Brain natriuretic peptide: is it a predictor of cardiomyopathy in cirrhosis?

Subtle cardiac abnormalities have been described in patients with cirrhosis. Natriuretic peptide hormones have been reported to be sensitive markers of early cardiac disease. We postulate that plasma levels of N-terminal pro-atrial natriuretic peptide and brain natriuretic peptide could be used as markers of cardiac dysfunction in cirrhosis. The aim of the study was to evaluate the levels of N-terminal pro-atrial natriuretic peptide and brain natriuretic peptide and their relationship with cardiac structure and function in patients with cirrhosis. The study population comprised 36 patients with cirrhosis of mixed aetiologies, but with no cardiac symptoms; 19 of the patients had ascites and 17 did not. The subjects underwent (i) trans-thoracic two-dimensional echocardiography, and (ii) radionuclide angiography for measurements of cardiac structural parameters, diastolic and systolic function. Levels of N-terminal pro-atrial natriuretic peptide and brain natriuretic peptide were also measured. The results were compared with those from eight age- and sex-matched healthy volunteers. Compared with the controls, the baseline mean ejection fraction was increased significantly in both patient groups (P=0.02), together with prolonged deceleration times (P=0.03), left atrial enlargement (P=0.03) and interventricular septal thickening (P=0.02), findings that are compatible with diastolic dysfunction. Levels of N-terminal pro-atrial natriuretic peptide and brain natriuretic peptide were significantly higher in all patients with cirrhosis with ascites (P=0.01 and P=0.05 respectively), but in only some of the pre-ascitic cirrhotic patients, compared with controls. All high levels of brain natriuretic peptide were correlated significantly with septal thickness (P<0.01), left ventricular diameter at the end of diastole (P=0.02) and deceleration time (P<0.01). We conclude that elevated levels of brain natriuretic peptide are related to interventricular septal thickness and the impairment of diastolic function in asymptomatic patients with cirrhosis. Levels of brain natriuretic peptide may prove to be useful as a marker for screening patients with cirrhosis for the presence of cirrhotic cardiomyopathy, and thereby identifying such patients for further investigations.

Effects of ascites resolution after successful TIPS on nutrition in cirrhotic patients with refractory ascites.

OBJECTIVE: Malnutrition is common in patients with decompensated cirrhosis and refractory ascites. The use of transjugular intrahepatic portosystemic stent shunt (TIPS) is effective in eliminating ascites. The purpose of this study was to investigate the effect of TIPS and resolution of refractory ascites on the nutritional status of patients with decompensated cirrhosis. METHODS: Fourteen consecutive patients with refractory ascites and a Pugh score of 9.0+/-0.5 had a TIPS insertion. Biochemical data, resting energy expenditure (REE), total body nitrogen (TBN), body potassium (TBK), body fat (TBF), muscle force (MF), and food intake were recorded before TIPS, and at 3 and 12 months after the procedure. RESULTS: Ten patients completed the study. Baseline values for REE, TBN, TBF, MF, and energy intake were below normal at baseline. There was a significant increase in dry weight, TBN, and REE at 3 and 12 months compared with baseline. TBF improved significantly at 12 months. There was a trend toward an increase in energy intake (p = 0.072). There was no change in protein intake, TBK, MF, and Pugh score. CONCLUSION: In cirrhotic patients with refractory ascites, resolution of the ascites after TIPS placement resulted in improvement of several nutritional parameters, especially for body composition.

Cytokine network in nonresponding chronic hepatitis C patients with genotype 1: role of triple therapy with interferon alpha, ribavirin, and ursodeoxycholate.

OBJECTIVE: (i) to characterize the profile of tumor necrosis factor alpha (TNF alpha), interleukin-6 (IL-6), IL 10, Fas-ligand and transforming growth factor beta (TGF beta), chronic hepatitis C (HCV) patients with genotype 1; (ii) to determine the influence of triple therapy (TT) with interferon alpha (IFN alpha) + ribavirin + ursodeoxycholic acid on these cytokines and (iii) to establish the relationship between the pro-inflammatory cytokines and the outcome of treatment. DESIGN AND METHODS: 22 patients infected with HCV-genotype 1 a/b and non responsive to IFN-alpha monotherapy were enrolled in the TT. The controls were 49 HCV naïve patients with genotype 1 a/b. Cytokine levels were measured using enzyme-linked immunosorbent assay (ELISA). RESULTS: The baseline TNF alpha values (pg/mL) in the sustained responders (SRs) (63+/-3) were significantly lower than non-responders (NRs) (140+/-16) (p < 0.001). Baseline Fas (ng/mL) levels were also lower in SRs (4.3+/-0.2) than NRs (5.4+/-0.4) (p < 0.05). CONCLUSIONS: Fas and TNF alpha may be used as serological markers of inflammation and effectiveness of therapy.

Accumulation of macrophages in primary sclerosing cholangitis.

OBJECTIVES: To determine what changes are occurring in patients with primary sclerosing cholangitis (PSC) by examining perisinusoidal macrophages (Kupffer cells) in liver biopsies; 2-to measure transforming growth factor beta (TGFbeta) as a marker of fibrosis in these patients. DESIGN AND METHODS: Transmission electron microscopy and immunohistochemistry of 15 PSC, 26 primary biliary cirrhosis (PBC), 30 alcoholic liver disease (ALD) and 51 with normal histology was used. Five PSC, 30 ALD and 120 normal volunteers were sampled for serum levels of TGFbeta. RESULTS: There was a three-fold increase in relative numbers of Kupffer cells in PSC compared to PBC and to patients whose livers had normal histology. In PSC there was an accumulation of perisinusoidal macrophages, which was not associated with focal necrosis or with cholestasis. The levels of TGFbeta in PSC were 54 +/- 2 in cirrhotic versus 34 +/- 5 in non-cirrhotic patients (p < 0.005). CONCLUSION: The persistent activation of these macrophages may lead to the chronic release of TGFbeta and contribute to chronic inflammation, fibrosis and cirrhosis.

Portal hypertension induces sodium channel expression in colonocytes from the distal colon of the rat.

Cellular mechanisms for Na(+) retention in portal hypertension are undefined, but epithelial Na(+) channels (ENaC) may be involved. Under high-salt diet, ENaC are absent from distal colon of rat but can be induced by mineralocorticoids such as aldosterone. Presence of rat ENaC was determined by amiloride inhibition of (22)Na(+) uptake in surface colonocytes 7 and 14 days after partial portal vein ligation (PVL) or sham surgery. At both times, uptake inhibition was significantly increased in PVL rats. Presence of mRNA transcripts, determined by RT-PCR, demonstrated that channel alpha- and gamma-subunits were similarly expressed in both groups but that beta-subunit mRNA was increased in PVL rats. This confirms that there was induction of rat ENaC and indicates that beta-subunit has a regulatory role. Urinary Na(+) was decreased for 3 days after PVL but was not different at other times, and serum aldosterone levels were elevated at 7 days, at a time when urinary Na(+) output was similar to that of sham-operated rats. We conclude that PVL leads to induction of ENaC in rat distal colon. An increase in aldosterone levels may prevent natiuresis and is probably one of several control mechanisms involved in Na(+) retention in portal hypertension.

The effects of hypothyroidism on liver status of cirrhotic patients.

We have shown, in animal models as well as in retrospective human study, that some degree of decreased thyroid function is beneficial for subjects with liver damage of various etiologies. Therefore, we herein present the results of a cohort population study. Between 1991 and 1994, 18 patients (12 women and 6 men; mean age, 59 +/- 24 years) with both biopsy-proven active cirrhosis (5 hepatitis C virus, 4 hepatitis B virus, 1 immunocompromised host, 2 primary biliary cirrhosis, 1 alcoholic, and 5 cryptogenic; Child's-Pugh criteria: A-8, B-8, C-2) and primary or induced (by either drug or surgery) thyroxine-treated hypothyroidism were prospectively followed. Each patient was examined at least twice yearly and served as their own control. The thyroid of the profiled patients ranged between euthyroidism and subclinical hypothyroidism. Liver function tests were evaluated and compared in states of normal versus increased thyroid-stimulating hormone (TSH) blood levels. A significant improvement in alanine aminotransferase (p < 0.001), alkaline phosphatase (p < 0.0001), albumin (p < 0.001), and bilirubin (p < 0.01) was found in the increased TSH group. Prothrombin time was also found to be significantly better (p < 0.001). We conclude that euthyroid patients with liver cirrhosis might benefit from a controlled hypothyroidism.

A pilot study on the hemodynamic effect of short-term ursodeoxycholic acid therapy in patients with stable liver cirrhosis.

OBJECTIVE: Total serum bile acid concentrations are elevated in individuals with liver disease. Ursodeoxycholic acid (UDCA) therapy in such patients results in a further significant rise in plasma levels to the extent that it becomes the major circulating bile acid. In laboratory animals, bile acids, such as taurocholic acid, have also been shown to possess a diuretic-like action, as they can promote diuresis, natriuresis, and kaliuresis by inhibiting tubular sodium reabsorption. The aim of the present study was to assess the effect of 1 month's UDCA therapy on cardiovascular function in cirrhotic patients. METHODS: Two groups of patients with cirrhosis were studied, six with primary biliary cirrhosis (PBC) and six with postnecrotic liver cirrhosis (PNC). Cardiovascular function was assessed by determination of blood pressure, heart rate, and by two-dimensional and pulsed Doppler echocardiography. RESULTS: In PBC patients, 1 month's treatment with UDCA significantly reduced diastolic volume without changing systolic, diastolic, and mean blood pressures, heart rate, systolic and stroke volumes, ejection fraction, cardiac output, and systemic vascular resistance. In PNC patients, UDCA significantly reduced cardiac output, with a tendency to reduce left ventricular volumes, without any changes in systolic, diastolic, and mean blood pressures. CONCLUSIONS: UDCA caused reductions in diastolic volume in the PBC patients and cardiac output in the PNC patients. Such reductions are not unlike that seen in individuals treated with diuretics. This diuretic-like action deserves further study, particularly in cirrhotic patients who are also being treated with diuretics or show evidence of cardiac myopathy.

Multivesicular stellate cells in primary biliary cirrhosis.

Stellate cells have only recently received attention in patients with primary biliary cirrhosis (PBC). We have used electron microscopy and morphometry to perform a qualitative and quantitative examination of lipid-storing activity of stellate cells in liver biopsies of 26 patients with noncirrhotic and cirrhotic PBC. In parallel with this study, a comparative analysis of the morphology of stellate cells in 51 patients with livers of normal histology was performed. There was a marked increased in the total number of lipid vesicles in stellate cells in all PBC patients when compared with livers with normal histology. Multiple multivesicular stellate cells were seen in the livers of 21 of 26 patients with PBC. There were 11 to 28 lipid vesicles per multivesicular stellate cell in sizes of 1 microm to 5 microm in diameter per lipid vesicle. Hepatocytes showed little or no steatosis in 24 of 26 (92%) PBC patients. Multivesicular stellate cells were not seen in female patients with normal liver histology. These results suggest that there is an alteration in hepatic lipid storage that involves stellate cells in PBC that could be an early manifestation of this disease. Its significance remains to be elucidated.

Multivesicular stellate cells in primary biliary cirrhosis.

Stellate cells have only recently received attention in patients with primary biliary cirrhosis (PBC). We used electron microscopy and morphometry to perform a qualitative and quantitative examination of lipid-storing activity of stellate cells in liver biopsies of 26 patients with noncirrhotic and cirrhotic PBC. Parallel with this study, a comparative analysis of the morphology of stellate cells in 51 patients with livers of normal histology was performed. There was a marked increase in the total number of lipid vesicles in stellate cells in all PBC patients when compared to livers with normal histology. Multiple multivesicular stellate cells were seen in the livers of 21 out of 26 patients with PBC. There were 11 to 28 lipid vesicles per multivesicular stellate cell from 1 micromol/L to 5 micromol/L in diameter per lipid vesicle. Hepatocytes showed little or no steatosis in 24 out of 26 (92%) PBC patients. Multivesicular stellate cells were not seen in female patients with normal liver histology. These results suggest that there is an alteration in hepatic lipid-storage that involves stellate cells in PBC, which could be an early manifestation of this disease. Its significance remains to be determined.

Experimental study in bile duct-ligated rats of vasopressin and preoperative volume loading to prevent hypotensive crises.

BACKGROUND: Systemic hypotension may result in postoperative renal failure in jaundiced patients. Attenuated responsiveness to catecholamines and hypovolaemia has been reported in jaundiced animals and may be a mechanism contributing to the increased susceptibility of jaundiced patients to haemorrhagic shock. This suggests that an alternative to vasoactive amines to control perioperative hypotension could be desirable. METHODS: This study evaluated the pressor response to vasopressin in normovolaemic 3-day bile duct-ligated rats and in 3-day bile duct-ligated rats after an acute controlled haemorrhage. It also evaluated the response after volume loading with 0.9 per cent saline, 7.5 per cent saline, colloid and mannitol before controlled haemorrhage. In addition, blood volume was measured using radiolabelled albumin. All the data obtained from bile duct-ligated rats were compared with data from sham-operated animals. RESULTS: Attenuated pressor responses to vasopressin were not observed in either normotensive bile duct-ligated rats or in the bile duct-ligated rats subjected to controlled haemorrhage. Volume loading with the four fluids over the dosing range 2.5-7.5 microliters per g body-weight in bile duct-ligated rats reversed the susceptibility to haemorrhagic hypotension. CONCLUSION: Although no reduction in blood volume was demonstrated, bile duct-ligated rats may have a reduced effective blood volume manifesting itself as a latent hypovolaemia and/or tendency to hypotension. Preoperative fluid loading could be beneficial because it corrects hypovolaemia and improves cardiovascular function, as well as improving the cardiovascular response to haemorrhage.

Cardiovascular, renal, and neurohumoral responses to single large-volume paracentesis in patients with cirrhosis and diuretic-resistant ascites.

OBJECTIVE: Large volume paracentesis is an effective treatment for refractory ascites, but the need for routine infusion of albumin or other volume expanders remains controversial. The aim of this study was to assess the short term effects of a single 5-L paracentesis without albumin replacement on total central blood volume, systemic and renal hemodynamics, sodium homeostasis, and neurohumoral factors. PATIENTS AND METHODS: Twelve patients with biopsy-proven cirrhosis and tense, diuretic-resistant ascites were studied before and 48 h after a single 5-L paracentesis without albumin infusion. Systemic hemodynamics and total central blood volume were assessed using radionuclide angiography. Glomerular filtration rate and effective renal plasma flow were measured by inulin and para-aminohippurate clearances, respectively. Lithium clearance was used as an index of proximal tubular reabsorption of sodium. In addition, plasma concentrations of neurohumoral factors were determined. RESULTS: Total central blood volume was 2.41 +/- 0.33 L/m2 (mean +/- SEM) before and 2.34 +/- 0.18 L/m2 48 h after large volume paracentesis (p = 0.76). Similarly, no differences were detected in the cardiac index, glomerular filtration rate, effective renal plasma flow, urinary sodium excretion, hematocrit, plasma renin activity, or concentrations of plasma aldosterone, norepinephrine, or atrial natriuretic factor. CONCLUSIONS: A single large volume paracentesis without albumin replacement causes no disturbances in systemic and renal hemodynamics 48 h after the procedure. These results suggest that a single 5-L paracentesis without albumin infusion is a safe and satisfactory short term option for the management of patients with cirrhosis and tense, diuretic-resistant ascites.

Evaluation of liver transplantation for high-risk indications.

BACKGROUND: Appropriate use of orthotopic liver transplantation (OLT) requires continued assessment of the indications for transplantation as a number of diseases are associated with a poor prognosis. High-risk patients are those who have a poor survival or high incidence of recurrent disease (patients with tumours, hepatitis B- or hepatitis C-induced cirrhosis, fulminant hepatic failure or primary graft non-function). In addition, retransplantation may be associated with a poor outcome. METHODS: A retrospective review was made of the records of all adult patients undergoing OLT at this hospital between October 1985 and July 1994. RESULTS: A total of 396 liver transplants were performed in 364 patients. The 1- and 3-year actuarial survival rates were 81 and 69 per cent respectively. The overall survival rate of high-risk patients was significantly lower than that for all OLT recipients (P < 0.05). While no patients transplanted for hepatitis C have developed graft failure, recurrent hepatitis occurred in 15 of 35 patients. CONCLUSION: Strict selection criteria and appropriate perioperative investigations and interventions are required to improve the results of OLT in these high-risk patients.

Is the Mayo model for predicting survival useful after the introduction of ursodeoxycholic acid treatment for primary biliary cirrhosis?

Treatment of patients with primary biliary cirrhosis (PBC) using ursodeoxycholic acid (UDCA) leads to a reduction in serum bilirubin. The first objective of this study was to assess the performance of certain prognostic indicators for PBC after the introduction of treatment with UDCA. Serum bilirubin is an important prognostic indicator for PBC and an important component of the Mayo model for grading patients into risk categories. In an analysis of patients enrolled in the Canadian multicenter trial, the Mayo score was calculated before and after treatment with UDCA. After treatment, the Mayo score continued to divide patients with PBC into groups with varying risk. In addition, the serum bilirubin alone was shown to do the same even after the introduction of treatment with UDCA. A second objective was to establish whether UDCA had an effect on long-term (2- to 6-year) survival in patients with PBC.

Prostaglandins in liver failure and transplantation: regeneration, immunomodulation, and cytoprotection. Prostaglandins in Liver Transplantation Research Group.

Prostaglandins (PG) are involved in the regulation of many physiological processes in the liver and play a major role in the pathophysiology and treatment of liver diseases. In addition to their effects of cell growth and immune function, PGs have shown cytoprotective effects on hepatocytes in various toxic, ischemic, and infectious models of liver injury. Although the mechanisms for these beneficial effects have not been precisely delineated, synthetic PG analogues have increasingly been used in patients with acute liver failure and chronic liver disease. There is also increasing evidence suggesting that PGs may reduce the early morbidity and mortality associated with liver transplantation, particularly in the context of primary graft nonfunction and renal dysfunction associated with cyclosporine and tacrolimus therapy. PG analogues have also been used for the treatment and control of recurrent hepatitis B virus infection in liver allograft recipients. The purpose of this review is to evaluate the role of PGs in hepatic physiology and disease and to review the use of synthetic PG analogues in the clinical settings of liver failure and transplantation.

Primary sclerosing cholangitis in 32 children: clinical, laboratory, and radiographic features, with survival analysis.

The clinical presentation and outcome of 32 children with primary sclerosing cholangitis (PSC) are reviewed, the largest North American series. The majority of patients were diagnosed in their second decade (median age: 13 years). Four children presented before the age of 2 years, but none in the neonatal period. Seventeen patients had inflammatory bowel disease (IBD), all with colitis, 14 ulcerative colitis, and 3 Crohn's disease. Eight patients presented with chronic liver disease before clinical onset of IBD. Only 8 of 32 patients were jaundiced at presentation. Fifteen of 32 had a normal serum alkaline phosphatase (ALP) level at presentation. Nine children presented with features similar to those of autoimmune hepatitis. Cholangiography was performed in all cases and classified by a scoring system specifically developed for pediatric patients. Intrahepatic disease predominated; in only three cases a common bile duct stricture was identified requiring stenting. Findings on the initial liver biopsy were classified according to Ludwig's criteria for staging PSC: there were 15 biopsies in stages 1 to 2 and 17 biopsies stages 3 to 4. HLA class I and II antigens were determined in 27 patients. An increased incidence of HLA B8 and DR2(15) but not DRw52a (DRB3*0101) was found. Anti-neutrophil cytoplasmic antibody (ANCA) was positive in 10 of 24 patients tested. Survival analysis indicated that a later age at presentation, splenomegaly, and prolonged prothrombin time (PT) at presentation were significant contributors to the prediction of poor outcome (i.e., death or listing for transplantation). Liver transplantation was successfully performed in seven children. Physicians must maintain a high index of suspicion of PSC in any child or young adult presenting with chronic liver disease, especially in the presence of IBD, even with a normal serum alkaline phosphatase level.

p53 expression in patients with cirrhosis with and without hepatocellular carcinoma.

BACKGROUND: Mutated p53 acts as a dominant oncogene, whereas the wild type (wt) p53 gene product suppresses cell growth. Abnormalities in the p53 gene are reported in more than 50% of malignant tumors. Recently, an allelic loss of chromosome 17p, where the p53 gene is located, was found to be more frequent in hepatocellular carcinoma (HCC) cell lines and human tumors. In addition, in half of the cases of HCC from endemic areas for hepatitis B virus and aflatoxin, a hot spot point mutation at codon 249 was detected, as previously reported. Missense mutations in p53, mdm-2 complex formation, and other unknown mechanisms may lead to stabilization of the gene product, thus rendering it detectable by immunohistochemistry. METHODS: To assess the relationship between p53 status at a premalignant stage and in HCC, the authors studied the immunohistologic expression of p53 in HCC and in the adjacent nontumorous resected liver tissue, using monoclonal antibody to wt and mutated p53. RESULTS: Twelve of the 14 patients with liver tumors had HCC. Of the 12 patients with HCC and underlying cirrhosis, 8 (67%) had increased p53 expression in HCC cells. Eight of the 12 patients with p53-positive HCC cells had p53 overexpression in the nontumorous hepatocytes within regenerative nodules adjacent to HCC tissue. Three of 21 cirrhotic livers without a detectable tumor had increased p53 expression in the regenerative nodules. None of the 12 patients with chronic active hepatitis without cirrhosis or the 13 with a normal liver histology had increased p53 expression. CONCLUSION: p53 overexpression in some cirrhotic livers and in nontumorous livers of patients with HCC may indicate a normal p53 gene response to cellular stress or, alternatively, to an abnormally or mutated p53 gene, and could occur before the development of HCC.

Hepatic and portal vein thrombosis in cirrhosis: possible role in development of parenchymal extinction and portal hypertension.

Obliterative lesions in portal veins (PVs) and hepatic veins (HVs) of all sizes are known to occur in cirrhotic livers. PV lesions have generally been attributed to thrombosis, but the pathogenesis of the HV (veno-occlusive) lesions is unknown. We have studied 61 cirrhotic livers removed at transplantation to clarify the prevalence, distribution, and pathogenesis of venous lesions, as well as the association of these lesions with other morphological features and clinical morbidity. Intimal fibrosis that is highly suggestive of healed HV or PV thrombosis was found in at least 70% and 36% of livers, respectively. The distribution of HV lesions was patchy and largely confined to veins between 0.1 and 3 mm in diameter, suggesting multifocal origin in small veins. PV lesions were more uniform throughout the liver, suggesting origin in large veins with propagation to the small veins. HV lesions were associated with regions of confluent fibrosis (focal parenchymal extinction), and PV lesions were associated with regional variation in the size of cirrhotic nodules and a history of bleeding varices. These observations suggest that thrombosis of medium and large PVs and HVs is a frequent occurrence in cirrhosis, and that these events are important in causing progression of cirrhosis.

Iron-chelation therapy with oral deferiprone in patients with thalassemia major.

BACKGROUND: To determine whether the orally active iron chelator deferiprone (1,2-dimethyl-3-hydroxy-pyridin-4-one) is efficacious in the treatment of iron overload in patients with thalassemia major, we conducted a prospective trial of deferiprone in 21 patients unable or unwilling to use standard chelation therapy with parenteral deferoxamine. METHODS: Hepatic iron stores were determined yearly by chemical analysis of liver-biopsy specimens or magnetic-susceptibility measurements. Detailed clinical and laboratory studies were used to monitor safety and compliance. RESULTS: The patients received deferiprone therapy for a mean (+/-SE) of 3.1 +/- 0.3 years. Ten patients in whom previous chelation therapy with deferoxamine had been ineffective had initial hepatic iron concentrations of at least 80 mumol per gram of liver, wet weight -- values associated with complications of iron overload. Hepatic iron concentrations decreased in all 10 patients, from 125.3 +/- 11.5 to 60.3 +/- 9.6 mumol per gram (P < 0.005), with values that were less than 80 mumol per gram in 8 of the 10 patients (P < 0.005). In all 11 patients in whom deferoxamine therapy had previously been effective, deferiprone maintained hepatic iron concentrations below 80 mumol of iron per gram. CONCLUSIONS: Oral deferiprone induces sustained decreases in body iron to concentrations compatible with the avoidance of complications from iron overload. The risk of agranulocytosis associated with deferiprone may restrict its administration to patients who are unable or unwilling to use deferoxamine.