeopardize the existence of smaller regional centers. Furthermore, the large programs favor establishing a limited number of megacenters where all liver transplants would take place, arguing that low volume centers cannot perform liver transplants with acceptable complication and survival rates. At the Regional Transplant Center of Willis-Knighton Hospital and Louisiana State University Medical Center in Shreveport (WK/LSUMC) we performed 122 liver transplants between July 1, 1991 and December 31, 1997. The purpose of this study was to examine our complication and survival rates and compare them to national averages. The actuarial graft survival at 1, 2, and 3 years in this series compared to the national average respectively was 76% and 70%, 66% and 66%, 62% and 62%. The actuarial patient survival (WK/LSUMC vs National) at 1, 2, and 3 years was 80% and 80%, 75% and 75%, 70% and 74%. The rate of retransplantation was 8% with a national average of 10% to 20%. Our rate of graft primary non-function was 5% with the national average being 2% to 10%. The rate of vascular thrombosis of the graft in this series was 2% with a national rate of 5%. The differences in these results were not statistically significant (P < .05). Low volume transplant centers can perform liver transplant successfully, allowing the regionalization of the treatment of choice for end-stage liver disease.

Actuarial Analysis↗

Therapeutic liver repopulation for the treatment of metabolic liver diseases.

Orthotopic liver transplantation is the treatment of choice for many inherited and acquired liver diseases. Unfortunately, the supply of donor organs is limiting and therefore many patients cannot benefit from this therapy. In contrast, hepatocyte suspensions can be isolated from a single donor liver can be transplanted into several hosts, and this procedure may help overcome the shortage in donor livers. In classic hepatocyte transplantation, however, only 1% of the liver mass or less can be replaced by donor cells. Recently though, we have used a mouse model of hereditary tyrosinemia to show that > 90% of host hepatocytes can be replaced by a small number of transplanted donor cells in a process we term "therapeutic liver repopulation". This phenomenon is analogous to repopulation of the hematopoietic system after bone marrow transplantation. Liver repopulation occurs when transplanted cells have a growth advantage in the setting of damage to recipient liver cells. Here we will review the current knowledge of this process and discuss the hopeful implications for treatment of liver diseases.

Animals↗

[Liver cirrhosis and liver cancer associated with viral hepatitis B and C in republic of Tatarstan].

Clinical and epidemiological data on 93 patients with liver cirrhosis, treated in the Gastroenterological Department of the Republican Clinical Hospital of the of the Republic of Tatarstan MoH in 1998-2000 were analyzed. The retrospective analysis of 856 cases of the liver cancer, diagnosed in the Republic of Tatarstan in 1996-2000, was made. In 20.4% of patients with liver cirrhosis and 16.2% of patients with liver cancer, registered in the Republic of Tatarstan, the serological markers of hepatitis B (HB) and hepatitis C (HC) were detected. The domination of HC markers was observed in the liver cirrhosis and that of HB markers in the cancer of the liver. The liver cirrhosis with HC markers was more often registered in the age group of 45-60 years and with HB markers at the age over 60 years, while the cancer of the liver was more often registered in persons aged 75 years and older. The necessity of introducing the official registration of the liver cirrhosis and cancer associated with chronic infection caused by hepatoviruses B and C is confirmed.

Adolescent↗

[Liver transection with the harmonic scalpel in elective liver surgery].

More procedures used in transection of the liver parenchyma include also resection by means of a harmonious scalpel with an enhanced haemostatic effect. Based on analysis of 51 patients operated on account of liver disease using a harmonious scalpel, the authors evaluate its asset to the liver resection technique. The harmonious scalpel was used in transection of the liver in seven patients with benign liver disease (inborn cysts, follicular nodular hyperplasia, haemangioma, hepatocellular adenoma) and in 44 with malignant disease (hepatocellular carcinoma, metastases, most frequently, i.e. 34x of colorectal carcinoma). Anatomical liver resection (hemihepatectomy, lateral bisegmentectomy, segmentectomy) was implemented in 34 patients, and in 17 a wedge-shaped resection. Transection of the parenchyma by a harmonious scalpel was made using 10 mm coagulation scissors, i.e. their blunt blade with a lower oscillation grade. The preoperative blood loss was from 30 to 300 ml. As to postoperative complications 2 patients developed cholascos, 2 fluidothorax, 1 respiratory failure and 2 early infection. Liver resection by means of a harmonious scalpel is a new method of parenchyma transection with adherence to the resection line without damage of the deeper structures, reducing preoperative haemorrhage and minimalizing the extent of resection in liver diseases with impaired regeneration of the parenchyma (cirrhosis). Liver transection by a harmonious scalpel is a safe method where it is essential to respect recommended technical parameters, incl. the necessary time.

Adult↗

[Anesthesia for living-donor liver transplantation in a patient with adult polycystic liver disease].

Anesthesia for living-donor liver transplantation (LDLT) was performed for two patients with adult polycystic liver disease (APLD). APLD is characterized by gradual cystic transformation of both lobes of the liver. Abdominal enlargement, poor appetite, abdominal pain, infection of liver cysts and portal hypertension are symptoms of this disease. Liver transplantation is indicated as the final therapy. Our two patients had very large livers (7400 g and 9500 g). The second patient had suffered renal failure due to a polycystic kidney so that continuous hemodiafiltration had to be performed after surgery. In both cases, sudden hypotension frequently occurred during manipulation of the enlarged liver. In the first case, sudden massive bleeding occurred as a result of laceration of the middle and left hepatic vein when the liver was dropped from the surgeon's hand. In both cases, the position of endotracheal tube became 2 cm shallower after surgery probably because of the shift in the position of the mediastinum after elimination of abdominal compression caused by the enlarged liver. One patient was discharged 39 days and the other 115 days after surgery. Anesthesiologists should pay special attention to the features reported here during LDLT for patients with APLD.

Anesthesia↗

Functional and non-functional liver blood flow in patients with liver cirrhosis measured by indocyanine green.

Indocyanine green administration was used in a group of ten patients with liver cirrhosis with portal hypertension to estimate hepatic extraction, liver blood flow and the degree of blood shunting. Extraction coefficients obtained by the hepatic catheterization were well correlated with the pharmacokinetic method. Values of the total liver blood flow measured by the classical method based on Fick's principle were always higher than those evaluated by the pharmacokinetic analysis estimating the functional liver blood flow only. Estimates of the degree of shunting varied between 32.0-78.9% of the total liver blood flow. A statistically significant correlation (r = 0.79) was found between the percentage of the functional fraction of the total liver blood flow and albuminemia. It is suggested that in liver cirrhosis with portal hypertension the reduction of the functional fraction of total liver blood flow is combined with partial impairment of hepatic cell metabolism in the remaining functional areas of the liver. In such a case neither the "intact" nor the "sick hepatocyte" hypotheses are appropriate in their strict sense for the interpretation of the findings.

Humans↗

[Relationship between NF-kappa B binding activity and expression of PPAR gamma-mRNA in the livers of rats with fatty liver disease].

OBJECTIVE: To investigate the changes of NF-kappa B binding activity, the expression of PPARr and their correlation in the liver of rats with fatty liver disease (FLD) induced by different pathogenic factors and to investigate the molecular mechanism of the inflammation in FLD. METHODS: 40 Wistar rats were randomly divided into 4 groups of ten each: normal group, alcohol group, fat-rich diet group, alcohol adding fat-rich diet group. The rats were sacrificed at the end of the 16th week from the starting day of the experiment. Serum and liver specimens were collected. Histological specimens were stained with HE, SudanIV, and Masson and then studied microscopically. The ultrastructural changes were also checked under an electron microscope. NF-kappa B binding activity and the expression of PPARr mRNA were determined by electrophoretic mobility shift assay (EMSA) and RT-PCR respectively. The correlations between NF-kappa B binding activity and the expression of PPARr and the biochemical indexes were analyzed. RESULTS: Steatosis, inflammation, necrosis and fibrosis were present in livers of the rats of all the experimental groups, and were most severe in the alcohol adding fat-rich diet group. NF-kappa B binding activity was markedly increased in the livers of the alcohol group (142+/-16.32) and of the alcohol adding fat-rich diet group (238+/-19.14) in comparison to the livers of the normal (73+/-9.24, F = 6.36, 17.93) and those of the fat-rich diet group (84+/-10.38, F = 5.96, 16.20). Binding activity was higher in the alcohol adding fat-rich diet group than that in the simple alcohol group, but there was no difference between those of the fat-rich diet and normal groups. The level of PPARr mRNA was lower in the livers of the alcohol, fat-rich diet, alcohol adding fat-rich diet groups (0.2530+/-0.069, 0.3647+/-0.082, 0.1226+/-0.054) than that of the controls (0.8097+/-0.094) (F = 15.43, 7.24, 21.45). NF-kappa B binding activity was correlated positively with the level of serum TNF alpha (r = 0.527, 0.639) and the content of MDA in the liver homogenates (r = 0.723, 0.537), but negatively with the expression of PPARr in the livers of the alcohol and the alcohol adding fat-rich diet groups (r = -0.568, -0.891). CONCLUSION: The enhanced nuclear factors NF-kappa B binding activity and decreased expression of PPARr play a pivotal role in the inflammatory response of FLD induced by alcohol and fat-rich diet. It may provide a new idea for treating FLD effectively.

Animals↗

[Changes in plasma vitronectin, fibronectin, and serum laminin P1 levels and immunohistochemical study of vitronectin in the liver of patients with chronic liver diseases].

Vitronectin (VN), fibronectin (FN) and laminin (LM), which are known to be important glycoproteins in cell attachment, are produced by such liver cells as hepatocytes, Kupffer cells endothelial cells and Ito cells. In this study, the levels of plasma VN, FN and serum LM P1 in patients with chronic hepatitis, liver cirrhosis and hepatocellular carcinoma accompanied with cirrhosis were examined and compared with those in normal subjects. Plasma VN levels in patients with chronic hepatitis, compensated cirrhosis and decompensated cirrhosis were less than that in normal subjects. As hepatic dysfunction deteriorated, plasma VN level decreased in chronic liver diseases. Plasma FN levels in patients with compensated and decompensated cirrhosis were also less than that of patients with chronic hepatitis, which was not significantly different from that of normal subjects. Plasma VN and FN levels in patients with hepatocellular carcinoma were similar to those in patients with compensated cirrhosis. Plasma VN and FN levels in patients with chronic liver diseases including hepatocellular carcinoma showed positive correlations with serum albumin content, cholinesterase activity, and normalized normo test value. On the other hand, serum LM P1 levels in patients with chronic hepatitis, compensated cirrhosis and decompensated cirrhosis were higher than that of normal subjects. As hepatic dysfunction deteriorated, serum LM P1 level increased in chronic liver diseases. Level of serum type IV collagen 7S, which is related to hepatic fibrosis, was similar to that of serum LM P1; serum LM P1 concentration in patients with chronic liver diseases showed a significant positive correlation with that of serum type IV collagen 7S. Immunolocalization of VN in liver tissue from patients with chronic hepatitis and cirrhosis was examined by the method of avidin-biotin-complex staining, and positive reaction was observed in enlarged portal tracts, central veins and fibrous septa. These results suggest that decreased levels of plasma VN and FN and increased level of serum LM P1 in patients with chronic liver diseases are related to hepatic dysfunction, and that changes in the levels of these glycoproteins involved in cell attachment are important in the development of hepatic fibrosis in patients with chronic liver diseases.

Adult↗