Biomedical subjects

Philip Hilgard

Publications and source records attributed to Philip Hilgard.

14 recordsLinked to original sources

PubMed2006

[Angiosarcoma of the liver as a rare cause of rapidly progressive liver failure].

BACKGROUND: Angiosarcoma of the liver is a rare, highly malignant and sometimes diffusely infiltrating vessel tumor with rapid progression and poor prognosis. CASE REPORT: A 46-year-old male patient with rapidly progressive liver failure, initially regarded as decompensation of known alcoholic liver cirrhosis, is reported. The patient was referred to the authors' center for evaluation of liver transplantation, but a massive weight loss despite long absence of any alcohol intake raised the suspicion of a malignant disease. The abdominal ultrasound examination showed a massive hepatomegaly with an extremely inhomogeneous echo structure as well as moderate ascites. A following MRI demonstrated diffuse focal contrast enhancement in the entire liver parenchyma, confirming diffuse infiltration of the organ by a malignant tumor. In addition, MRI was suspicious of bone metastases. The usual tumor markers were normal. Sonographically guided percutaneous liver biopsy established the diagnosis of a malignant vascular tumor with diffuse infiltration of the liver parenchyma. 3 days later the patient died of uncontrollable bleeding from esophageal varices. Macroscopic examination of the liver during autopsy showed multiple lacunae filled with blood. Therefore, the differential diagnosis of a peliosis hepatis was raised. However, histology confirmed the diagnosis of a malignant angiosarcoma with diffuse osseous metastases. CONCLUSION: A diffuse infiltration of the liver by an angiosarcoma in the absence of any definite lesions may lead to a substantial delay of the diagnosis. The only relevant differential diagnosis in this case is the equally rare peliosis hepatis.

Biopsy↗

PubMed2006

Cyclosporine versus tacrolimus in patients with HCV infection after liver transplantation: effects on virus replication and recurrent hepatitis.

AIM: To determine the effects of the calcineurin inhibitors, cyclosporine and tacrolimus, on hepatitis C virus (HCV) replication and activity of recurrent hepatitis C in patients post liver transplantation. METHODS: The data of a cohort of 107 patients who received liver transplantation for HCV-associated liver cirrhosis between 1999 and 2003 in our center were retrospectively analyzed. The level of serum HCV-RNA and the activity of recurrent hepatitis were compared between 47 patients who received either cyclosporine or tacrolimus as the primary immunosuppressive agent and an otherwise similar immunosuppressive regimen which did not lead to biliary complications within the first 12 mo after transplantation. RESULTS: HCV-RNA increased within 3 mo after transplantation but the differences between the cyclosporine group and the tacrolimus group were insignificant (P=0.49 at 12 mo). In addition, recurrent hepatitis as determined by serum transaminases and histological grading of portal inflammation and fibrosis showed no significant difference after 12 mo (P=0.34). CONCLUSION: Cyclosporine or tacrolimus as a primary immunosuppressive agent does not influence the induction or severity of recurrent hepatitis in HCV-infected patients after liver transplantation.

Adult↗

PubMed2006

Balloon dilatation vs. balloon dilatation plus bile duct endoprostheses for treatment of anastomotic biliary strictures after liver transplantation.

Biliary strictures after liver transplantation are a therapeutic challenge for endoscopy. Anastomotic strictures occur in 10% of patients after liver transplantation, leading untreated to mortality and ultimately to graft failure. Despite of successful reports, to date, there is no defined endoscopic therapy regimen for these cases. Therefore the aim of this study was to determine the most suitable concept for endoscopic treatment of post-liver transplant anastomotic strictures (PTAS). A total of 72 patients post-liver transplantation, who received endoscopic retrograde cholangiography (ERC) as a consequence of suspected biliary complications were retrospectively screened for the presence of PTAS. In all patients graft rejection or bile duct ischemia were excluded prior to ERC by liver biopsy or Doppler ultrasound respectively. We compared either balloon dilatation (BD) alone or dilatation plus placement of an increasing number of bile duct endoprostheses (BD + endoprostheses) in a retrospective analysis. A total of 25 of 75 patients showed PTAS. Overall, endoscopic therapy was successful in 22 of 25 patients (88%). BD was initially successful in 89% but showed recurrence in 62%. BD + endoprostheses was initially successful in 87%, and recurrence was observed only in 31%. All recurrences were successfully retreated by BD + endoprostheses. During 22 of 109 (20%) treatment sessions stone extraction was necessary. Complication rate was low with bacterial cholangitis in 8 of 109 (7.3%) sessions, mild pancreatitis in 10 of 109 (9%) sessions and minor bleeding in 2 of 25 (8%) sphincterotomies. Median follow-up after conclusion of endoscopic therapy is 6 months (range 1-43). In conclusion, our data confirm that endoscopic therapy of PTAS is highly effective and safe. As primarily successful BD shows a high rate of recurrence, we recommend a combination of BD followed by an increasing number and diameter of endoprostheses. Therapy sessions are effective at short intervals of every 2-3 months.

Adult↗

PubMed2005

Diagnosis of biliary strictures after liver transplantation: which is the best tool?

AIM: To evaluate the diagnostic value of different indirect methods like biochemical parameters, ultrasound (US) analysis, CT-scan and MRI/MRCP in comparison with endoscopic retrograde cholangiography (ERC), for diagnosis of biliary complications after liver transplantation. METHODS: In 75 patients after liver transplantation, who received ERC due to suspected biliary complications, the result of the cholangiography was compared to the results of indirect imaging methods performed prior to ERC. The cholangiography showed no biliary stenosis (NoST) in 25 patients, AST in 27 and ITBL in 23 patients. RESULTS: Biliary congestion as a result of AST was detected with a sensitivity of 68.4% in US analysis (specificity 91%), of 71% in MRI (specificity 25%) and of 40% in CT (specificity 57.1%). In ITBL, biliary congestion was detected with a sensitivity of 58.8% in the US, 88.9% in MRI and of 83.3% in CT. However, as anastomotic or ischemic stenoses were the underlying cause of biliary congestion, the sensitivity of detection was very low. In MRI detected the dominant stenosis at a correct localization in 22% and CT in 10%, while US failed completely. The biochemical parameters, showed no significant difference in bilirubin (median 5.7; 4,1; 2.5 mg/dL), alkaline phosphatase (median 360; 339; 527 U/L) or gamma glutamyl transferase (median 277; 220; 239 U/L) levels between NoST, AST and ITBL. CONCLUSION: Our data confirm that indirect imaging methods to date cannot replace direct cholangiography for diagnosis of post transplant biliary stenoses. However MRI may have the potential to complement or precede imaging by cholangiography. Optimized MRCP-processing might further improve the diagnostic impact of this method.

Adult↗

PubMed2005

Controlled and reversible induction of differentiation and activation of adult human hepatocytes by a biphasic culture technique.

AIM: Clinical application of human hepatocytes (HC) is hampered by the progressive loss of growth and differentiation in vitro. The object of the study was to evaluate the effect of a biphasic culture technique on expression and activation of growth factor receptors and differentiation of human adult HC. METHODS: Isolated HC were sequentially cultured in a hormone enriched differentiation medium (DM) containing nicotinamide, insulin, transferrin, selenium, and dexame-thasone or activation medium (AM) containing hepatocyte growth factor (HGF), epidermal growth factor (EGF), and granulocyte-macrophage colony-stimulating factor (GM-CSF). Expression, distribution and activation of the HC receptors (MET and EGFR) and the pattern of characteristic cytokeratin (CK) filaments were measured by fluorometry, confocal microscopy and Western blotting. RESULTS: In the biphasic culture system, HC underwent repeated cycles of activation (characterized by expression and activation of growth factor receptors) and re-differentiation (illustrated by distribution of typical filaments CK-18 but low or absent expression of CK-19). In AM increased expression of MET and EGFR was associated with receptor translocation into the cytoplasm and induction of atypical CK-19. In DM low expression of MET and EGFR was localized on the cell membrane and CK-19 was reduced. Receptor phosphorylation required embedding of HC in collagen type I gel. CONCLUSION: Control and reversible modulation of growth factor receptor activation of mature human HC can be accomplished in vitro, when defined signals from the extracellular matrix and sequential growth stimuli are provided. The biphasic technique helps overcome de-differentiation, which occurs during continuous stimulation by means of growth factors.

Adult↗

PubMed2005

Liver cirrhosis as a consequence of iron overload caused by hereditary nonspherocytic hemolytic anemia.

Nonspherocytic hereditary anemias are occasionally accompanied by significant iron overload but the significance for the development of chronic liver disease is not clear. We described two cases of patients with chronic liver disease and severe iron overload due to chronic hereditary hemolysis. Both patients have had signs of liver cirrhosis and severe hemolysis since childhood. A hereditary pyruvate kinase deficiency (PKD) was discovered as the underlying reason for the hemolysis. Sequencing of the pyruvate kinase gene showed a mutation within exon 11. Liver histology in both patients revealed cirrhosis and a severe iron overload but primary hemochromatosis was excluded by HFE-gene analysis. An iron reduction therapy with desferrioxamine led to significant decrease of serum ferritin and sustained clinical improvement. PKD-induced hemolysis may cause severe iron overload even in the absence of HFE-genotype abnormalities. This secondary iron overload can lead to chronic liver disease and cirrhosis. Therefore, the iron metabolism of PKD patients has to be closely monitored and iron overload should be consequently treated.

Anemia, Hemolytic, Congenital Nonspherocytic↗

PubMed2005

Preservation of the synthetic and metabolic capacity of isolated human hepatocytes by coculture with human biliary epithelial cells.

Bioartificial liver support systems have demonstrated limited efficacy in compensation of liver detoxification and substitution of liver-derived factors. However, in these devices, the biological substitution of the complex liver function has been restricted to xenogeneic or transformed hepatocytes. Therefore, we have examined the long-term effect of coculturing normal human hepatocytes (HCs) with allogeneic biliary epithelial cells (BECs). We applied functional in vitro assays to examine their metabolic potential by ammonia detoxification to urea, cytochrome P450-dependent lignocaine conversion to mono-ethyl-glycine-xylidide (MEGX), and protein expression and secretion. As the liver has a pivotal role in the synthesis of coagulation factors, we measured antithrombin III (AT III), factor VII, and albumin, comparing HCs plated on collagen or inside 3-dimensional collagen gels. Over 30 days, expression and secretion of albumin and clotting factors by human HCs were augmented by culture inside collagen gel, but were also enhanced and better maintained by coculture with BECs. Higher proportions of BECs cocultured with HCs substantially increased the protein synthesis and urea production. Remarkably, the almost absent cytochrome P450 activity of HC alone after 1 week could be reversed and maintained over 3 weeks by coculture with BECs. The pattern of these effects differed from the extent of interleukin-6 (IL-6) production and HC viability under the compared conditions. In conclusion, coculture of human HCs with BECs impressively restores the synthetic and metabolic liver function in vitro. These results suggest mechanisms of improved liver epithelial differentiation supported by coculture conditions. This technique offers new perspectives in bioartificial liver support, hepatocyte transplantation, and stem cell differentiation.

Bile Ducts↗

PubMed2005

Endoscopic therapy of posttransplant biliary stenoses after right-sided adult living donor liver transplantation.

BACKGROUND & AIMS: Endoscopic treatment of biliary strictures after liver transplantation is a therapeutic challenge. In particular, outcomes of endoscopic therapy of biliary complications in the case of duct-to-duct anastomosis after living related liver transplantation are limited. The aim of this study was to evaluate the feasibility and success of an endoscopic treatment approach to posttransplant biliary strictures (PTBS) after right-sided living donor liver transplantation (RLDLT) with duct-to-duct anastomosis. METHODS: Ninety patients who received adult-to-adult RLDLT in our center were screened retrospectively with respect to endoscopic treatment of PTBS. Therapy was judged as successful when cholestasis parameters returned to normal and bile duct narrowing was reduced significantly after the completion of therapy. RESULTS: Forty of 90 RLDLT patients received duct-to-duct anastomosis, 12 (30%) showed PTBS. Seven of 12 patients were treated successfully by endoscopy; the remaining 5 patients were treated primarily by surgery. Most patients were treated by balloon dilatation followed by insertion of endoprostheses. A median of 2.5 dilatation sessions were necessary and the median treatment duration was 8 months. One patient developed endoscopy-treatable recurrent stenosis, no surgical intervention was necessary. Mild pancreatitis occurred in 7.9% and cholangitis in 5.3% of the procedures. One minor bleeding episode occurred during sphincterotomy. Bleeding was managed endoscopically. CONCLUSIONS: Endoscopic therapy of adult-to-adult right living related liver transplantation with duct-to-duct anastomosis is feasible and frequently is successful. The duct-to-duct anastomosis offers the possibility of endoscopic treatment. Endoscopic treatment of posttransplant biliary strictures is safe, with a low specific complication rate.

Catheterization↗

PubMed2004

[Hepatic encephalopathy].

Hepatic encephalopathy (HE) may develop within the course of acute or chronic liver failure and is characterized by a complex of psychomotor symptoms. In addition, HE can be induced by portocaval shunting even in the absence of any apparent liver disease. HE is caused by substances, which are either reabsorbed from the gut or are a product of the body metabolism. Normally, these substances are effectively eliminated during their first passage through the liver. However, a decreasing number of functional hepatocytes or the presence of portocaval collaterals in liver disease may significantly impair hepatic detoxification. Ammonia seems to take a central position in the pathogenesis of HE, although the exact cerebral effects of this metabolite are still not known in detail. The actual pathogenetic hypotheses are subject of this review. Depending on the underlying liver disease, HE is divided into an acute and a chronic form. Chronic HE may be present as a persistent or an episodic form, the latter being usually induced by defined precipitating factors, such as diet failures, infection and gastrointestinal-bleeding. With regard to the psychomotor symptoms and the coma depth, the clinical picture is classified into five grades (West Haven criteria). Diagnosis is made by clinical examination of the mental status after relevant differential diagnoses have been excluded. The only causal therapeutic option in the presence of acute or chronic liver failure is liver transplantation. Therefore, the indication for transplantation has to be evaluated in all forms of HE. Symptomatic treatment has three principal aims: (1) stabilization of circulation, oxygen supply, blood sugar and nutrition; (2) identification of the precipitating factor and its removal; (3) reduction of ammonia and other potential toxins in the circulation. In the case of acute HE, these therapeutic aims are complemented by an effective prophylaxis or therapy of brain edema.

Animals↗

PubMed2004

Proapoptotic function of protein kinase CK2alpha" is mediated by a JNK signaling cascade.

Protein kinase CK2 (formerly casein kinase II) is a tetrameric enzyme constitutively expressed in all eurakyotic tissues that plays a significant role in the regulation of cell proliferation, malignant transformation, and apoptosis. The catalytic alpha-subunit of the enzyme is known to exist in three isoforms CK2alpha, CK2alpha' and CK2alpha". CK2alpha" is highly expressed in liver compared with other tissues and is required for the normal trafficking of several hepatocellular membrane proteins. Initial studies of dengue virus infection indicated that the CK2alpha"-deficient membrane trafficking mutant cell line (Trf1) was resistant to virus-induced cell death compared with the parental human hepatoma (HuH)-7 hepatoma line. Expression of recombinant CK2alpha" in Trf1 was capable of reverting this resistant phenotype. This study was extended to TNF-alpha in addition to other stimuli of cell death in an attempt to uncover common death pathways that might be modulated by CK2alpha". Evaluation of different pathways involved in death signaling suggest that the regulation of a critical proapoptotic step in HuH-7 cells by CK2alpha" is mediated by a JNK signaling cascade.

Apoptosis↗

PubMed2004

Asialoglycoprotein receptor facilitates hemolysis in patients with alcoholic liver cirrhosis.

Hemolysis in patients with advanced alcoholic liver disease is a common clinical problem and indicates an unfavorable prognosis. In many cases, the etiology of the hemolysis remains unknown. We observed three patients with alcoholic liver disease, suffering from severe hemolytic anemia, requiring multiple blood transfusions. Steroid therapy was ineffective and two of the patients died. All patients had a soluble variant of the human asialoglycoprotein receptor (s-ASGP-R) in their serum, as well as high titers of autoantibodies against this receptor (anti-ASGP-R). Consecutively, examination of 60 patients with alcoholic liver disease revealed a high incidence for s-ASGP-R (36%) and anti-ASGP-R (27%) in patients with alcoholic liver cirrhosis (ALC) compared to patients with cirrhosis due to viral hepatitis. The potential etiology of hemolysis was studied in vitro on erythrocytes from patients with ALC and from healthy donors. Isolated ASGP-R but not anti-ASGP-R bound to the surface of erythrocytes preferentially of blood group A1 and caused dose-dependent agglutination and hemolysis, while this phenomenon was much lower using erythrocytes of the blood group B and almost absent with blood group O-erythrocytes. Furthermore, agglutination and hemolysis only occurred in erythrocytes from ALC-patients or after the pre-treatment of cells with neuraminidase. ASGP-R induced agglutination and hemolysis was blocked by the competitive ASGP-R inhibitor asialofetuin. In conclusion, our results indicate a new, non-immunological mechanism for hemolysis in patients with alcoholic liver disease, mediated through agglutination by a soluble variant of the human asialoglycoprotein receptor and mechanical shear stress.

Agglutination Tests↗

PubMed2002

Translated Alu sequence determines nuclear localization of a novel catalytic subunit of casein kinase 2.

Casein kinase 2 (CK2) is a tetrameric enzyme constitutively expressed in all eukaryotic tissues. The two known isoforms of the catalytic subunit, CK2alpha and CK2alpha', have been reported to have distinct tissue-dependent subcellular distributions. We recently described a third isoform of the catalytic subunit, designated CK2alpha", which is highly expressed in liver. Immunoblot analysis of HuH-7 human hepatoma cell fractions as well as immunofluorescent microscopy revealed that CK2alpha" was exclusively localized to the nucleus and preferentially associated with the nuclear matrix. CK2alpha and CK2alpha' were found in nuclear, membrane, and cytosolic compartments. Deletion of the carboxy-terminal 32 amino acids from the CK2alpha" sequence resulted in release of the truncated green fluorescent protein fusion protein from the nuclear matrix and redistribution to both the nucleus and the cytoplasm. Demonstration that the carboxy terminus is necessary but not sufficient for nuclear retention indicates that the underlying mechanism of CK2alpha" nuclear localization is dependent on the secondary structure of the holoenzyme directed by the carboxy-terminal sequence.

Active Transport, Cell Nucleus↗

PubMedDate not supplied

Cryoglobulin-associated uptake of hepatitis C virus into human hepatocytes.

AIMS: The mechanisms of binding and uptake of hepatitis C-virus (HCV) are critical determinants of the infection-reinfection cycle but due to ongoing absence of a robust cell culture system, these mechanisms are still largely hypothetical. Cryoglobulins are atypical immunoglobulins, present in 40% of HCV patients. The aim of this study was to determine the role of these HCV-containing cryoglobulins as carrier molecules for viral uptake into primary human hepatocytes. METHODOLOGY: Cryoglobulins were precipitated from serum of chronically HCV-infected patients, labeled with biotin and incubated with freshly prepared hepatocytes from human liver tissue. Binding and endocytosis of HCV-cryoglobulins were studied by specific assays, ligand blot analysis and electron microscopy on hepatocellar plasma membranes. RESULTS: Biotinylated HCV-cryoglobulins specifically bound to hepatocytes and inhibitors of homotypic endosomal fusion reduced their uptake and intracellular trafficking, Ligand-blot and electron microscopy analysis revealed adhesion to hepatocellular plasma membranes. Inoculation of human hepatocytes with HCV-cryoglobulins but not serum from the same patients induced HCV infection in vitro. CONCLUSIONS: HCV may enter hepatocytes in conjunction with cryoglobulins via immunoglobulin or related receptors. We hypothesize, that this mechanism plays a role in chronic hepatitis to support the infection-reinfection cycle of the virus.

Aged↗

PubMedDate not supplied

Resectability of hepatocellular carcinoma: evaluation of 333 consecutive cases at a single hepatobiliary specialty center and systematic review of the literature.

BACKGROUND/AIMS: To determine resectability rates in patients with hepatocellular carcinoma (HCC) evaluated for surgical therapy. Liver resection constitutes a potentially curative treatment for HCC. However, because of the co-existing cirrhosis or the late diagnosis, only a percentage of the patients evaluated can undergo surgery. METHODOLOGY: We evaluated 333 patients with HCC admitted to our center with the intent to treat by means of tumor resection during a 6-year time period. RESULTS: Surgical resection with curative intent was undertaken in 116 patients (35%). In our series, resectability rates were significantly higher in patients with solitary HCCs (p<0.001), unilobar tumor distribution (p=0.03), and no cirrhosis (p <0.001). Transarterial chemoembolization (TACE) was the most frequent approach for nonresectable cases (18% of patients). A systematic literature review was performed in order to estimate resectability rates at other hepatobiliary centers offering multimodal treatment approaches to HCC. Results showed an overall resectability rate of 30%, with 1808 resections reported in 6108 cases. Resectability rates were significantly higher in Japanese and Eastern series when compared to American and Western studies respectively (p<0.001). CONCLUSIONS: Treatment strategies for HCC require a multidisciplinary comprehensive approach encompassing surgeons, hepatologists, radiologists, and oncologists. Surgical resection was possible in only 35% and 30% of patients with HCC evaluated for surgical therapy in our series and in the world literature, respectively. TACE was the primary treatment modality for non-resectable cases. A "no therapy" option was chosen in 21% of cases worldwide.

Carcinoma, Hepatocellular↗