Andrea Zambruni

Treatments for hepatocellular carcinoma in elderly patients are as effective as in younger patients: a 20-year multicentre experience

Objectives The number of elderly patients diagnosed with hepatocellular carcinoma (HCC) is expected to increase. We compared the presenting features and outcome of HCC in elderly (≥70 years) and younger patients (<70 years). Design Multicentre retrospective cohort study and nested case–control study. Patients 614 elderly and 1104 younger patients from the ITA.LI.CA database, including 1834 HCC cases consecutively diagnosed from January 1987 to December 2004. Both groups were stratified according to treatment: hepatic resection, percutaneous procedures, transarterial chemoembolisation (TACE). Survival was assessed in the whole population and in each treatment subgroup. Age, sex, aetiology, cirrhosis, comorbidities and cancer stage (CLIP score) were tested as predictors of survival. In each subgroup, differences in patient survival were also assessed after adjustment and matching by propensity score. Results Ageing was associated with a higher prevalence of comorbidities, better liver function and CLIP score. Regardless of age, two-thirds of patients underwent radical treatments or TACE. Elderly patients underwent more ablative procedures and fewer resections or TACE sessions. The survival of elderly and younger patients was comparable in each treatment subset, and was predicted by CLIP score. This result was confirmed by the propensity analysis. Conclusions The overall applicability of radical or effective HCC treatments was unaffected by old age. However, treatment distribution differed, elderly individuals being more frequently treated with percutaneous procedures and less frequently with resection or TACE. Survival was unaffected by age and primarily predicted by cancer stage, assessed by the CLIP system, both in the overall population and in treatment subgroups.

QT interval in patients with non-cirrhotic portal hypertension and in cirrhotic patients treated with transjugular intrahepatic porto- systemic shunt

BACKGROUND/AIMS A prolonged QT interval is frequent in chronic liver disease and its aetiology remains unsettled. The studys aim was to assess the role of portal hypertension in the pathogenesis of QT prolongation. METHODS We measured the QT interval in: (1) 10 patients with non-cirrhotic portal hypertension (NCPH) and preserved liver function; (2) 19 cirrhotic patients before, 1-3 and 6-9 months after transjugular intrahepatic porto-systemic shunt (TIPS) insertion. RESULTS Baseline corrected maximum QT interval (QTcmax) was prolonged (>440 ms) in eight NCPH and 16 cirrhotic patients, and its value did not differ between the two groups (453+/-8 vs. 465+/-6 ms, P=NS). No patients showed an abnormal baseline QT dispersion. In cirrhotic individuals, QTcmax further increased 1-3 months after TIPS (P=0.042), thereafter remaining steadily elevated. QT dispersion only increased at the second post-TIPS determination (P=0.030). Such changes occurred despite no deterioration of liver function, plasma electrolytes and haemoglobin. CONCLUSIONS QT interval is frequently prolonged in patient with both non-cirrhotic and cirrhotic portal hypertension and portal decompression by TIPS worsens this abnormality. These results suggest that the porto-systemic shunting is responsible for the altered ventricular repolarisation possibly through a dumping into the systemic circulation of splanchnic-derived cardioactive substances.

Effect of chronic β-blockade on QT interval in patients with liver cirrhosis

BACKGROUND/AIMS QT interval prolongation is frequent in cirrhosis, predicts a poor prognosis and may trigger severe ventricular arrhythmias. Our aim was to evaluate the effect of chronic beta-blockade on QT prolongation. METHODS Clinical and laboratory evaluation, ECG and hepatic vein pressure gradient (HVPG) measurement were performed in 30 cirrhotic patients before and 1-3 months after prophylactic nadolol. QT was corrected for heart rate by the cirrhosis-specific formula and other formulas. RESULTS QT(cirrhosis) was prolonged in 10 patients (33%); HVPG was increased in all cases. QT(cirrhosis) was correlated with the Child-Pugh score (r=0.40; p=0.027). Nadolol shortened QT interval only with the Bazett formula (p=0.01), remaining unchanged with the other formulas. The QT interval shortened only if prolonged at baseline (from 473.3+/-5.5 to 458.4+/-6.5 ms; p=0.007), while it lengthened when normal (from 429.8+/-3.1 to 439.3+/-2.9 ms; p=0.01). QTc changes were directly related to the baseline value (p<0.001). HVPG decreased from 19.4+/-0.8 to 15.6+/-1.3 mmHg (p=0.004). The HVPG changes did not correlate with QTc changes. CONCLUSIONS Chronic beta-blockade shortens the QT interval only in patients with prolonged baseline values, and this is likely due to a direct cardiac effect.

Cannabinoid Type 1 Receptor Antagonism Delays Ascites Formation in Rats With Cirrhosis

BACKGROUND & AIMS Endocannabinoids contribute to hemodynamic abnormalities of cirrhosis. Whether this favors renal sodium retention and ascites formation is unknown. We determined whether cannabinoid type 1 receptor antagonism prevents sodium retention and ascites formation in preascitic cirrhotic rats. METHODS Once renal sodium handling was impaired, rats with carbon tetrachloride-induced cirrhosis were randomized to receive either vehicle or rimonabant (3 [group 1] or 10 [group 2] mg x kg(-1) x day(-1)) for 2 weeks. Natriuresis, sodium intake, and sodium balance were measured daily. At the end of the protocol, systemic hemodynamics, renal blood flow, ascites volume, and liver fibrosis were assessed. RESULTS A significant reduction in ascites formation (group 1: 54%; group 2: 10%; vehicle: 90%) and volume (group 1: 1.6 +/- 0.3 mL; group 2: 0.5 mL; vehicle: 5.5 +/- 0.8 mL) occurred in treated rats. Rimonabant significantly improved sodium balance during week 2 (group 1: 0.98 +/- 0.08 mmol; group 2: 0.7 +/- 0.08 mmol; vehicle: 3.05 +/- 0.11 mmol). Both treated groups showed lower cardiac output and higher mean arterial pressure, peripheral vascular resistance, and renal blood flow (P < .05). Liver fibrosis was reduced in group 2 by 30% (P < .05 vs vehicle). Mean arterial pressure inversely correlated with sodium balance (R = -0.61; P = .003), but not with fibrosis score. CONCLUSIONS Rimonabant improves sodium balance and delays decompensation in preascitic cirrhosis. This is achieved though an improvement in systemic and renal hemodynamics, although it cannot be excluded that the antifibrotic effect of the drug may play a role.

QT interval prolongation by acute gastrointestinal bleeding in patients with cirrhosis

QT interval prolongation is frequent in cirrhosis, and stressful conditions could further prolong QT. We aimed to test this hypothesis and, if it proved correct, to assess its prognostic meaning.

Torsade de pointes during amiodarone infusion in a cirrhotic woman with a prolonged QT interval

We describe an interesting case of a woman with decompensated cirrhosis, ischaemic heart disease and prolonged QT interval, who developed a new-onset atrial fibrillation. During amiodarone infusion a torsade de pointes occurred, which was immediately converted to sinus rhythm by synchronized cardioversion. A new episode of atrial fibrillation was treated with infusion of a beta-blocker (metoprolol) that restored sinus rhythm and normalized the QT interval. Delayed repolarization, frequently observed in ischaemic heart disease, cirrhosis and pro-arrhythmic drugs administration, represents the background for the development of torsade de pointes. Our report underlines that the potential harmfulness of a prolonged QT interval in cirrhotic patients is currently not perceived in its entirety, so that various categories of drugs affecting ventricular repolarization are rather thoughtlessly used in clinical practice without monitoring the QT interval. Thus, amiodarone should be avoided, if possible, or used with extreme care in arrhythmic patients with advanced liver disease. Moreover, beta-blockers may be considered the first-line treatment for rate-control during supraventricular tachyarrhythmias in cirrhotic patients with delayed repolarization.

Muscle circulation contributes to hyperdynamic circulatory syndrome in advanced cirrhosis

BACKGROUND/AIMS Muscle wasting likely influences blood flow to muscle districts in advanced cirrhosis. Thus, we assessed systemic hemodynamics and femoral artery blood flow corrected by muscle mass of the lower limb in 13 patients (Child-Pugh classes B and C) and 11 healthy controls. METHODS Systemic hemodynamics were assessed by transthoracic electrical bioimpedance, femoral artery blood flow by duplex-Doppler and muscle mass by magnetic resonance imaging. RESULTS As expected, patients exhibited increased cardiac index and reduced peripheral vascular resistance. Femoral artery blood flow did not differ between patients and controls. However, when this parameter was indicized by the muscle mass of the lower limb, which was reduced in patients (median: 3391; range: [2546-4793] vs 5118 [3562-7077]cm3, p=0.0006), it proved almost doubled in patients (91.1 [59.9-119.4] vs 50.5 [38.6-69.8]microl/min cm3; p=0.0001). Patient femoral blood flow indicized by muscle mass correlated inversely with peripheral vascular resistance (r= -0.65; p=0.017) and directly with cardiac index (r=0.57; p=0.042). CONCLUSIONS Vasodilation of muscle districts contributes to the reduced peripheral vascular resistance in advanced cirrhosis. Our findings provide a stronger rationale for the use of non-selective vasoconstrictors to treat hemodynamic-dependent complications of cirrhosis, such as hepatorenal syndrome.

Daily profile of circulating C-type natriuretic peptide in pre-ascitic cirrhosis and in normal subjects: relationship with renal function.

Objective. To investigate whether the C-type natriuretic peptide (CNP) has a role in the regulation of fluid and sodium homeostasis in normal subjects and in pre-ascitic cirrhotic patients. Material and methods. The daily profile of CNP plasma levels was assessed by serial measurements (0700 h, 0900 h, 1800 h, 2300 h) in 10 pre-ascitic cirrhotic outpatients (age 56±4 years) and in 10 age-matched healthy controls (54±2 years) on a normal sodium diet (150 mmol/day) while carrying on their usual activities (mobile from 0700 h to 2200 h), after an equilibration period of 5 days. Daily diuresis and natriuresis were also monitored. Results. Mean daily CNP was comparable in cirrhotic and healthy subjects (3.64±0.32 versus 3.20±0.20 pg/ml; p=0.139); CNP concentration showed a tendency towards a circadian fluctuation in healthy subjects (p=0.053) but not in patients (p=0.171). Mean daily CNP concentration significantly correlated with 24-h natriuresis (r=0.709; p=0.022) and urine volume (r=0.745; p=0.013) in patients but not in healthy subjects. Conclusions. CNP plasma levels appear to play a role in the water-sodium balance regulation in patients with pre-ascitic cirrhosis.