Fat-storing cells as liver-specific pericytes. Spatial dynamics of agonist-stimulated intracellular calcium transients.

Liver perisinusoidal fat-storing cells (FSC) show morphological and ultrastructural characteristics similar to pericytes regulating local blood flow in other organs. In the present study we have analyzed whether FSC respond to local vasoconstrictors such as thrombin, angiotensin-II, and endothelin-1 with an increase in intracellular free calcium concentration ([Ca2+]i) coupled with effective cell contraction. All agonists tested induced a rapid and dose-dependent increase in [Ca2+]i followed by a sustained phase lasting several minutes in confluent monolayers of Fura-2-loaded human FSC. Pharmacological studies performed using different Ca2+ channel blockers indicated that, at least for thrombin and angiotensin-II, the sustained phase is due to the opening of voltage-sensitive membrane Ca2+ channels. To analyze the temporal and spatial dynamics of Ca2+ release in response to these agonists, we performed experiments on individual Fura-2-loaded human FSC using a dual wavelength, radiometric video imaging system. The rise in [Ca2+]i was exclusively localized to the cytoplasm, particularly in the branching processes. Increases in [Ca2+]i more than four-fold were associated with a simultaneous and transient reduction of cell area indicating reversible cell contraction. Our results indicate that the Ca(2+)-dependent contraction of human FSC in vitro may reflect a potential role in regulating sinusoidal blood flow in vivo.

HNE interacts directly with JNK isoforms in human hepatic stellate cells.

4-Hydroxy-2,3-nonenal (HNE) is an aldehydic end product of lipid peroxidation which has been detected in vivo in clinical and experimental conditions of chronic liver damage. HNE has been shown to stimulate procollagen type I gene expression and synthesis in human hepatic stellate cells (hHSC) which are known to play a key role in liver fibrosis. In this study we investigated the molecular mechanisms underlying HNE actions in cultured hHSC. HNE, at doses compatible with those detected in vivo, lead to an early generation of nuclear HNE-protein adducts of 46, 54, and 66 kD, respectively, as revealed by using a monoclonal antibody specific for HNE-histidine adducts. This observation is related to the lack of crucial HNE-metabolizing enzymatic activities in hHSC. Kinetics of appearance of these nuclear adducts suggested translocation of cytosolic proteins. The p46 and p54 isoforms of c-Jun amino-terminal kinase (JNKs) were identified as HNE targets and were activated by this aldehyde. A biphasic increase in AP-1 DNA binding activity, associated with increased mRNA levels of c-jun, was also observed in response to HNE. HNE did not affect the Ras/ERK pathway, c-fos expression, DNA synthesis, or NF-kappaB binding. This study identifies a novel mechanism linking oxidative stress to nuclear signaling in hHSC. This mechanism is not based on redox sensors and is stimulated by concentrations of HNE compatible with those detected in vivo, and thus may be relevant during chronic liver diseases.

Conventional versus cytokinetic polychemotherapy with estrogenic recruitment in metastatic breast cancer: results of a randomized cooperative trial.

Diethylstilbestrol (DES) can induce a recruitment into the proliferative pool of previously resting breast cancer cells in vivo. In order to verify if estrogenic recruitment could result in a larger tumor cell killing by chemotherapy, 117 patients with metastatic breast cancer were randomized to receive CEF (cyclophosphamide, 600 mg/m2; epidoxorubicin, 60 mg/m2; and 5-fluorouracil, 600 mg/m2 on day 1); DES-CEF (cyclophosphamide, 600 mg/m2 on day 1; DES, 1 mg orally on days 5, 6, and 7; and epidoxorubicin, 60 mg/m2, and 5-fluorouracil, 600 mg/m2, on day 8) every 21 days. No significant difference in objective response rates, survival, or progression-free survival was seen between the two regimens. Patients in the DES-CEF arm experienced a higher complete response (CR) rate (24.1% v 16.1%), which reached statistical significance in the case of soft-tissue metastasis (48% v 27.3%; P less than .05) and estrogen receptor-negative tumors (35.7% v 11.1%; P less than .025). Survival and progression-free survival of patients refractory to treatment were not worsened by estrogenic recruitment. In the subset of patients failing after adjuvant polychemotherapy, DES-CEF unexpectedly induced a significantly longer survival (greater than 802 days v 375 days; P = .029) and progression-free survival (239 days v 192 days; P = .041) than CEF. The DES-CEF regimen was more myelotoxic, and 43.3% of the DES-CEF cycles had to be delayed because of leukopenia in comparison with 11.8% of the CEF cycles (P less than .0001). In conclusion, chemotherapy with estrogenic recruitment was able to induce more CRs in certain subsets of patients and a significant prolongation in survival and progression-free survival of patients failing after adjuvant polychemotherapy. These results have been achieved despite a significantly lower dose intensity of chemotherapy.

Nongastrointestinal low-grade mucosa-associated lymphoid tissue lymphoma: analysis of 75 patients.

PURPOSE: Nongastrointestinal locations represent about 30% to 40% of all low-grade mucosa-associated lymphoid tissue (MALT) lymphomas. We report a retrospective analysis of 75 patients with nongastrointestinal low-grade MALT lymphoma, presenting their clinical, therapeutic, and follow-up data with respect to the initial location of the lymphoma. PATIENTS AND METHODS: From January 1988 to October 1997, 75 patients with untreated nongastrointestinal low-grade MALT lymphoma were subjected to treatments ranging from local radiotherapy and local interferon alfa administration to chemotherapy. The lymphomas were located in the lung (19 patients), orbital soft tissue (16 patients), skin (seven patients), thyroid (seven patients), lachrymal gland (six patients), conjunctiva (six patients), salivary gland (six patients), breast (three patients), eyelid (two patients), larynx (one patient), bone marrow (one patient), and trachea (one patient). RESULTS: Complete and partial remissions were achieved in 59 (79%) and 16 (21%) of the 75 patients, respectively, with an overall response rate of 100%. All but two of the patients are still alive, with a median follow-up of 47 months; these two patients died from other causes. The estimated time to treatment failure rate is 30% at 5 years. In the thyroid and lachrymal gland sites, no relapses were reported. CONCLUSION: Our data regarding the largest reported series of nongastrointestinal MALT lymphomas confirm the good prognosis of this particular clinicopathologic entity and the significant efficacy of different therapeutic approaches to specific sites.

Randomized trial of fludarabine versus fludarabine and idarubicin as frontline treatment in patients with indolent or mantle-cell lymphoma.

PURPOSE: A first comparative trial of fludarabine (FLU) alone versus FLU plus idarubicin (FLU-ID) for indolent or mantle-cell lymphomas. PATIENTS AND METHODS: From September 1995 to July 1998, 199 patients aged 25 to 65 years (median, 54 years) with newly diagnosed stages II to IV indolent or mantle-cell lymphomas (standard risk according to the International Prognostic Index) were enrolled onto a multicenter, 1:1 randomized study. Of the 199 patients who were able to be assessed, 101 were assigned to the FLU group (six monthly cycles of FLU 25 mg/m(2)/d on days 1 through 5) and 98 to the FLU-ID group (six monthly cycles of FLU 25 mg/m(2)/d on days 1 through 3 and idarubicin 12 mg/m(2) on day 1). RESULTS: In the FLU group, complete response (CR) and partial response rates were 47% and 37%, respectively, whereas in the FLU-ID group, they were 39% and 42%, respectively. In-depth analysis of the CR rate with respect to histologic type showed that FLU seemed to be superior to FLU-ID in treating follicular lymphomas (60% v 40%, respectively), whereas FLU-ID seemed to be more effective than FLU in treating nonfollicular lymphomas (small lymphocytic, 43% v 29%, respectively; immunocytoma, 38% v 23%, respectively; P = not significant), excluding the mantle-cell subset (in which there was no difference between the two groups). No striking differences were observed between the two protocols in terms of overall response or toxicity, which was generally mild. However, with a median follow-up of 19 months, only 29 patients (62%) who received FLU alone have maintained their initial CR, compared with 32 (84%) of those who received FLU-ID therapy (P =.021). CONCLUSION: Although the FLU-ID regimen may not significantly improve the induction of CR in most indolent-lymphoma patients, our preliminary data do suggest that, with respect to FLU alone, it may be capable of conferring a longer-lasting CR and that it might be superior in terms of CR rate in small lymphocytic and immunocytoma subtypes.

Involvement of phosphatidylinositol 3-kinase in the activation of extracellular signal-regulated kinase by PDGF in hepatic stellate cells.

Phosphatidylinositol 3-kinase (PI 3-K) is a lipid and protein kinase which associates with the activated platelet-derived growth factor (PDGF) receptor and other tyrosine kinases. We studied the effects of wortmannin, a selective inhibitor of PI 3-K, on the activation of extracellular-signal regulated kinase (ERK) by PDGF in cultured hepatic stellate cells, mesenchymal cells responsible for extracellular matrix synthesis within the liver. Incubation with 100 nM wortmannin, a dose which almost completely blocks PI 3-K, resulted in 50% reduction of ERK activity. Direct inhibition of ERK by wortmannin could not be considered responsible for this effect, since wortmannin did not inhibit ERK activity in vitro. Rather, inhibition of PI 3-K acts on the kinase cascade that leads to ERK activation, since PDGF-dependent phosphorylation of ERK was found to be reduced after incubation with wortmannin. Wortmannin also inhibited the increase in c-fos mRNA induced by PDGF, which is dependent on ERK activation. The results of this study show that in hepatic stellate cells PI 3-K is involved in ERK activation, although it is not necessary. These data indicate cross-talk between PI 3-K and the Ras/ERK pathway in PDGF-stimulated cells.

Molecular mechanism underlying impaired platelet responsiveness in liver cirrhosis.

We have studied platelet function in 10 patients with severe liver cirrhosis, compared to healthy subjects. Using washed platelets, we have investigated the molecular mechanism underlying the defect in platelet aggregation frequently observed in these patients. We have found that platelets from cirrhotic patients have a reduced responsiveness to thrombin and collagen in terms of aggregation, and receptor-dependent activation of phospholipase C, A2 and cyclooxygenase/thromboxane synthetase. We thus suggest that this impairment in transmembrane signalling is responsible for the defective platelet function observed in cirrhosis.

Integrin-mediated stimulation of monocyte chemotactic protein-1 expression.

We investigated whether activation of integrin receptors could modulate the expression of monocyte chemotactic protein-1 (MCP-1) in human hepatic stellate cells (HSC), mesenchymal cells responsible for extracellular matrix synthesis within the liver. When compared to non-adherent cells, HSC plated on collagen types I or IV, or fibronectin, showed increased MCP-1 gene expression and protein secretion in the conditioned medium. Increased MCP-1 secretion was also observed when cells were plated on dishes coated with a monoclonal antibody directed against the beta1-integrin subunit, demonstrating that ligation of beta1-integrins is sufficient to stimulate MCP-1 expression. Conversely, integrin-independent cell adhesion on poly-L-lysine did not modify MCP-1 secretion. Disruption of the actin cytoskeleton by cytochalasin D blocked the collagen-dependent increase in MCP-1 secretion. Chemotactic assay of HSC-conditioned medium showed that HSC plated on collagen secrete higher amounts of chemotactic factors for lymphomonocytes, and that MCP-1 accounts for the great majority of this effect. These findings indicate a novel mechanism of MCP-1 regulation possibly relevant in those conditions where HSC interact with an altered extracellular matrix.

Inhibition by pentoxifylline of extracellular signal-regulated kinase activation by platelet-derived growth factor in hepatic stellate cells.

1. It has been proposed that pentoxifylline (PTF) acts an antifibrogenic agent by reducing the synthesis of extracellular matrix components, and this possibility has been confirmed in animal models of hepatic fibrosis. In this study the effects of PTF on the proliferation of extracellular matrix producing cells induced by platelet-derived growth factor (PDGF) were evaluated. The study was performed on hepatic stellate cells, currently indicated as the major source of extracellular matrix in fibrotic liver. 2. PTF caused a dose-dependent reduction of PDGF-induced mitogenesis with an IC50 of 170 microM, identical to the EC50 for the increase in intracellular cyclic AMP levels. Preincubation with PTF did not affect either PDGF-receptor autophosphorylation or phosphotidylinositol 3-kinase activity, whereas it markedly reduced PDGF-stimulated extracellular signal-regulated kinase (ERK) activity and ERK isoform phosphorylation. PTF also reduced PDGF-induced c-fos mRNA expression, which is dependent on activation of the RAS/ERK pathway. In addition, the PDGF-induced increase in cytsolic-free calcium was almost completely prevented by pretreating the cells with PTF. 3. The results of the present study indicate that PTF, in addition to its effect on collagen deposition and degradation, may exert an antifibrogenic effect by reducing the PDGF-induced proliferation of extracellular matrix producing cells. This effect appears to be mediated by a reduction of PDGF-stimulated ERK activity as well as of other intracellular signalling pathways such as the PDGF-induced elevation of cytosolic-free calcium.

Effect of pentoxifylline on the degradation of procollagen type I produced by human hepatic stellate cells in response to transforming growth factor-beta 1.

1. Pentoxifylline (PTF) may act as a potential antifibrogenic agent by inhibiting cell proliferation and/or collagen deposition in cell type(s) responsible for the accumulation of extracellular matrix. The aim of the present study was to investigate at which level PTF may affect synthesis and degradation of type I collagen in human hepatic stellate cells (HSCs), a key source of connective tissue in fibrotic liver. 2. Procollagen type I synthesis and release were evaluated in cells maintained in serum free/insulin free medium for 48 h and then stimulated with transforming growth factor-beta 1 (TGF-beta 1) for different time periods in the presence or absence of PTF. TGF-beta 1 caused an upregulation of procollagen I mRNA levels with a peak increase after 3-6 h of stimulation. This effect was followed by an increase in both the cell associated and the extracellular levels of the corresponding protein, with a peak effect at 9-12 h after the addition of TGF-beta 1. Co-incubation with PTF slightly but consistently reduced basal as well as stimulated procollagen I mRNA levels, with negligible effects on the cell-associated expression of the corresponding protein. Conversely, PTF dose-dependently reduced procollagen type I levels detected in supernatants from unstimulated and stimulated cells. 3. Pulse-chase experiments employing L-[3H]-proline revealed that PTF was able to induce significantly the degradation of procollagen, mainly in the extracellular compartment. We next analysed the effect of PTF on the major pathway involved in type I collagen degradation. PTF did not affect the expression of metalloproteinase 1 (MMP-1) mRNA both in basal and stimulated conditions, whereas it markedly reduced the expression of tissue inhibitor of metalloproteinase 1 (TIMP-1) mRNA. Accordingly incubation with PTF increased the levels of 'activated MMP-1' in cell supernatants in both basal and stimulated conditions. 4. These results suggest that the antifibrogenic action of PTF on human HSCs is mainly mediated by extracellular collagen degradation rather than by a reduction of collagen synthesis.

Arachidonic acid derivatives and renal function in liver cirrhosis.

Prostaglandins (PGs) are arachidonic acid (AA) derivatives via the PG endoperoxyde H synthase (PGHS) complex. Two PGHS isoforms have been recognized, constitutive (PGHS-1) and inducible (PGHS-2), respectively. Within the kidney, vascular endothelium mainly produces PGI2; the whole glomerulus synthesizes several prostanoids, the predominant AA metabolite in humans being PGI2; tubules and medullary interstitial cells produce mainly PGE2. Renal PGs modulates the action of other hormones and autacoids involved in the regulation of renal hemodynamics, glomerular filtration and the renal handling of sodium and water. Renal PGs are, at least in part, excreted into urine. Measurement of urinary PGs or their metabolites has been found to provide a reliable estimation of basal as well as stimulated PG synthesis. Patients with cirrhosis of the liver show an increased renal synthesis of vasodilating PGs, as indicated by the high urinary excretion of PGs and/or their metabolites. Administration of nonsteroidal anti-inflammatory drugs (NSAIDs) to these patients causes a profound reduction in renal blood flow and glomerular filtration rate, a reduction in sodium excretion, and an impairment of free water clearance. These data clearly indicate that the increased renal synthesis of vasodilating PGs has a relevant role in maintaining renal hemodynamics, sodium and water excretion in a clinical setting characterized by a reduction of effective plasma volume and a striking activation of the major vasoconstricting systems, namely the renin-angiotensin-aldosterone, the sympathetic nervous system, and vasopressin. Patients with hepato-renal syndrome have a reduced renal synthesis of vasodilating PGE2 in the setting of a striking activation of endogenous vasoconstrictors and a maintained or increased renal production of thromboxane A2. Therefore, an imbalance between vasoconstricting systems and the renal vasodilator PGE2 was proposed to explain the renal failure observed in this condition. The urinary excretion of 2-3-dinor 6-keto-PGF1 alpha, an index of systemic PGI2 synthesis, is increased in patients with cirrhosis and hyperdynamic circulation, thus raising the possibility that systemic synthesis of PGI2 may contribute to the arterial vasodilatation of these patients. Finally, administration of exogenous prostanoids to patients with cirrhosis is not effective either in ameliorating renal function or in preventing the deleterious effect of NSAIDs.

In vivo manipulation of human breast cancer growth by estrogens and growth hormone: kinetic and clinical results.

Since 1983, a series of experimental and clinical studies have been carried out on the possibility of enhancing the chemotherapy effectiveness in breast cancer by expanding the fraction of cycling cells. Theoretically estrogens should recruit breast cancer cells and this fact should result in a higher killing efficiency of antiproliferative drugs. Actually it has been clearly shown, by means of the thymidine labeling index and primer-dependent alpha-DNA polymerase assay, that low doses of diethylstilbesterol are able to increase the tumor proliferative activity of human breast cancer in vivo (estrogenic recruitment). Three randomized trials have been carried out (one in locally advanced and two in metastatic breast cancer) comparing conventional polychemotherapy vs chemotherapy with estrogenic recruitment. Only limited advantages have been observed in these trials. Searching for new modalities of kinetic manipulation of tumors, recombinant human growth hormone has been employed in a pilot study: the preliminary results indicate that it largely enhances tumor proliferative activity, suggesting the possibility of employing a growth factor system to increase chemosensitivity.

Patterns and mechanisms of hepatitis B/hepatitis D reinfection after liver transplantation.

Viral recurrence is the limiting factor in orthotopic liver transplantation (OLT) for hepatitis B virus (HBV) related liver disease. In fact, high rates of HBV infection of the transplanted liver are reported, followed by the recurrence of liver disease in a high percentage of cases. The importance of reinfection stimulates the study of its modalities and mechanisms in order to better identify preventive measures and better select patients for OLT. In HBV and HDV positive patients, the outcome of liver transplantation appears significantly better than in patients that are solely HBV positive, in spite of a high rate of HDV reinfection. Long-term analysis (5 years) of HBV and HDV infection, using the PCR technique, in 15 patients transplanted for an HBV/HDV positive liver disease and treated with anti-HBs immunoglobulin (HBIG), revealed that all patients experienced an HDV reinfection, but only about 7 were still harboring the virus after four years of follow-up. HDV reinfection was either associated to HBV reinfection or isolated whereas no cases of HBV isolated reinfection was observed. Isolated HDV reinfection was frequent and transient in all but one case that was superinfected by HBV. Infected peripheral blood mononuclear cells seem to be implicated in HBV superinfection of HDV infected liver. Liver damage was observed only in cases of HBV/HDV co-infection, suggesting that, in vivo, HBV is necessary to produce liver damage although it is not essential for HDV absorption to target cells, HDV penetration of these cells or HDV genomic replication. In addition, in isolated HDV infection, transient HDV viraemia and its low levels suggest that, perhaps in these patients HDV uses a very limited presence of HBV or alternative ways which are not efficient enough for envelope production. These data suggest that, particularly in HDV positive patients, antiHBs Ig administration, which has previously been proven to significantly reduce HBV reinfection in HBsAg-positive patients, may be useful in changing the natural history of repetition of the original viral infection and liver disease after OLT.

Anthracycline containing regimens in intermediate grade lymphoma. Italian Cooperative Study Group on Intermediate Grade Malignant Lymphoma.

From March 1991 to April 1992, 44 previously untreated patients with stage II to IV intermediate-grade non-Hodgkin's lymphoma (according to the Kiel classification) were entered in a phase III comparative trial. The objectives of the study were to compare the efficacy and safety of using idarubicin instead of doxorubicin in the combination chemotherapeutic regimen CHOP (cyclophosphamide, doxorubicin, vincristine, prednisolone). Forty-four patients were randomly assigned to receive either CI(idarubicin)OP or CH(doxorubicin)OP. The study is ongoing and so far no significant differences in complete response rate and (non-)hematologic toxicity have been observed.

Vascular complications in patients receiving chemotherapy - what role do 3rd-generation antiemetics play.

Vascular diseases in oncology are often attributed to several factors (hospitalisation, paraneoplastic syndrome, probable damaging effect on epithelium by chemotherapeutic agents) however they are reasonably infrequent events. From 7/10/1993 to 21/3/1994 we observed 8 cases of vascular diseases (venous and arterial) of varying intensity in patients receiving anticancer chemotherapy in association with third generation antiemetics. On the basis of similar experiences reported in the literature of patients undergoing chemotherapy and serotonin-antagonist antiemetics, we performed a detailed analysis of these 8 cases. Few-cases of vascular diseases have been observed in phase II and III studies inpatients treated with ondansetron but the physiopathological mechanism is still not well understood. Of our 8 patients, 5 were female and 3 male, with ages ranging from 36 to 73 years. All cases had different types of solid tumors and had been treated with different chemotherapeutic schemes (two containing cisplatin). All the patients had received varying doses (from 16 to 96 mg for 5 days) of ondansetron. Vascular complications occurred 1 to 3 weeks after treatment and 3 cases are still receiving therapy. It can be noted that two patients who had previously been treated with ondansetron did not develop vascular problems. This drug has been in use in our department since May 1991, but problems of a vascular nature only arose in October 1993. At present a final conclusion cannot be reached as to the link between ondansetron and vascular complications.

Hepatitis C virus as a lymphotropic agent: evidence and pathogenetic implications.

Hepatitis C virus has been proven to be the major cause of NANB hepatitis, cirrhosis and hepatocellular carcinoma worldwide. Based on the genome similarities between HCV and flavivirus or pestivirus, this agent has been included within the family Flaviviridae as a separate genus. Among the analogies between HCV and the other members of the same family there is the possibility of infecting blood cells. In particular, significant evidence obtained through studies performed in vivo and in vitro support the concept that HCV is not only a hepatotropic but also a lymphotropic virus. This suggests that, in addition to playing a role in inducing hepatic diseases (both of a non-tumoral and a neoplastic nature), HCV infection may also play a role in extrahepatic pathologies. The striking association observed between HCV infection and some autoimmune-lymphoproliferative disorders of either benign or neoplastic nature is consistent with this hypothesis. However, in analogy with what has been observed in the case of liver disease, the mechanisms involved in the pathogenesis of HCV-related extra-hepatic manifestations have to be more deeply analysed and clarified.

Hepatorenal syndrome and its treatment today.

The pathogenesis of ascites, a severe and the most frequent complication during cirrhosis, is still not completely understood, but present evidence indicates that portal hypertension principally triggers renal sodium and water retention. Ascites is associated with profound disturbances of splanchnic and systemic haemodynamics, which in turn may influence renal function. Within the kidney the balance between vasoconstricting and vasodilating factors is critical for the maintenance of renal function. As the disease progresses, vasoconstricting factors (mainly angiotensin II, catecholamines, thromboxane, leucotrienes and endothelins) prevail, probably due to the exhaustion of the vasodilating renal autacoid system (mainly prostaglandins). In this setting, vasoconstriction of the intrarenal vascular system induces marked and often irreversible sodium and water retention, leading to refractory ascites, a progressive rise in plasma creatinine levels and reduction of renal clearances (hepatorenal syndrome, HRS). This persistent renal hypoxia may also favour the occurrence of tubular damage due to several causes. A careful therapeutic approach is first based on sequential diuretic treatment (and the addition of adequate plasma expansion with human albumin for patients with diuretic resistant ascites), which may lead to control of ascites for years. However, when HRS occurs, all the proposed treatments (such as paracentesis, administration of renal vasodilators, systemic vasoconstrictors, calcium channel antagonists, TIPS, surgical portosystemic shunts) have been shown to moderately or temporarily improve renal function only, leaving liver transplantation as the only choice of treatment for patients.

Ascites and hepatorenal syndrome.

Ascites is a frequent complication of chronic liver disease with severe portal hypertension. Moreover, in the presence of tense ascites, renal dysfunction and hepatorenal syndrome may occur. Unfortunately, there is no explanation that thoroughly describes the complex relationship between the liver and kidney in either physiological or pathological conditions. Nevertheless, available evidence indicates that early sodium and water retention precedes decompensation, characterized by hyperdynamic circulation. The best approach to the treatment of these patients should be aimed at the prevention of ascites formation. An accurate sequential treatment is indicated in patients with ascites. In the case of hepatorenal syndrome, the only definitive approach is liver transplantation.

Is the use of albumin of value in the treatment of ascites in cirrhosis? The case in favour.

In patients with cirrhosis, ascites accumulates because of sodium retention, triggered by a reduction of the effective arterial blood volume, and imbalanced Starling forces in the splanchnic area due to portal hypertension and hypoalbuminemia. Albumin is the ideal plasma expander in this setting, since it ameliorates systemic and reneal haemodynamics, so reducing sodium retention, and increases oncotic pressure in the splanchnic compartment. In particular, albumin proved useful in patients treated with diuretics, as demonstrated by a randomised study performed at our Instituition in which 126 ascitic inpatients were treated according to a stepped-care diuretic regimen. In fact, patients receiving diuretics plus albumin (n = 63) had a higher cummulative rate of response (p < 0.05) and a shorter hospital stay (20 +/- 1 versus 24 +/- 2 days, p < 0.05) than those given diuretics alone. Treatment with albumin on an outpatient basis (25 g/week) resulted in a lower probability of developing ascites (p < 0.02 vs. patients not given albumin) and a lower probability of readmission (p < 0.02). Patients given albumin also had a better quality of life. As discussed in another article, evidence also supports the use of albumin in patients treated for paracentesis, as well as in patients with spontaneous peritonitis or hepatorenal syndrome.

Update on ascites and hepatorenal syndrome.

Ascites is the most common complication occurring during liver cirrhosis. Even if a significant decrease in renal clearance may be observed in the first step of chronic active liver disease, renal impairment, at times complicated by the typical signs of hepatorenal syndrome, occurs only in patients with ascites, especially when tense and refractory. Experimental and clinical data seem to suggest a primary sodium and water retention in the pathogenesis of ascites, in the presence of an intrahepatic increase of hydrostatic pressure, which, by itself, physiologically occurs during digestion. Abnormal sodium and water handling leads to plasma volume expansion, followed by decreased peripheral vascular resistance and increased cardiac output. This second step is in agreement with the peripheral arterial vasodilation hypothesis, depicted by an increase in total blood volume, but with a decreased effective arterial blood volume. This discrepancy leads to the activation of the sympathetic nervous and renin-angiotensin-aldosterone systems associated with the progressive activation of the renal autacoid systems, especially, that of the arachidonic acid. During advanced cirrhosis, renal impairment becomes more sustained and renal autacoid vasodilating substances are less available, possibly due to a progressive exhaustion of these systems. At the same time ascites becomes refractory inasmuch as it is no longer responsive to diuretic treatment. Various pathogenetic mechanisms leading to refractory ascites are mentioned. Finally, several treatment approaches to overcome the reduced effectiveness of diuretic therapy are cited. Paracentesis, together with simultaneous administration of human albumin or other plasma expanders is the main common approach to treat refractory ascites and to avoid a further decrease in renal failure. Other effective tools are: administration of terlipressin together with albumin, implantation of the Le Veen shunt, surgical porto-systemic shunting or transjugular intrahepatic portosystemic stent-shunt, or orthotopic liver transplantation, according to the conditions of the individual patient.