Neutrophil gelatinase-associated lipocalin is a biomarker of acute-on-chronic liver failure and prognosis in cirrhosis.

BACKGROUND & AIMS: Acute-on-chronic liver failure (ACLF) is a syndrome that occurs in cirrhosis characterized by organ failure(s) and high mortality rate. There are no biomarkers of ACLF. The LCN2 gene and its product, neutrophil gelatinase-associated lipocalin (NGAL), are upregulated in experimental models of liver injury and cultured hepatocytes as a result of injury by toxins or proinflammatory cytokines, particularly Interleukin-6. The aim of this study was to investigate whether NGAL could be a biomarker of ACLF and whether LCN2 gene may be upregulated in the liver in ACLF. METHODS: We analyzed urine and plasma NGAL levels in 716 patients hospitalized for complications of cirrhosis, 148 with ACLF. LCN2 expression was assessed in liver biopsies from 29 additional patients with decompensated cirrhosis with and without ACLF. RESULTS: Urine NGAL was markedly increased in ACLF vs. no ACLF patients (108(35-400) vs. 29(12-73)µg/g creatinine; p<0.001) and was an independent predictive factor of ACLF; the independent association persisted after adjustment for kidney function or exclusion of variables present in ACLF definition. Urine NGAL was also an independent predictive factor of 28day transplant-free mortality together with MELD score and leukocyte count (AUROC 0.88(0.83-0.92)). Urine NGAL improved significantly the accuracy of MELD in predicting prognosis. The LCN2 gene was markedly upregulated in the liver of patients with ACLF. Gene expression correlated directly with serum bilirubin and INR (r=0.79; p<0.001 and r=0.67; p<0.001), MELD (r=0.68; p<0.001) and Interleukin-6 (r=0.65; p<0.001). CONCLUSIONS: NGAL is a biomarker of ACLF and prognosis and correlates with liver failure and systemic inflammation. There is remarkable overexpression of LCN2 gene in the liver in ACLF syndrome. LAY SUMMARY: Urine NGAL is a biomarker of acute-on-chronic liver failure (ACLF). NGAL is a protein that may be expressed in several tissues in response to injury. The protein is filtered by the kidneys due to its small size and can be measured in the urine. Ariza, Graupera and colleagues found in a series of 716 patients with cirrhosis that urine NGAL was markedly increased in patients with ACLF and correlated with prognosis. Moreover, gene coding NGAL was markedly overexpressed in the liver tissue in ACLF.

Human myofibroblastic hepatic stellate cells express Ca(2+)-activated K(+) channels that modulate the effects of endothelin-1 and nitric oxide.

BACKGROUND/AIMS: High-conductance Ca(2+)-activated K(+) (BK(Ca)) channels modulate the effects of vasoactive factors in contractile cells. It is unknown whether hepatic stellate cells (HSCs) contain BK(Ca) channels and what their role in the regulation of HSCs contractility is. METHODS: The presence of BK(Ca) channels in HSCs was assessed by the patch-clamp technique. The functional role of BK(Ca) channels was investigated by measuring intracellular calcium concentration ([Ca(2+)](i)) and cell contraction in individual cells after stimulation with endothelin-1 in the presence or absence of specific modulators of BK(Ca) channels. RESULTS: BK(Ca) channels were detected by patch-clamp in most of the activated HSCs studied. Incubation of cells with iberiotoxin, a BK(Ca) channel blocker, increased both the sustained phase of [Ca(2+)](i) elicited by endothelin-1 and the number of cells undergoing contraction, while the use of NS1619, a BK(Ca) channel opener, induced opposite effects. Stimulation of HSCs with S-nitroso-N-acetyl-penicillamine (SNAP), a nitric oxide (NO)-donor, increased the opening of BK(Ca) channels and reduced the effects of endothelin-1. Conversely, iberiotoxin abolished the inhibitory effect of SNAP on endothelin-induced [Ca(2+)](i) increase and cell contraction. CONCLUSIONS: Activated human HSCs contain BK(Ca) channels that modulate the contractile effect of endothelin-1 and mediate the inhibitory action of NO.

Human hepatic stellate cells secrete adrenomedullin: potential autocrine factor in the regulation of cell contractility.

BACKGROUND/AIMS: Hepatic stellate cells (HSCs) are perisinusoidal pericytes which have receptors for vasoactive factors, such as endothelin-1, which can regulate cell contractility in an autocrine manner. It is unknown whether human HSCs have receptors for and are able to synthesize the vasodilator peptide adrenomedullin (ADM), a peptide produced by most contractile cells. METHODS AND RESULTS: Stimulation of HSCs with ADM resulted in a dose-dependent raise in cAMP concentration (radioimmunoassay) and markedly blunted the endothelin-induced increase in [Ca2+]i and cell contraction, as assessed in cells loaded with fura-2 using a morphometric method. The existence of the receptor CRLR for ADM and their associated proteins RAMP-1 and RAMP-2 was demonstrated by reverse transcriptase-polymerase chain reaction (RT-PCR). Moreover, activated human HSCs spontaneously secreted ADM in the culture medium in a time-dependent manner. ADM secretion was markedly enhanced by tumour necrosis factor-alpha and interleukin-1beta. Specific mRNA for ADM (RT-PCR and Northern blot) was detected in HSCs and increased after incubation of cells with cytokines. CONCLUSIONS: Human HSCs have functional receptors for ADM, the stimulation of which blunts the contractile effect of endothelin-1. Cultured human HSCs secrete ADM in baseline conditions. This secretion is markedly increased by cytokines. These results suggest that ADM can regulate HSCs' contractility in an autocrine manner.

Hepatocyte-derived cysteinyl leukotrienes modulate vascular tone in experimental cirrhosis.

BACKGROUND & AIMS: The leukotrienes C(4)/D(4)/E(4) (cysteinyl-LTs) are 5-lipoxygenase (5-LO)-derived eicosanoids with potent vasoconstrictor, proliferative, and profibrogenic properties that may participate in key pathophysiologic events in liver cirrhosis. We examined the cysteinyl-LT biosynthetic pathway in liver tissue and purified liver cells isolated from rats with carbon tetrachloride-induced cirrhosis, and assessed the vasoactive properties of LTD(4) in hepatic stellate cells (HSCs) and anesthetized rats. METHODS & RESULTS: Liver homogenates from cirrhotic rats had increased 5-LO mRNA and cysteinyl-LT content, as determined by Northern blot and enzyme immunoassay, respectively. In isolated rat liver cells, 5-LO mRNA expression was found to be restricted to Kupffer cells. However, among the liver cells (i.e., hepatocytes, Kupffer cells, HSCs, and sinusoidal endothelial cells), hepatocytes exhibited the highest ability to generate cysteinyl-LTs from the unstable intermediate LTA(4). Hepatocytes from cirrhotic rats showed an enhanced baseline generation of cysteinyl-LTs, but their ability to synthesize cysteinyl-LTs from exogenous LTA(4) was found to be similar to that of hepatocytes from normal animals. Both LTD(4) and hepatocyte-conditioned medium increased intracellular Ca(2+) concentration and induced contraction in HSCs, suggesting that hepatocyte-derived cysteinyl-LTs could act in a paracrine fashion on nearby nonparenchymal liver cells. The relevance of these in vitro findings was further established in vivo by the observation that LTD(4) significantly increased portal pressure in anesthetized rats. CONCLUSIONS: These data suggest a role for hepatocyte-derived cysteinyl-LTs in mediating hepatic vascular tone abnormalities in cirrhosis.

Altered biosynthesis of leukotrienes and lipoxins and host defense disorders in patients with cirrhosis and ascites.

BACKGROUND & AIMS: Advanced cirrhosis is associated with impaired leukocyte function, but the mechanism underlying this host defense alteration is unknown. The aim of this study was to investigate the lipoxygenase pathway of arachidonic acid metabolism and its influence in leukocyte trafficking in patients with cirrhosis and ascites. METHODS: Neutrophils (polymorphonuclear leukocytes [PMN]) were isolated from patients with cirrhosis and ascites and healthy subjects, and 5-lipoxygenase (5-LO) messenger RNA levels and 5-LO-derived products were measured. The effect of leukotrienes (LT) and lipoxins (LX) on PMN adhesion and migration was also assessed. RESULTS: PMN from patients with cirrhosis showed increased 5-LO messenger RNA expression. However, in vitro generation of LTB4, cysteinyl-containing LT and LX was significantly decreased in cirrhotic patients. Interestingly, a close relationship between the activity of the renin-angiotensin system and LXA4 biosynthesis was observed both in vitro and in vivo. PMN isolated from cirrhotic patients with ascites showed significantly decreased adhesion and migration in response to LTB4. LXA4 did not provoke PMN adhesion and migration, but rather abrogated the differences between control and cirrhotic PMN. Cirrhotic monocytes showed marked impairment in adherence to laminin when stimulated with either LTB4 or LXA4. CONCLUSIONS: These results show the existence of altered biosynthesis of LT and LX and defective response to these lipoxygenase products in leukocytes from patients with cirrhosis and ascites. This abnormality may be relevant to the pathogenesis of host defense disorders in chronic liver disease.

Increased adrenomedullin levels in cirrhosis: relationship with hemodynamic abnormalities and vasoconstrictor systems.

BACKGROUND & AIMS: Arterial vasodilation in cirrhosis may be related to increased circulating levels of vasodilators. This study was designed to assess the circulating levels of adrenomedullin, a recently described vasodilator peptide, in cirrhosis. METHODS: Plasma adrenomedullin levels were measured in 17 healthy subjects and 34 cirrhotic patients. Hemodynamic parameters, renal function, and levels of vasoactive substances were also assessed. RESULTS: Patients with ascites had increased adrenomedullin levels (289 +/- 47 pg/mL) compared with healthy subjects and patients without ascites (135 +/- 17 and 142 +/- 32 pg/mL, respectively; P < 0.05). Adrenomedullin levels correlated inversely with arterial pressure, glomerular filtration rate, and renal plasma flow and correlated directly with pulse rate, endothelin levels, and aldosterone and plasma renin activity. In cirrhotic patients, no significant differences in adrenomedullin levels were found between samples obtained from hepatic vein, renal vein, pulmonary artery, and femoral artery. Plasma expansion with albumin suppressed the renin-angiotensin system but did not affect adrenomedullin levels. CONCLUSIONS: Circulating levels of adrenomedullin are increased in patients with ascites and correlate with hemodynamic and renal abnormalities and activation of vasoconstrictor systems. These increased levels seem to result from a generalized increase in adrenomedullin production from vascular tissue and are not suppressed by plasma expansion. Adrenomedullin may participate in the pathogenesis of arterial vasodilation in cirrhosis.

Lack of renal effects of fish oil administration in patients with advanced cirrhosis and impaired glomerular filtration.

The treatment of renal failure in cirrhotic patients with ascites remains unsatisfactory. Recent studies have shown that the dietary supplementation with fish oil improves the renal function of normal subjects, as well as that of patients with renal failure of different etiologies. We have investigated the renal effects of a daily supplementation for 1 month of 12 g fish oil (27% C20:5 n-3 eicosapentanoic acid [EPA], and 23% C22:6 n-3 docosahexanoic acid [DHA]) in a prospective study of cirrhotic patients with ascites, nine with normal renal function (group 1) and eight with renal failure (glomerular filtration rate [GFR] < 60 mL/min, group 2). Compliance with the dietary regimen was confirmed by fatty acid chromatography that showed increased plasma concentration of EPA (from 1.5 +/- 0.7% to 3.7 +/- 0.8%, P = .024, in group 1; and from 0.53 +/- 0.3% to 2.9 +/- 0.8%, P = .03, in group 2) and of DHA (from 2.1 +/- 0.4% to 3.4 +/- 0.3%, P = .008, in group 1; and from 1.45 +/- 0.5% to 3.8 +/- 0.4%, P = .05, in group 2). At the end of the study, in patients from group 1, the glomerular filtration rate increased by 19% (from 94 +/- 8 to 113 +/- 13 mL/min, P = .039), and the urine flow increased by 39% (from 0.85 +/- 0.14 to 1.12 +/- 0.2 mL/min, P = .039), while no changes occurred in the renal function of patients from group 2. No changes were observed in the urinary excretion of prostaglandin (PG) E2 or of 6-keto prostaglandin-1-alpha (6-K-PGF1-alpha) nor in plasma renin activity (PRA) or the plasma concentration of aldosterone (PA) or antidiuretic hormone (ADH) in both groups. As far as undesirable effects of fish oils were considered, the mean arterial pressure (MAP) decreased in both groups (group 1: from 88.6 +/- 2 to 85.3 +/- 2 mm Hg, P = .015; group 2: from 88.2 +/- 3 to 82.8 +/- 3 mm Hg, P = .05), and bleeding time displayed a significant increase when patients were considered collectively (from 744 +/- 89 to 872 +/- 106 seconds, P = .0068). In conclusion, the administration of fish oil for 1 month was unable to improve renal function in cirrhotic patients with ascites and renal failure. The occurrence of undesirable effects, such as the reduction of arterial pressure and the prolongation of bleeding time, argues against the use of fish oils in these patients.

Inhibitory actions of cyclic adenosine monophosphate and pertussis toxin define two distinct epidermal growth factor-regulated pathways leading to activation of mitogen-activated protein kinase in rat hepatocytes.

Increased intracellular cyclic adenosine monophosphate (cAMP) levels have been shown in some reports to inhibit and in other studies to stimulate growth factor-mediated activation of the mitogen-activated protein kinase (MAP kinase) pathway, depending on the cell type examined. The relationship between cAMP and MAP kinase in hepatocytes has not been examined. In the current study, stimulation of primary cultures of rat hepatocytes with hepatocyte growth factor (HGF) or epidermal growth factor (EGF) increased Ras, Raf, and MAP kinase activity. Incubation of hepatocytes with cAMP-increasing agents blocked activation of Raf by both HGF and EGF, whereas activation of Ras was unaffected. MAP kinase activation by HGF was completely inhibited, whereas EGF-stimulated MAP kinase activity was only slightly reduced. Incubation of hepatocytes with pertussis toxin slightly blunted MAP kinase activation by EGF but not HGF. Increasing cAMP in hepatocytes preincubated with pertussis toxin completely inhibited the activation of MAP kinase by EGF. In conclusion, HGF activates MAP kinase in hepatocytes exclusively through an Raf-dependent pathway and this activation may be completely blocked by increasing cAMP. In contrast, EGF activates MAP kinase in hepatocytes through both Raf-dependent and Raf-independent pathways: the latter pathway probably involves a pertussis toxin-sensitive G protein.

Impact of shunt surgery for variceal bleeding in the natural history of ascites in cirrhosis: a retrospective study.

Despite the efficacy of shunt surgery in the treatment of variceal bleeding, less effective nonoperative therapies are being substituted because surgical shunt does not modify survival and increases hepatic encephalopathy. However, the real impact of shunt surgery on the natural history of ascites and its complications has not been established. The course of 204 Child-Pugh A and B cirrhotic patients with variceal bleeding included in three controlled trials of our units who survived first hospitalization was updated. Ninety-eight patients (group I) were treated by portacaval (56 patients) or distal splenorenal (42 patients) shunt, whereas 106 (group II) were treated by nonshunt procedures (sclerotherapy in 89 patients and staple transection in 17 patients). As expected, the 5-yr probability of variceal rebleeding was lower (13% vs. 44%) and hepatic encephalopathy higher (50% vs. 28%) in group I than in group II, and survival was similar (67% vs. 60%). Shunt surgery had a great impact on the natural history of ascites and its complications. The probability of occurrence of ascites (15% vs. 73%; p < 0.0001), spontaneous bacterial peritonitis (2% vs. 21%; p < 0.0001) and hepatorenal syndrome (4% vs. 21%; p < 0.01) was greatly reduced. These beneficial effects accounted for the lower percentage patients requiring readmissions (51% vs. 70%; p = 0.02) and shorter total time spent in hospital (14 +/- 22 vs. 26 +/- 39 days/patient; p = 0.01) in group I. These data indicate that shunt surgery, in addition to reducing the probability of rebleeding, markedly decreases the probability of ascites, spontaneous bacterial peritonitis and hepatorenal syndrome development.(ABSTRACT TRUNCATED AT 250 WORDS)

Acute liver failure due to non-Hodgkin's lymphoma.

Acute hepatic failure secondary to involvement of the liver by hematologic malignancies is a very uncommon condition, and usually has a fatal prognosis. We describe the case of a woman who developed acute hepatic failure due to infiltration by a non-Hodgkin's lymphoma 18 yr after the initial diagnosis of a nodular-type lymphocytic lymphoma, while she was apparently in remission. Early diagnosis was achieved through liver biopsy; therefore, rapid administration of chemotherapy allowed her complete recovery. Hepatic biopsy may provide a diagnosis in patients in whom the etiology of liver failure is unknown, thus establishing the possible need for specific treatment.

Effect of dipyridamole on kidney function in cirrhosis.

Adenosine is a potent endogenous renal vasoconstrictor. To investigate the sensitivity of the renal circulation to adenosine in cirrhosis, we evaluated kidney function and vasoactive hormones in 20 patients with cirrhosis before and after administration of dipyridamole (0.4 mg/kg, intravenously), a drug that increases extracellular levels of adenosine. In patients with ascites and increased plasma renin activity (6.9 +/- 4.0 ng/ml.hr [mean +/- S.D.]) (n = 7), dipyridamole induced marked reductions in renal plasma flow (from 623 +/- 294 to 374 +/- 188 ml/min, p = 0.03), glomerular filtration rate (from 89 +/- 22 to 48 +/- 16 ml/min, p = 0.009), urine volume (from 7.1 +/- 2.1 to 1.5 +/- 1.1 ml/min, p = 0.0001), free water clearance (from 4.0 +/- 1.7 to 0.4 +/- 0.6 ml/min, p = 0.001) and sodium excretion (from 28 +/- 36 to 7 +/- 15 mu Eq/min, p = 0.05) in the absence of changes in arterial pressure, plasma renin activity and levels of aldosterone, norepinephrine and antidiuretic hormone. In patients without ascites (n = 5) and in patients with ascites and normal plasma renin activity (0.9 +/- 0.5 ng/ml.hr) (n = 8), renal plasma flow and glomerular filtration rate did not change significantly after dipyridamole administration, whereas excretion of sodium and free water was reduced. These results indicate that in cirrhotic patients with ascites and overactivity of the renin-angiotensin system, dipyridamole induces renal vasoconstriction in the absence of changes in systemic hemodynamics, suggesting that these patients are particularly sensitive to the renal vasoconstrictor effect of endogenous adenosine.

Bile-duct hamartomas presenting as multiple focal lesions on hepatic ultrasonography.

Multiple bile-duct hamartomas are usually diagnosed at autopsy as an incidental finding. We report a case of a 50-yr-old male in whom multiple bile-duct hamartomas were suspected in an abdominal ultrasonography and confirmed by an echo-guided needle liver biopsy. The ultrasonography disclosed multiple scattered hyperechoic lesions with a diameter of up to 1 cm, associated with some anechoic lesions of a larger size and a cystic appearance. Computed tomography demonstrated multiple hypodense lesions that were not modified by the administration of contrast. Bile-duct hamartomas should be included in the differential diagnosis of multiple focal hepatic lesions at ultrasonography or computed tomography.

[Liver transplantation: candidate selection and results of a program for adult patients]. / Trasplante hepático: selección de candidatos y resultados obtenidos en un programa para pacientes adultos.

During the first 18 months of liver transplantation program for adult patients we evaluated 98 potential candidates for this treatment. Forty five patients were refused for transplantation and 53 were accepted. Forty six out of these 53 cases were transplanted. Ten (22%) out of the 46 patients undergoing transplantation had chronic hepatic cholestasis, 31 (67%) chronic hepatic diseases of non biliary origin (3 patients had an associated hepatocarcinoma), and 5 patients (11%) suffered an acute hepatic failure. All transplanted patients with previous chronic hepatic diseases had clinical and biological signs of advanced hepatic failure. There were no operative deaths. During the follow-up period 6 transplanted patients (13%) died. The survival probability among the 46 operated patients was about 84% at 12 months after the transplant. This survival was theoretically higher than that expected to occur without transplantation. The survival probability among the 46 transplanted patients was significantly higher (p = 0.0001) than that recorded in 36 patients with comparable hepatic diseases who were evaluated during the same study period and who were not considered for transplantation due to several reasons. The survival probability at the first year in the later group of 36 patients was 20%.

Prognostic factors of hepatocellular carcinoma in the west: a multivariate analysis in 206 patients.

To investigate the prognostic factors in Western patients with hepatocellular carcinoma, 206 patients with confirmed diagnoses of hepatocellular carcinoma were studied in terms of survival. All patients were diagnosed between 1983 and 1987. A multivariate survival analysis (Cox regression model) using clinical, biochemical, ultrasonographical and pathological data obtained at diagnosis disclosed that bilirubin (p = 0.0001), ascites (p = 0.0001), toxic syndrome (defined by the presence of weight loss greater than 10% premorbid weight, malaise and anorexia) (p = 0.009), blood urea nitrogen (p = 0.025), tumor size (p = 0.001), gamma-glutamyltranspeptidase (p = 0.0006), age (p = 0.0005), serum sodium (p = 0.003) and presence of metastases (p = 0.002) were independent predictors of survival. According to the contribution of each of these factors to the final model, a prognostic index was constructed allowing division of patients in different groups according to their relative risk of death: RRD = EXP (Age x 0.03 + Ascites x 0.8281 + BUN x 0.0137 + Serum sodium x (-0.0538) + gamma-Glutamyltranspeptidase x 0.0019 + Bilirubin x 0.0734 + Tumor size x 0.33 + Toxic syndrome x 0.4965 + Metastases x 0.55). These results facilitate the stratification of hepatocellular carcinoma patients to design and evaluate future controlled trials.

Urinary excretion of endogenous digitalis-like natriuretic substances in healthy subjects. Effect of sodium load.

In the current study digoxin-like immunoreactivity (DLIA), Na-K-ATPase inhibition and natriuretic activity of urinary extracts from 10 healthy volunteers following a low and a high-sodium intake, respectively, were measured. Detectable urinary DLIA (46.1 +/- 5.6 ng eq digoxin/day), Na-K-ATPase inhibition (182.9 +/- 22.7 nmol eq oub/day) and natriuretic activity (UNaV: 0.38 +/- 0.11 microEq/min) were observed during the low-sodium diet period in all subjects. High-sodium diet was associated with a significant increase in DLIA (87.9 +/- 9.2 ng eq digoxin/day, p less than 0.001) which parallelled changes in Na-K-ATPase inhibition (359.8 +/- 51.9 nmol eq oub/day, p less than 0.005) and natriuretic activity (UNaV: 1.33 +/- 0.3 microEq/min, p less than 0.025). These results support the contention that DLIA is related to NH.

Natriuretic hormone activity in the urine of cirrhotic patients.

The ability of urine extracts to inhibit sodium and potassium-activated ATPase, cross-react with antidigoxin antibodies and induce natriuresis in rats was investigated in 10 healthy subjects, 10 cirrhotic patients without ascites (compensated cirrhotics), 27 nonazotemic cirrhotic patients with ascites and 10 cirrhotic patients with ascites and functional renal failure to assess whether reduced activity of natriuretic hormone contributes to sodium retention in cirrhosis. No significant differences were seen between healthy subjects and compensated cirrhotic patients in any of these parameters (sodium and potassium-activated ATPase inhibition = 178.5 +/- 19.8 vs. 247.4 +/- 48.7 nmol equivalent of ouabain/day; digoxinlike activity = 43.9 +/- 6.1 vs. 48.0 +/- 5.6 ng equivalent of digoxin/day; natriuretic activity = 0.36 +/- 0.15 vs. 0.63 +/- 0.27 mumol/min). Cirrhotic patients with ascites with and without functional renal failure showed significantly higher values of sodium and potassium-activated ATPase inhibition (708.1 +/- 94.0 and 529.2 +/- 53.9 nmol equivalent of ouabain/day, respectively), digoxinlike activity (136.9 +/- 7.2 and 116.3 +/- 7.9 ng equivalent of digoxin/day) and natriuretic activity (1.78 +/- 0.48 and 1.93 +/- 0.37 mumol/min) than healthy subjects and compensated cirrhotic patients. We saw no significant differences between these two groups of cirrhotic patients with ascites with respect to these parameters. In the cirrhotic patients studied, sodium and potassium-activated ATPase inhibition and antidigoxin antibodies directly correlated with the degree of impairment of hepatic and renal function, plasma renin activity and plasma levels of aldosterone and norepinephrine.(ABSTRACT TRUNCATED AT 250 WORDS)

Natural history of hepatocellular carcinoma in Spain. Five year's experience in 249 cases.

In this study we attempted to define the clinical pattern and prognosis of hepatocellular carcinoma (HCC) patients in Spain. Two hundred and forty-nine patients were included in the study. One hundred and eighty-seven were male and 62 female, with their mean age being 62.5 +/- 0.6 years. The majority of patients (92.8%) had an underlying cirrhosis. In most of the patients, the disease appeared as decompensated liver disease. Only 18.5% of the HCC cases were asymptomatic. Only 8.2% of the cases were HBsAg positive. alpha-Fetoprotein reached diagnostic values in only 37.2% of the patients. Surgical treatment was successfully performed in 14 patients: one underwent orthotopic liver transplantation and the 13 others complete tumor resection. Chemotherapy was administered to 38 subjects, while percutaneous ethanol injection was applied in seven cases. Patients receiving only symptomatic treatment, comprised 76.7%. Survival was related to tumor size and liver function. While the median survival of the whole series was 3.3 +/- 0.4 months, it was 14.5 +/- 2.2 months in patients with preserved liver function and small tumors. These results reflect that in Spain HCC patients are diagnosed at a moderately advanced phase. Since early diagnosis is the only way to increase the proportion of patients suitable for curative treatment, early detection plans are mandatory in the population at risk.