Hepatocellular Dysfunction Research Articles

Hydrogel-embedded endothelial progenitor cells evade LPS and mitigate endotoxemia.

Sepsis and its complications are associated with poor clinical outcomes. The circulatory system is a well-known target of lipopolysaccharide (LPS). Recently, several clinical studies documented mobilization of endothelial progenitor cells (EPCs) during endotoxemia, with the probability of patients' survival correlating with the rise in circulating EPCs. This fact combined with endotoxemia-induced vascular injury led us to hypothesize that the developing functional EPC incompetence could impede vascular repair and that adoptive transfer of EPCs could improve hemodynamics in endotoxemia. We used LPS injection to model endotoxemia. EPCs isolated from endotoxemic mice exhibited impaired clonogenic potential and LPS exerted Toll-like receptor 4-mediated cytotoxic effects toward EPCs, which was mitigated by embedding them in hyaluronic acid (HA) hydrogels. Therefore, intact EPCs were either delivered intravenously or embedded within pronectin-coated HA hydrogels. Adoptive transfer of EPCs in LPS-injected mice improved control of blood pressure and reduced hepatocellular and renal dysfunction. Specifically, EPC treatment was associated with the restoration of renal microcirculation and improved renal function. EPC therapy was most efficient when cells were delivered embedded in HA hydrogel. These findings establish major therapeutic benefits of adoptive transfer of EPCs, especially when embedded in HA hydrogels, in mice with LPS-induced endotoxemia, and they argue that hemodynamic and renal abnormalities of endotoxemia are in significant part due to developing incompetence of endogenous EPCs.

Markedly Elevated Serum Transaminases in Glycogen Storage Disease Type III

Glycogen storage disease type III (GSD III) is an autosomal recessive metabolic disorder that is caused by the deficiency of the glycogen-debranching enzyme. Presenting problems often include hepatomegaly, elevated transaminases, hyperlipidemia, mild hypoglycemia, and failure to thrive. We describe a patient who developed marked elevation in serum transaminases (alanine aminotransferase [ALT] > 2000 IU/L), without evidence of significant hepatocellular necrosis or liver dysfunction. A 17-month-old girl presented to our emergency department with acute vomiting and diarrhea. Physical examination revealed hepatosplenomegaly (liver and spleen 6 and 2 cm below the costal margins, respectively). Her weight and height were at the 75th percentile. Laboratory tests showed elevated transaminases: ALT 408 IU/L (reference range <40 IU/L), aspartate aminotransferase (AST) 328 IU/L (reference range <40 IU/L), gamma-glutamyl transpeptidase (gGTP) 53 IU/L (reference range 8–78 IU/L), and total bilirubin 0.3 mg/dL (reference range <1.0 mg/dL). Initial workup revealed unremarkable acetaminophen level, creatine phosphokinase (CPK), coagulation studies, hepatitis virus panel, thyroid function tests, ceruloplasmin, α-1 antitrypsin phenotype, auto-immune studies, and liver ultrasound. Although the symptoms of acute gastroenteritis improved, her transaminases remained elevated. Additional history revealed that the patient had episodes of shakiness, crankiness, and vomiting in the morning before eating breakfast. Fasting laboratory studies revealed hypoglycemia (glucose 55 mg/dL [reference range 70–110 mg/dL] and hyperlipidemia (triglyceride 316 mg/dL [reference range 28–153 mg/dL] and cholesterol 188 mg/dL [reference range 75–200]). Given the clinical picture, a suspicion for GSD III arose, so genetic studies of peripheral blood DNA were undertaken. Although genetic studies were pending, the patient experienced a sudden spike in transaminases on routine testing (ALT 2104 IU/L, AST 1441 IU/L) without any signs of illness or other laboratory abnormalities (total bilirubin 0.5 mg/dL, direct bilirubin 0.2 mg/dL (0.1–0.4), gGTP 142 IU/L, prothrombin time 12.6 seconds (11.5–16.1 seconds), albumin 4.2 g/dL (3.8–5.4 g/dL), and CPK 71 IU/L (29–168 IU/L). A liver biopsy was performed to exclude other etiologies aside from GSD III for this elevation of transaminases. The biopsy revealed enlarged hepatocytes with abundant glycogen-rich material (Fig. 1), and enzymatic analysis of liver tissue revealed absent debranching enzyme activity (0 μmol/min/g tissue [control 0.31 ± 0.1 μmol/min/g tissue]), supporting the diagnosis of GSD III. Of note, there was minimal evidence of hepatocellular injury or inflammation. Subsequently, genetic studies revealed heterozygous mutations in the amylo-1,6-glucosidase (AGL) gene, including a nonsense mutation, c.2590C>T (R864X), previously reported to be causative for GSD type III (1–3), and a potentially pathological missense mutation in a highly conserved tyrosine residue, c.1484A>G (Y495C), not previously associated with GSD type III. During the ensuing 2 years, her serum transaminase levels remained elevated between 300 and 500 IU/L (Fig. 2). Her other biochemical markers of liver disease have remained unremarkable, and she has not developed any clinical stigmata of advanced liver disease. FIGURE 1 Microscopic appearance of GSD III. Left, The hepatocytes are plant-like with clear cytoplasm and prominent cell membranes. The nuclei are small and uniform. Scattered glycogenated nuclei are seen. No cholestasis or significant inflammation is present ... FIGURE 2 Clinical course of GSD III. Serum transaminase levels over time are shown.

Outcomes of patients with cystic fibrosis undergoing lung transplantation with and without cystic fibrosis‐associated liver cirrhosis*

People with severe cystic fibrosis (CF) lung disease with co-existent CF-associated liver disease (CFLD) are often excluded from consideration of sole lung transplantation, largely because of the concerns that they will subsequently develop hepatic decompensation. This retrospective cohort study aimed at determining whether patients with severe cirrhosis caused by CFLD have any differences in perioperative and relevant post-transplant outcomes compared to CF patients without CFLD when undergoing sole lung transplantation. Six patients with CFLD were matched with 18 CF patients without CFLD undergoing sole lung transplant at the same institution. There were no differences in total operative time or intra-operative requirements for cardiopulmonary bypass or blood products. Over a period of five yr post-transplant, no differences were observed between the two groups in body mass index, six-min walk, lung function, and survival. None of the CFLD subjects developed variceal bleeding; however, one developed hepatocellular and renal failure at four yr post-transplant and is being assessed for liver-kidney transplant. One additional patient with CFLD required repeat lung transplantation for bronchiolitis obliterans syndrome. This study provides evidence that CF patients with liver cirrhosis caused by CFLD can safely be considered for sole lung transplantation provided there is no evidence of significant hepatocellular dysfunction with decompensated cirrhosis or hepatic synthetic failure.

Insulin-like growth factor-I and the liver

Insulin-like growth factors (IGFs) play an essential role in growth and development, as well as in the overall cellular regulation and metabolism in the human body. In chronic liver disease, IGF levels are decreased, and the circulating levels correlate to the extent of hepatocellular dysfunction. Patients with cirrhosis are characterised by a variety of metabolic disturbances, including nutritional and metabolic complications such as insulin resistance, malnutrition, osteopenia and hypogonadism, all related to IGF-I deficiency. The complex process of hepatic fibrogenesis and the systemic consequences in cirrhosis are only partly understood. Disruption of the growth hormone (GH)-IGF-I axis seems to be closely associated with the development of liver disease, and treatment with recombinant human IGF (rhIGF)-I has been shown to halt, and even reverse, the fibrotic degeneration. IGF-I in itself has a strong antifibrotic effect that acts directly through the GH/IGF system and indirectly by the regulation of hepatoprotective and profibrogenic factors. It is most likely that IGF-I deficiency contributes to the diverse metabolic complications of cirrhosis. At present, liver transplantation remains the only efficient treatment of cirrhosis, and thus new methods of managing the disease are called for. RhIGF-I supplementation and IGF-I gene therapy may represent future perspectives of treatment.

Hepatocyte growth factor and chronic hepatitis C

The hepatocyte growth factor (HGF) is a pleiotropic cytokine produced by hepatic stellate cells and implicated in liver regeneration and fibrosis. Serum levels of HGF vary in liver diseases, reflecting hepatic damage and hepatocellular dysfunction. In this study, serum levels of HGF and the relationship between HGF and biochemical, histological and virological data, have been analysed in patients suffering from chronic hepatitis C (CHC). Serum HGF concentration was measured by ELISA in sandwich in 45 patients with CHC. Correlation between HGF levels and histological (necroinflammatory activity and fibrosis score) and biochemical (transaminases, prothrombin activity, albumin, bilirubin), or virological (hepatitis C virus load) parameters was analyzed. Serum HGF concentration was also studied in a subgroup of the original sample treated with interferon and ribavirin. Sserum HGF concentrations of patients with CHC were significantly higher than those detected in healthy controls. Patients with significant fibrosis (F > or = 2) had a significantly older age, lower count of platelets and higher values of AST, GGT and HGF, than those patients with a fibrosis score F < 2. HGF concentration was identified by multivariate analysis as the only independent factor associated with significant fibrosis. Moreover, area under receiver operating curve, using HCG levels, showed similar values to those of previously validated non-invasive indexes of fibrosis. However, levels of HGF did not show a significant decrease in patients with a sustained response to anti-virus C therapy. Serum HGF concentration correlates with fibrosis score in patients with CHC, but is insensitive to monitor changes induced by anti-virus C therapy.

Alpha-1 Antitrypsin Deficiency Identification and Management: It is the Team More than the Genes

Alpha-1 antitrypsin deficiency (AATD) is an important cause of premature emphysema, infantile jaundice accompanied by hepatocellular dysfunction, and liver disease throughout adult life. Since its ...

Of Guinea Pigs and Men – an Unusual Case of Jaundice

A 21-year-old male presented at the emergency room with jaundice, itching, dry cough, malaise and weight loss of 10 kg during the preceding four weeks. Eighteen months earlier, the patient had suffered an automobile accident leading to polytrauma. Serological markers for viral or other causes of hepatitis were absent. For suspected secondary sclerosing cholangitis, ultrasound and ERCP were performed but failed to reveal pathological findings. A liver biopsy showed cholestatic liver disease without signs of portal field-associated hepatitis. Hepato-biliary scintigraphy demonstrated hepatocellular dysfunction. The patient finally mentioned his guinea pig farm with around 50 animals, 20 of which had recently died for unknown reasons. The patient and three of his guinea pigs were subsequently tested for serological evidence of leptospirosis. IgG and IgM antibodies reacting with Leptospira interrogans were detected in the patient's serum, and all 3 guinea pigs were serologically positive for serovar Bratislava. Bacterial culture was not successful, and also PCR tests remained negative. The clinical symptoms quickly resolved after the initiation of antibiotic therapy with amoxicillin.

Hepatocellular carcinoma: prevalence and molecular pathogenesis of Helicobacter spp.

Helicobacter pylori infection is one of the most common chronic bacterial infections in humans. The association of other Helicobacter spp. with extragastric diseases in animals is well established, and a role of these bacteria in human liver disease is becoming clearer. Several case-control studies have reported possible associations of Helicobacter spp. with various liver diseases, including hepatocellular carcinoma, which is the fifth most common type of carcinoma among men worldwide, and the eighth most common among women. Thus, it is important to understand molecular mechanisms that may lead to hepatotoxicity or hepatocellular dysfunction in which Helicobacter spp. may play a role in inducing malignant transformation of liver cells.

The inhibitory effect of ghrelin on sepsis-induced inflammation is mediated by the MAPK phosphatase-1

Hepatocellular dysfunction occurs early in sepsis and this appears to be caused by Kupffer cell-derived TNF-alpha production from the liver as a result of the increased release of the sympathetic neurotransmitter, norepinephrine, from the gut. Ghrelin, a novel stomach-derived peptide, is down-regulated in sepsis and administration of ghrelin into rodents decrease pro-inflammatory cytokines, attenuates hepatic and other organ injuries and improves survival. Ghrelin's beneficial effect in sepsis is mediated by the inhibition of the sympathetic nervous system (SNS), as evidenced by the reduced gut-derived norepineprine (NE) release in sepsis after ghrelin treatment. Recent data suggest that MKP-1, the MAPK phosphatase-1, is involved in the innate immune responses. To determine that the beneficial effect of ghrelin in sepsis is mediated by MKP-1, rats were subjected to sepsis by cecal ligation and puncture (CLP) alone, or treated with ghrelin, beginning at 5-h post-CLP and liver tissues were harvested and examined for MKP-1 mRNA and protein expression. CLP alone produced a significant decrease in MKP-1 gene expression in liver tissues at 20 h after CLP (P<0.05). MKP-1 mRNA was decreased by 30-40% at 2 and 5 h after CLP, but not statistically significant. MKP-1 protein expression was significantly decreased as early as 2 h after CLP and remained low at 5-20 h after CLP. While septic rats treated with vehicle produced significant decreases from sham rats, ghrelin treatment improved both mRNA and protein from vehicle group (0.58+/-0.069 vs. 0.91+/-0.16, P<0.05; 0.14+/-0.027 vs. 0.22+/-0.017, P=0.013), respectively. Since ghrelin's inhibitory effect is mediated by the SNS, we hypothesized that NE treatment in Kupffer cells may downregulate MKP-1. Kupffer cells were treated with NE and examined for MKP-1. Treatment with NE for 60 min showed an average of 46.9% decrease in MKP-1 mRNA expression compared to untreated cells (P<0.001). Likewise, NE treatment in RAW264.7 cells produced significantly lower MKP-1 mRNA than that of control cells. To further confirm the effect of NE on MKP-1, normal rats were infused with NE for 2 h through the portal vein and MKP-1 mRNA from the liver was examined. Infusion with NE produced a significant 73.7% decrease in MKP-1 mRNA. Therefore, ghrelin's inhibitory effect on gut-derived NE release in sepsis leading to the downregulation of pro-inflammatory cytokines is mediated by MKP-1.

Effect of polymyxin B-immobilized fiber hemoperfusion on respiratory impairment, hepatocellular dysfunction, and leucopenia in a neonatal sepsis model

Sepsis and septic shock remain a major source of morbidity and mortality in neonates despite advances in antimicrobials and aggressive supportive care. Our aim was to study the effects of polymyxin-B direct hemoperfusion (PMX-DHP) therapy on sepsis-induced respiratory impairment, liver dysfunction and leucopenia in a neonatal cecal ligation and perforation (CLP) model. Fourteen anesthetized and mechanically ventilated 3-day-old piglets underwent CLP and an arteriovenous extracorporeal circuit from 3 h until 6 h post-CLP, with a PMX column in the PMX-DHP treated group (7 piglets). Changes in oxygen saturation, PCO(2), base excess, white blood cell (WBC) count, platelet count, hematocrit (Hct%), serum glutamate pyruvate transaminase (SGPT), and serum glutamic oxaloacetic transaminase were measured before CLP and at 1, 3 and 6 h after. At 6 h, the PMX-DHP group showed lower Hct%, and SGPT in comparison to the control group, but higher oxygen saturation and WBC count. No effects on the platelet count were found. The survival times of the PMX-DHP group were longer than in control. PMX-DHP therapy limited the respiratory impairment, liver dysfunction and leucopenia in a neonatal septic model, which resulted in an improvement of survival time.

An Unusual Cause of Fulminant Liver Failure

Purpose: Amyloidosis is a disorder of fibrillary protein deposition in various organ systems and it may be primary (AL) or secondary (AA). Primary amyloidosis can occur alone or in association with plasma cell dyscrasias such as multiple myeloma. Involvement of the liver has been reported in up to 70% of cases with AL amyloidosis. Fulminant liver failure is characterized by rapid development of hepatocellular dysfunction and encephalopathy in a patient with no prior history of liver disease. We report a case of fulminant liver failure due to amyloidosis in the setting of multiple myeloma. A 66-year-old white male with a 50-pack-year history of smoking presented with shortness of breath, atrial fibrillation, and hypotension. His past medical history consisted of hypertension, hyperlipidemia and benign prostatic hypertrophy. Two months prior he had been told of a mild elevation in his liver enzymes. He had not started any new medications in the past six months. His shortness of breath was due to new onset atrial fibrillation. His atrial fibrillation was controlled but he developed worsening hypotension and renal failure. The patient's hypotension did not improve with fluids and required intravenous vasopressors. He developed bilateral pleural effusion, anasarca and congestive heart failure with an EF of 60%. He slowly started developing hepatic failure and was worked up for secondary causes of liver disease and no etiology was found. Upon transfer to our hospital he was frankly jaundiced, had mild asterixis, and small ascites. A right heart catheterization and MRI were consistent with restrictive cardiomyopathy. Lytic lesions were identified. A bone marrow aspirate showed moderate atypical plasmacytosis and focal amyloid deposition. Flow cytometry was compatible with multiple myeloma. A liver biopsy showed widespread amyloid deposition throughout the hepatic parenchyma. He was deemed not a liver transplant candidate or bone marrow transplant and family decided for hospice care. An autopsy showed severe amyloid deposition in the liver and heart along with left ventricular hypertrophy. There was no amyloid deposition in the kidneys or lungs. Hepatic failure as a consequence of amyloidosis and multiple myeloma is a rare condition with few cases reported. This case adds to the literature of acute liver failure caused by amyloidosis.

Amiodarone pretreatment of organ donors exerts anti-oxidative protection but induces excretory dysfunction in liver preservation and reperfusion

The continuous shortage of organs necessitates the use of marginal organs from donors with various diseases, including arrhythmia-associated cardiac failure. One of the most frequently used anti-arrhythmic drugs is amiodarone (AM), which is given in particular in emergency situations. Apart from its anti-arrhythmic actions, AM provides anti-oxidative properties in cardiomyocytes. Thus, we were interested in whether AM donor pretreatment affects the organ quality and function of livers procured for preservation and transplantation. Donor rats were pretreated with AM (5 mg/kg of body weight) 10 minutes before flush-out of the liver with a cold (4 degrees C) histidine-tryptophan-ketoglutarate solution (n = 8). Livers were then stored for 24 hours at 4 degrees C before ex situ reperfusion with a 37 degrees C Krebs-Henseleit solution for 60 minutes in a nonrecirculating system. At the end of reperfusion, tissue samples were taken for histology and Western blot analysis. Animals with vehicle only (0.9% NaCl) served as ischemia/reperfusion controls (n = 8). Additionally, livers of untreated animals (n = 8) not subjected to 24 hours of cold ischemia served as sham controls. AM pretreatment effectively attenuated lipid peroxidation, stress protein expression, and apoptotic cell death. This was indicated by an AM-mediated reduction of malondialdehyde, heme oxygenase-1, and caspase-3 activation. However, AM treatment also induced mitochondrial damage and hepatocellular excretory dysfunction, as indicated by a significantly increased glutamate dehydrogenase concentration in the effluate and decreased bile production. In conclusion, AM donor pretreatment exerts anti-oxidative actions in liver preservation and reperfusion. However, these protective AM actions are counteracted by an induction of mitochondrial damage and hepatocellular dysfunction. Accordingly, AM pretreatment of donors for anti-arrhythmic therapy should be performed with caution.

Hepatic Perturbations Provoked by Azathioprine: A Paradigm To Rationalize The Cytoprotective Potential of Ficus Hispida Linn

The present study was embarked upon in an endeavor to ascertain whether Ficus hispida leaf extract (FHLE) modulates azathioprine-induced hepatic damage. Azathioprine treated rats displayed a plethora of pathological events, which include loss of hepatocellular membrane integrity, mitochondrial dysfunction, and nuclear damage; whilst FHLE pretreated rats significantly precluded these abnormalities. These data were in harmony with the transmission electron microscopic studies. Observations from this investigation directed us to propose the plausible mechanisms through which FHLE thwarts the repercussions of azathioprine-induced hepatocellular necrosis: upholding of thiol homeostasis, curtailing the membrane effects, and perpetuation of adenine nucleotide status. These data offer credence to the notion that FHLE might be a beneficial intervention in the prevention of hepatotoxicity in azathioprine therapy.

Hemorrhage-Induced Hepatic Injury and Hypoperfusion can be Prevented by Direct Peritoneal Resuscitation

BackgroundCrystalloid fluid resuscitation after hemorrhagic shock (HS) that restores/maintains central hemodynamics often culminates in multi-system organ failure and death due to persistent/progressive splanchnic hypoperfusion and end-organ damage. Adjunctive direct peritoneal resuscitation (DPR) using peritoneal dialysis solution reverses HS-induced splanchnic hypoperfusion and improves survival. We examined HS-mediated hepatic perfusion (galactose clearance), tissue injury (histopathology), and dysfunction (liver enzymes). MethodsAnesthetized rats were randomly assigned (n = 8/group): (1) sham (no HS); (2) HS (40% mean arterial pressure for 60 min) plus conventional i.v. fluid resuscitation (CR; shed blood + 2 volumes saline); (3) HS + CR + 30 mL intraperitoneal (IP) DPR; or (4) HS + CR + 30 mL IP saline. Hemodynamics and hepatic blood flow were measured for 2 h after CR completion. In duplicate animals, liver and splanchnic tissues were harvested for histopathology (blinded, graded), hepatocellular function (liver enzymes), and tissue edema (wet–dry ratio). ResultsGroup 2 decreased liver blood flow, caused liver injuries (focal to submassive necrosis, zones 2 and 3) and tissue edema, and elevated liver enzymes (alanine aminotransferase (ALT), 149 ± 28 μg/mL and aspartate aminotransferase (AST), 234 ± 24 μg/mL; p < 0.05) compared to group 1 (73 ± 9 and 119 ± 10 μg/mL, respectively). Minimal/no injuries were observed in group 3; enzymes were normalized (ALT 89 ± 9 μg/mL and AST 150 ± 17 μg/mL), and tissue edema was similar to sham. ConclusionsCR from HS restored and maintained central hemodynamics but did not restore or maintain liver perfusion and was associated with significant hepatocellular injury and dysfunction. DPR added to conventional resuscitation (blood and crystalloid) restored and maintained liver perfusion, prevented hepatocellular injury and edema, and preserved liver function.

A comparative study of serum F protein and other liver function tests as an index of hepatocellular damage in epileptic patients.

Gamma glutamyl transferase (GGT) and alkaline phosphatase (ALP) may not be sensitive indicators of hepatocellular damage in patients taking anticonvulsant drugs as raised levels may only reflect enzyme induction. Aspartate aminotransferase (AST) is a specific, but relatively insensitive marker of liver damage and has a poor correlation with liver histology. Serum F protein is found in high concentration in the liver and levels are not influenced by enzyme induction. We measured serum F protein levels in patients taking carbamazepine (CBZ) and phenytoin (PHT) as monotherapy and in patients receiving multiple drugs. We compared the results with patients taking sodium valproate (VPA). Serum F protein levels were elevated in 6%, 22% and 13% of patients receiving CBZ, PHT and VPA, respectively. Raised GGT levels were reported for both the CBZ (26%) and PHT (78%) groups. Raised ALP levels were observed in 16%, 25% and 4% of the CBZ, PHT and VPA groups, respectively. Raised levels of serum F protein in the VPA group and the absence of any associated increases in either GGT or AST may further support the suggestion that serum F protein is an indicator of hepatocellular dysfunction associated with anticonvulsant therapy. However, further correlation with liver histology is required.

The Pringle manoeuvre should be avoided in hepatectomy for cancer patients due to its side effects on tumor recurrence and worse prognosis

Curative hepatectomy is still the best therapeutic strategy for liver cancer treatment up to now. The Pringle manoeuvre has been commonly used to avoid massive blood loss during operation since its advent, which greatly accelerates the advance of liver surgery and oncological surgery. In the past century, more attentions have been paid to different effects of ischemia-reperfusion injury elicited by Pringle manoeuvre. Theses include its impacts on complex metabolic, immunological, and microvascular changes, which altogether might contribute to hepatocellular damage and dysfunction, and contribute to haemodynamic instability. Despite these adverse impacts, the short-term outcome of affected patients under hepatectomy was greatly improved with the advances of surgical techniques and perioperative management in recent years. While the long-term prognosis remains unsatisfactory due to a high incidence of intra/extrahepatic recurrence. The reason for it was not totally elucidated. Furthermore, the effect of the Pringle manoeuvre on the prognosis of oncologic patients and behavior of the tumor cell was not deliberately mentioned. This point was put forward to the front-desk by the specific phenomenon from recent animal studies. It is showed that ischemia-reperfusion injury of the liver remnant may be a significant factor to promote the tumor recurrence and metastasis. If it is a truth in human, there must be a big challenge to the Pringle manoeuvre. So we hypothesized that the long-term prognosis of cancer patients could be worsened by the ischemia-reperfusion injury elicited by Pringle manoeuvre during the hepatectomy and it should be revised, or even, avoided in future hepatectomy for oncologic patients. The less surgical stress including ischemia-reperfusion injury in the hepatic resection without Pringle manoeuvre might contribute to a better prognosis. To get a deeper understanding, prospective randomized clinical trials need to be done. It is surely supposed to provide more important information about the long-term effects of the Pringle manoeuvre, and to our hypothesis.

Systemic and pulmonary hemodynamics in patients with extrahepatic portal vein obstruction is similar to compensated cirrhotic patients

Patients with cirrhosis and portal hypertension exhibit a hyperdynamic circulation manifesting as increased cardiac output, heart rate and plasma volume; and decreased arterial blood pressure, systemic vascular resistance, and pulmonary vascular resistance. It is believed that these changes are related to both hepatocellular dysfunction and portal hypertension. However, the role of portal hypertension per se in producing these changes in circulation has not been clear. Extrahepatic portal vein obstruction (EHPVO), a vascular disorder of the liver characterized by cavernomatous transformation of the main portal vein, is an excellent model to study the role of portal hypertension per se in producing these changes because there is no hepatic dysfunction in EHPVO. The main aim of our study was, therefore, to evaluate alterations of systemic and pulmonary vascular systems in patients with EHPVO and compare them with patients with compensated cirrhosis. Consecutive patients of EHPVO, 15 years or older, and past variceal bleeders were studied. For comparison, consecutive patients with compensated cirrhosis and history of variceal bleed, matched for variceal status, and body surface area were included. The hemodynamic studies included the measurements of cardiac index (by Fick's oxygen method), and systemic and pulmonary vascular resistance indices. Fifteen patients of EHPVO and same number of controls (compensated cirrhotics) were included in the study. The baseline parameters in the two groups were comparable. Both EHPVO patients and cirrhotics had similar values in all the measured systemic and pulmonary hemodynamic parameters. The median (range) cardiac index in EHPVO was 3.8 (2.3-7.7) l min(-1) m(-2), whereas it was 4.4 (2.8-8.9) l min(-1) m(-2) in cirrhosis (P = 0.468). The median (range) systemic vascular resistance index in EHPVO was 1,835 (806-3400) dyne s cm(-5) m(-2), which was similar to that in cirrhotic patients (1,800 [668-3022], P = 0.520). Similarly, the values of median (range) pulmonary vascular resistance index were comparable in the two groups (71 [42-332] vs. 79 [18-428], P = 0.885). A subgroup analysis was done for 8 patients of EHPVO and 8 age-matched compensated cirrhotic patients, which also revealed similar values of cardiac index, cardiac output, systemic vascular resistance index, systemic vascular resistance, pulmonary vascular resistance index, and pulmonary vascular resistance in the two groups. EHPVO patients have hyperdynamic circulation manifested by high cardiac index and low systemic and pulmonary vascular resistance indices. These hemodynamic changes are comparable with compensated cirrhotic patients who have similar grade of portal hypertension. This suggests a predominant role of portal hypertension per se in the genesis of systemic and pulmonary hemodynamic alterations.

Elevated Serum Cobalamin in Patients With Decompensated Biventricular Failure

Serum cobalamin (vitamin B12), bound to transcobalamin II, is taken up by the endothelium of the hepatic vasculature via a receptor-mediated membrane transport process. We hypothesized hepatic congestion is associated with elevated serum B12 without hepatocyte necrosis. Serum B12, aspartate and alanine transaminases, alkaline phosphatase, bilirubin (Bili), and brain natriuretic peptide (BNP) were monitored at the time of admission in 91 hospitalized patients: (a) 38 with decompensated biventricular failure having systemic venous distention, tricuspid regurgitation (TR), and echocardiographic evidence of inferior vena cava dilation and moderate to marked TR; (b) 18 with acute left heart failure having a myocardial infarction, an ischemic cardiomyopathy, or hypertensive heart disease; and (c) 35 without clinical evidence of failure despite myocardial infarction, pericarditis, or atrial arrhythmia. Serum cobalamin (normal 180-600 pg/mL) was elevated with biventricular failure (861.4 +/- 53.0 pg/mL) compared with (P < 0.0001) left heart or no failure, where B12 remained normal. Serum aspartate, alanine, and alkaline phosphatase were normal in each group whereas Bili was increased (1.8 +/- 0.2 mg/dL; P < 0.05) with biventricular failure. Plasma BNP was elevated in each group. Elevated cobalamin and Bili are respective biomarkers of hepatocellular dysfunction and cholestasis in patients having decompensated biventricular failure with systemic venous distention and TR without hepatocyte necrosis vis-à-vis left heart failure or in the absence of clinical failure. Elevated plasma BNP did not distinguish between the presence or absence of systemic venous congestion.

Avaliação da ressecção hepática em pacientes cirróticos com carcinoma hepatocelular

The hepatocellular carcinoma is a disorder that affects patients suffering from cirrhosis. Liver resection, orthotopic liver transplantation and percutaneous ablation are some forms of therapy currently used to provide a cure for this disease. To assess the results achieved through liver resection for the treatment of the hepatocellular carcinoma in patients with cirrhosis being under treatment in a general hospital. Clinical observation, laboratory test results, endoscopic and histopathologic analysis were taken into consideration in the case of 22 patients who underwent liver resection between 1996 and 2005. To verify the survival rates, identify the prognostic factors and determine the risk of recurrence, special attention was given to the serologic levels of bilirubins and alpha-fetoprotein, and to the level of the hepatocellular dysfunction (classified according to the Child-Pugh-Turcotte and the Model for End-Stage Liver Disease parameters). The size and number of tumours, microvascular invasion and the presence of satellite lesions were also taken into consideration. The level of statistic significance employed was of 95%. In the cases studied, patients had an average age of 62.09 years, being 17 of them male. In 10 cases the liver cirrhosis was associated to the hepatitis C chronic infection; in 4 cases there was a combination of chronic ingestion of ethanol and the hepatitis C virus; in 3 cases there was an association with the hepatitis B virus chronic infection. Two cases were related to the chronic ingestion of ethanol alone and in one case the use of medications was reported. It was not possible to establish the etiology in two of the cases studied. Eighteen patients had a single tumour, 11 of them smaller than 5 cm. The survival rate varied between 10 days and 120 months, being of 33.5 months on average. At the end of the 1st, 3rd and 5th year, the survival rates were 61.90%, 16.67% and 11.11%, respectively. Three patients died within the first 3 months after the liver resection. Thirteen patients died after the first 3 months, 12 of the cases associated to tumour recurrence and tumour progression. There was one death in the immediate post-operative period of a second operation carried out to remove a recurrent tumour. When it comes to the survival rate and the identification of prognostic factors, a relationship between patients survival and microvascular invasion was observed. No statically significant relationship was established between the survival rate and the serologic levels of bilirubins and alpha-fetoprotein or the level of hepatocellular dysfunction, size or number of tumours. However, a more significant incidence of tumour recurrence was observed in patients with microvascular invasion in the histopathologic study. In spite of the reduced number of cases studied, the surgical treatment of the hepatocellular carcinoma produced bad results. A careful selection of cases where surgery could be an option may be a decisive factor to improve such results. A careful selection of cases might be a decisive factor in order to improve such results.

HEMIN ARGINATE-INDUCED HEME OXYGENASE 1 EXPRESSION IMPROVES LIVER MICROCIRCULATION AND MEDIATES AN ANTI-INFLAMMATORY CYTOKINE RESPONSE AFTER HEMORRHAGIC SHOCK

Microvascular failure is a major determinant for the development of hepatocellular dysfunction after hemorrhagic shock. Induction of heme oxygenase (HO) 1 may confer hepatocellular protection. Hemin arginate (HAR) induces HO-1 and protects against shock-induced organ failure. The mechanisms are not completely understood, but HO-1-mediated protective effects on the microcirculation and on the inflammatory response may contribute. Therefore, the aim of the present study was to investigate the influence of HAR pretreatment on liver microcirculation and cytokine response to assess the role of HO-1-mediated effects under these conditions. Male Sprague-Dawley rats (200-300 g; n=8 per group) were subjected to hemorrhage (MAP, 30-40 mmHg for 1 h) 24 h after pretreatment with vehicle (Ringer solution) or HAR (5 mg kg(-1)), followed by 2 h of resuscitation. The microcirculation and the redox state (nicotinamide adenine dinucleotide phosphate [reduced form; NADPH] autofluorescence) of the liver were assessed using intravital microscopy. Cytokine levels (TNF-alpha and IL-10) were quantified using an enzyme-linked immunosorbent assay. A profound induction of HO-1 was observed 24 h after pretreatment with HAR. Hemorrhage significantly reduced sinusoidal perfusion and increased NADPH autofluorescence and cytokine levels. Hemin arginate pretreatment significantly improved liver microcirculation, reduced NADPH autofluorescence, significantly increased IL-10, and tended to decrease TNF-alpha serum levels compared with shock vehicle. Blockade of the HO pathway with tin-mesoporphyrin-IX after HAR pretreatment abolished the observed beneficial effects, whereas the additional administration of the carbon monoxide donor dichloromethane reversed the tin-mesoporphyrin-IX-mediated changes. These results suggest that HAR pretreatment improves liver microcirculation and mediates an anti-inflammatory cytokine response after hemorrhagic shock through induction of HO-1 and in part through an increased carbon monoxide release.