Meritxell Ventura-Cots

Characteristics, risk factors, and mortality of cirrhotic patients hospitalized for hepatic encephalopathy with and without acute-on-chronic liver failure (ACLF)

BACKGROUND & AIMS In spite of the high incidence of hepatic encephalopathy (HE) in cirrhosis, there are few observational studies. METHODS We performed an analysis to define the characteristics of HE and associated features using the database of the Canonic Study. Clinical, laboratory and survival data of 1348 consecutive cirrhotic patients admitted with an acute decompensation were compared according to the presence (n=406) or absence of HE and of acute-on-chronic liver failure (ACLF) (n=301). RESULTS HE development was independently associated with previous HE episodes; survival probabilities worsen in relation to the presence and grade of HE. There were marked differences between HE associated (n=174) and not associated (n=286) to ACLF. HE not associated with ACLF occurred in older cirrhotics, inactive drinkers, without severe liver failure or systemic inflammatory reaction and in relation to diuretic use. In contrast, HE associated with ACLF occurred in younger cirrhotics, more frequently alcoholics, with severe liver failure and systemic inflammatory reaction, and in relation to bacterial infections, active alcoholism and/or dilutional hyponatremia. Prognosis was relatively preserved in the first and extremely poor in the second group. Independent risk factors of mortality in patients with HE were age, bilirubin, INR, creatinine, sodium, and HE grade. CONCLUSIONS In cirrhosis, previous HE identifies a subgroup of patients that is especially vulnerable for developing new episodes of HE. The course of HE appears to be different according to the presence of ACLF.

Safety of ornithine phenylacetate in cirrhotic decompensated patients: an open-label, dose-escalating, single-cohort study.

Aims: Confirm in patients with cirrhosis and gastrointestinal bleeding the safety of ornithine phenylacetate (OP) and assess the pharmacokinetic profile of OP and its effects on plasma ammonia. Background: OP is a drug that has shown experimentally to decrease hyperammonemia and improve hepatic encephalopathy. OP is safe in healthy subjects and in stable patients with cirrhosis, but there are no data in decompensated cirrhosis. Methods: We performed a study to assess safety and tolerance of OP in cirrhotic patients after an episode of upper gastrointestinal bleeding.Ten patients were included within 24 hours of an upper gastrointestinal bleeding. OP was administered as a continuous infusion up to a maximum of 10 g/24 h (0.42 g/h) for 5 days. The infusion was started at 33% of the target dose and increased at 12-hour intervals achieving target dose at 24 hours. Ammonia was also assessed in control group of 10 patients. Results: No severe adverse events were observed. Mild adverse events were reported in 4 patients. Plasma ammonia (baseline: 80±43 &mgr;mol/L) showed a progressive drop between baseline and 36 hours (42±15 &mgr;mol/L), 72 hours (44±15 &mgr;mol/L), 96 hours (40±24 &mgr;mol/L), and 120 hours (33±14 &mgr;mol/L). Plasma ammonia at 24 hours was significantly higher in the control group. Plasma glutamine showed a significant decrease (−37% at day 5) and its excretion in urine as phenylacetylglutamine, a progressive rise (52±35 mmol at day 5). Conclusions: OP is a safe and well-tolerated drug in decompensated cirrhotics that may decrease plasma ammonia by inducing its appearance as phenylacetylglutamine in urine.

Impact of ornithine phenylacetate (OCR-002) in lowering plasma ammonia after upper gastrointestinal bleeding in cirrhotic patients

Background: Ornithine phenylacetate (OP) has been proven effective in lowering ammonia plasma levels in animals, and to be well tolerated in cirrhotic patients. A trial to assess OP efficacy in lowering plasma ammonia levels versus placebo in cirrhotic patients after an upper gastrointestinal bleeding was performed. The primary outcome was a decrease in venous plasma ammonia at 24 hours. Methods: A total of 38 consecutive cirrhotic patients were enrolled within 24 hours of an upper gastrointestinal bleed. Patients were randomized (1:1) to receive OP (10 g/day) or glucosaline for 5 days. Results: The primary outcome was not achieved. A progressive decrease in ammonia was observed in both groups, being slightly greater in the OP group, with significant differences only at 120 hours. The subanalysis according to Child–Pugh score showed a statistically significant ammonia decrease in Child–Pugh C-treated patients at 36 hours, as well as in the time-normalized area under the curve (TN-AUC) 0–120 hours in the OP group [40.16 μmol/l (37.7–42.6); median (interquartile range) (IQR)] versus placebo group [65.5 μmol/l (54–126);p = 0.036]. A decrease in plasma glutamine levels was observed in the treated group compared with the placebo group, and was associated with the appearance of phenylacetylglutamine in urine. Adverse-event frequency was similar in both groups. No differences in hepatic encephalopathy incidence were observed. Conclusions: OP failed to significantly decrease plasma ammonia at the given doses (10 g/day). Higher doses of OP might be required in Child–Pugh A and B patients. OP appeared well tolerated.

Rapid liver and spleen stiffness improvement in compensated advanced chronic liver disease patients treated with oral antivirals

Background We aimed to investigate the early changes in liver and spleen stiffness measurement (LSM, SSM) in hepatitis C virus (HCV) patients with compensated advanced chronic liver disease (cACLD) treated with new antivirals (DAA) to elucidate factors determining the initial change in stiffness and its implications for the long-term follow up of HCV-cured patients. Methods: A total of 41 patients with cACLD who started DAA therapy underwent LSM and SSM at baseline, week 4, end of treatment (EOT), 24 and 48 weeks of follow up using transient elastography. Results: LSM improved rapidly during the first 4 weeks of treatment (baseline: 20.8kPa; week 4: 17.5kPa, p = 0.002), with no significant changes between week 4 and EOT (18.3kPa, p = 0.444) and between EOT and 48-week follow up (14.3kPa, p = 0.148). Likewise, SSM improved rapidly (baseline: 45.7kPa; week 4: 33.8kPa, p = 0.047), with no significant changes between week 4 and EOT (30.8kPa, p = 0.153) and between EOT and 48-week follow up (31.2kPa, p = 0.317). A higher decrease in LSM was observed in patients with baseline ALT ⩾ twofold upper limit normal (2 × ULN) than in those with ALT < 2 × ULN (–5.7kPa versus –1.6kPa). Patients who presented a decrease in LSM ⩾ 10% during treatment compared with those with LSM < 10% decrease, showed lower SSM values, higher platelet counts and lower bilirubin levels at 24-week follow up. Those with decrease in SSM ⩾ 10%, presented a higher increase in platelets than those with SSM < 10% change (p = 0.015). Conclusions: LSM and SSM decrease very rapidly during DAA treatment in cACLD patients suggesting that it most probably reflects a reduction in inflammation rather than in fibrosis. cACLD patients should be maintained under surveillance independently of stiffness changes, because advanced fibrosis can still be present.

Basal values and changes of liver stiffness predict the risk of disease progression in compensated advanced chronic liver disease

BACKGROUND AND AIMS Transient elastography has been proposed as a tool to predict the risk of decompensation in patients with chronic liver disease. We aimed to identify risk groups of disease progression, using a combination of baseline liver stiffness measurement (LSM) and its change over time (delta-LSM) in patients with compensated advanced chronic liver disease (cACLD). METHODS Ninety-four patients with baseline LSM ≥10kPa, Child-Pugh score 5 and without previous decompensation were included. A second LSM was performed during follow-up and data on liver function and liver-related events were collected. The primary endpoint was a composite that included death, liver decompensation and impairment in at least 1 point in Child-Pugh score. RESULTS After a median follow-up of 43.6 months, 15% of patients presented the primary endpoint. Multivariate analysis identified baseline LSM (OR 1.12, P=0.002) and delta-LSM (OR 1.02, P=0.048) as independent predictors of the primary endpoint. A high risk group represented by patients with baseline LSM ≥21kPa and delta-LSM ≥10% (risk of progression 47.1%, 95% CI: 23-71%) was identified, while patients with LSM <21kPa and delta-LSM <10% presented zero risk of progression (P=0.03). CONCLUSIONS Simple classification rules using baseline LSM and delta-LSM identify cACLD patients at low or high risk of disease progression.

Alcohol consumption and risk of infection after a variceal bleeding in low-risk patients.

Antibiotic prophylaxis is a cornerstone in the management of acute variceal bleeding. However, emergence of multiresistant bacteria and antibiotic‐associated complications is a growing problem in cirrhosis. It has been proposed that certain low‐risk populations may have good outcomes without antibiotic. We aimed to analyse the stratified risk of bacterial infection after a variceal bleeding in previously considered low‐risk patients.

α1 and α2-adrenergic agonists on cirrhotic patients with refractory ascites.

Ascites is the most common complication of cirrhosis and 60% of patients with compensated cirrhosis develop ascites within 10 years during the course of their disease (1). Ascites only occurs when portal hypertension has developed. As a consequence of increased portal pressure, patients develop arterial splanchnic vasodilation, that results in progressive systemic hypotension with water and sodium renal retention. This situation is then maintained through the permanent activation of endogenous antinatriuretic and vasoconstrictor mechanisms (2), leading to renal arterial vasoconstriction. When liver function further deteriorates, systemic haemodynamics worsens and finally renal dysfunction occurs. The development of ascites has been associated with a poor prognosis; mortality ranges from 40 to 50% at 1–2 years. Ascites can be simply classified as uncomplicated ascites (diuretic sensitive) and difficult to treat or refractory ascites. The standard medical treatment proposed by the EASL and AASLD guidelines includes low salt diet and diuretic use (3, 4). Diuretics work well for mild or moderate ascites, but with liver deterioration, removal of ascites becomes more difficult and renal function declines. Two different types of refractory ascites have been described, diuretic-resistant ascites and diuretic-intractable ascites; in both cases diuretics do not mobilize ascites because of a lack of effect or the appearance of complications. The standard therapy for refractory ascites is large volume paracentesis that require hospitalization. The removal of large volumes of ascitic fluid is associated with circulatory dysfunction characterized by a reduction of effective blood volume, a condition known as paracentesis-induced circulatory dysfunction (PICD) (4). The best treatment to prevent this phenomenon is albumin replacement (5). Paracentesis is expensive and cumbersome for the patient. Both a1 and a2-adrenergic agonists have been proposed as coadjuvant treatment to control refractory ascites. In addition, a1-adrenergic agonists has also been recommended for the treatment of hepatorenal syndrome (3, 4). Midodrine is a a1-adrenergic agonist, acting in the peripheral a-receptors, that has been widely used in hypotension disorders. Although data on portal pressure effects is not available, midodrine has been used for the treatment of refractory ascites, PICD and hepatorenal syndrome. Focusing in the treatment of ascites and PICD, midodrine has been proved to be effective in increasing mean arterial pressure (MAP), systemic vascular resistance (SVR), urine output and urinary Na output, as well as decreasing cardiac output (CO), heart rate (HR), plasma aldosterone (PA) and plasma renin activity (PRA). These effects are based in a heterogeneous group of studies, with different doses (from 10 to 22.5 mg/daily), different follow-up (7 days to 6 months) and in some studies, midodrine is associated with other vasopressor agents (2, 6–12) (Table 1). From a clinical point of view, midodrine does not seem to be better than albumin in the prevention of PICD, and the evidences from two small randomized trials, indicate a possible benefit in ascites control compared to standard medical treatment in difficult to treat ascitic patients (6, 7). A mild effect on survival was also observed in one of the studies (7). Midodrine is now recommended for refractory ascites in the AASLD guidelines (3). Droxidopa is an oral synthetic amino acid precursor of norepinephrine (NE). It has been proved to be a safe drug in preclinical and clinical studies, showing that droxidopa increases standing blood pressure and improves orthostatic tolerance in patients with neurogenic orthostatic hypotension (13). Droxidopa has been tested in cirrhotic animal models causing a remarkable improvement in haemodynamic parameters after single or repeated doses. Animals receiving droxidopa increased MAP, splanchnic arterial resistance, diuresis and natriuresis. Beneficial molecular effects in superior mesenteric artery samples were also observed (14). However, droxidopa has not been tested in cirrhotic patients. Droxidopa could help to increase MAP in cirrhotic patients with refractory ascites, improve water and salt excretion, and finally diminish the need for large volume paracentesis. Safety and tolerance is a critical point to be assessed. Clonidine is a a2-adrenergic agonist that theoretically reduces central sympathetic outflow, efferent sympathetic neuronal firing and release of NE. Similar to midodrine, clonidine has been proposed for the treatment of ascites and PICD. Clonidine seems to have a favourable risk-benefit ratio at low doses. At high doses, although it induces a significant decrease in portal pressure, this is accompanied by a marked reduction in MAP and sodium output. The clinical studies performed in cirrhotic patients with ascites

Palmoplantar pustulosis and chest pain

A 32-year-old man presented to the emergency department with 1-month history of continuous chest pain, which was worse with movement and on application of pressure to the anterior chest wall. Physical examination showed a pustule on the sole of his left foot (fi gure A) and multiple pustules on his palms (fi gure B). Blood analysis, chest radiography, and ECG results were normal. Microscopy and culture for bacteria of the pustules was negative, as was serology for Treponema pallidum and HIV. Immunological tests were done, but no abnormalities were found.