Jan G. Freeman

Randomized, Placebo-Controlled Trial of Pioglitazone in Nondiabetic Subjects With Nonalcoholic Steatohepatitis

BACKGROUND & AIMS Nonalcoholic steatohepatitis (NASH) is a leading cause of chronic liver disease for which there is limited therapy available. Insulin sensitizing, anti-inflammatory, and antifibrotic properties of thiazolidinediones support their use in treating NASH. We have evaluated pioglitazone in the treatment of nondiabetic patients with NASH. METHODS We randomized 74 nondiabetic patients (45 men; median age, 54 y) with histologically proven NASH to 12 months of standard diet, exercise, and either placebo or pioglitazone (30 mg/day). Sixty-one patients (30 placebo, 31 pioglitazone) had liver biopsies both at the beginning and the end of the study. RESULTS Compared with placebo, pioglitazone therapy was associated with an increase in weight (mean change, -0.55 vs +2.77 kg; P = .04) and a reduction in glucose (+0.4 vs -0.1 mmol/L; P = .02), HbA1c (+0.16% vs -0.18%; P = .006), insulin C peptide level (+42 vs -78 pmol/L; P = .02), alanine aminotransferase level (-10.9 vs -36.2 u/L; P = .009), gamma-glutamyltransferase level (-9.4 vs -41.2 u/L; P = .002), and ferritin (-11.3 vs -90.5 microg/L; P = .01). Histologic features including hepatocellular injury (P = .005), Mallory-Denk bodies (P = .004), and fibrosis (P = .05) were reduced in patients treated with pioglitazone compared with those in the placebo group. CONCLUSIONS Pioglitazone therapy over a 12-month period in nondiabetic subjects with NASH resulted in improvements in metabolic and histologic parameters, most notably liver injury and fibrosis. Larger extended trials are justified to assess the long-term efficacy of pioglitazone in this patient group.

A pilot study to investigate the use of oxpentifylline (pentoxifylline) and thalidomide in portal hypertension secondary to alcoholic cirrhosis

Background : Tumour necrosis factor‐α is thought to be important in the pathogenesis of portal hypertension. Oxpentifylline (pentoxifylline) and thalidomide inhibit endotoxin‐induced tumour necrosis factor‐α production in vitro.

Towards noninvasive detection of oesophageal varices.

Current guidelines recommend that all cirrhotic patients should undergo screening endoscopy at diagnosis to identify patients with varices at high risk of bleeding who will benefit from primary prophylaxis. This approach places a heavy burden upon endoscopy units and the repeated testing over time may have a detrimental effect on patient compliance. Noninvasive identification of patients at highest risk for oesophageal varices would limit investigation to those most likely to benefit. Upper GI endoscopy is deemed to be the gold standard against which all other tests are compared, but is not without its limitations. Multiple studies have been performed assessing clinical signs and variables relating to liver function, variables relating to liver fibrosis, and also to portal hypertension and hypersplenism. Whilst some tests are clearly preferable to patients, none appear to be as accurate as upper GI endoscopy in the diagnosis of oesophageal varices. The search for noninvasive tests continues.

Is There a Role for Probiotics in Liver Disease

Intestinal microbiota plays an important role in health and disease. Alteration in its healthy homeostasis may result in the development of numerous liver disorders including complications of liver cirrhosis. On the other hand, restoration and modulation of intestinal flora through the use of probiotics is potentially an emerging therapeutic strategy. There is mounting evidence that probiotics are effective in the treatment of covert and overt hepatic encephalopathy, as well as in the prevention of recurrence of encephalopathy. The beneficial effect of probiotics also extends to liver function in cirrhosis, nonalcoholic fatty liver disease, and alcoholic liver disease. On the other hand, data associating probiotics and portal hypertension is scanty and conflicting. Probiotic therapy has also not been shown to prevent primary or secondary spontaneous bacterial peritonitis. Larger clinical studies are required before probiotics can be recommended as a treatment modality in liver diseases.

Vasopressin in liver disease--should we turn on or off?

Arginine vasopressin is a naturally occurring peptide with established physiological functions acting as a vasoconstrictor through V1 receptors or an aquagenic agent allowing free water retention through V2 receptors in the kidney. Portal haemodynamic changes of chronic liver disease are responsible for the lethal consequences of cirrhosis--bleeding oesophageal varices and hepatorenal syndrome. Increasing hepatic vascular resistance to blood flow coupled with central hypovolaemia and a hyperdynamic circulation driven by changes in nitric oxide responsiveness disturbs the normal circulatory physiology raising portal pressure. Vasopressin and its analogues are potent vasoconstrictors and can be utilised in the management of the complications of cirrhosis. Hyponatraemia is common in end stage liver disease due in part to sodium retention and a decreased free water clearance. Diuretic therapy often leads to a worsening of the sodium status and have little true effect on improving free water clearance. Recently a new class of drugs, V2 receptor antagonists, have been evaluated in chronic liver disease whereby increasing free water clearance they may reduce ascitic fluid development. This review addresses the pharmacology of both vasopressin agonists and antagonists, their clinical application and future potential roles in managing patients with acute on chronic liver failure.

Screening for Liver Disease - are LFTs Old HAT?

The economic burden of end stage liver disease is set to increase due to the rising prevalence of cirrhosis secondary to alcohol, viral hepatitis and fatty liver disease. Screening for liver disease has been advocated, as most cases of cirrhosis are preventable with early interventions. Liver function tests (LFTs) are routinely used as a first line investigation to screen for liver diseases but can be normal despite significant underlying liver fibrosis, hepatitis, steatohepatitis or even cirrhosis. Their relationships are far from linear and with little predictive value in some cases. Newer non-invasive modalities are emerging but currently their roles are largely experimental. This review will discuss the role of serum biomarkers and imaging techniques as new modalities to screen for liver disease.

Association of Mannose-Binding Lectin Gene Polymorphisms with Liver Diseases: A Review

Mannose-Binding Lectin (MBL) is a member of the collectin family and is an important protein in the immune system. It is a pathogen pattern-recognition molecule that binds to specific carbohydrate motifs on the surface of many pathogens. MBL activates complement via lectin pathway. Single nucleotide polymorphisms in the MBL gene influence serum MBL concentration and function. MBL deficiencies increase the risk of infection and disease-specific complications, especially in those who are already immune compromised with pre-existing conditions. This review discusses the molecular genetics of human MBL and the association of MBL polymorphisms with liver diseases including liver fibrosis, viral hepatitis B, viral hepatitis C, and infection post-liver transplantation.

P37 IDENTIFYING CIRRHOTICS AT RISK OF PARACENTESIS-INDUCED CIRCULATORY DYSFUNCTION (PICD): THE SIGNIFICANCE OF AN EARLY FALL IN STROKE VOLUME

Background and Aims: In studies using invasive techniques with intermittent measurements, a proportion of patients undergoing large volume paracentesis (LVP) with albumin infusion appear to still develop PICD. The mechanisms for circulatory disturbance in this situation are not fully understood. We conducted a pilot study to characterise in detail haemodynamics during drainage using continuous, non-invasive monitoring. Methods: 10 patients with tense ascites were recruited prospectively. Participants underwent non-invasive haemodynamic monitoring during LVP, with albumin given at 6 hours, using a FinometerTM to provide beat-by-beat measurement of blood pressure, cardiac output (CO), stroke volume (SV), and systemic vascular resistance (SVR). Results: Finometry enabled assessment of haemodynamic parameters at multiple time points, of which a sample is shown in the table.

P24 Presence of impaired baroreceptor sensitivity is a poor prognostic marker in cirrhosis

Introduction Autonomic function is essential for blood pressure control and baroreceptor sensitivity (BRS) acts as a composite marker of overall function. Both sympathetic and parasympathetic function is impaired in cirrhosis. Impaired BRS predicts death in cardiovascular diseases and chronic kidney disease. Aim The aim of the present study was to assess the relationship between BRS and liver disease severity, systemic and portal haemodynamics and mortality in cirrhosis. Method Prospective study of 29 cirrhotic patients. Systemic haemodynamics and BRS were assessed non-invasively using the Finometer.® Spontaneous BRS was calculated from the regression of pulse interval on systolic blood pressure. Portal pressure was assessed by measurement of the hepatic venous pressure gradient (HVPG). Gastroscopy assessed variceal size and 1-year probability of bleeding according to the NIEC index. Results 20 male (69%), median age 47 years (42–55), Child-Pugh score 6 (Class A 18, B 10, C 1) and MELD 10 (8–13). BRS was impaired in cirrhosis (median 4.2 ms/mm Hg, IQR 2.5–6.2 ms/mm Hg) but was not related to Child-Pugh score or MELD. Significant differences in BRS were seen with respect to gender (Female 2.0 ms/mm Hg vs male 5.8 ms/mm Hg, p=0.0125), presence of varices (present 3.8 ms/mm Hg vs absent 8.3 ms/mm Hg, p=0.0206), and ascites (ascites 2.0 ms/mm Hg vs no ascites 5.3 ms/mm Hg, p=0.0433). No significant differences in BRS were seen according to alcohol intake. A significant negative correlation was seen between BRS and age (r=−0.46, p=0.0130), heart rate (r=−0.56, p=0.0015), HVPG (r=−0.69, p<0.0001) and 1-year probability of variceal bleeding (r=−0.43, p=0.0199). Over a median follow-up of 710 days, 8/29 (27.6%) patients died with median time to death 854 days. Mortality was significantly higher in patients with HVPG greater than or equal to 10 mm Hg than without clinically significant portal hypertension (p=0.0024) and with a MELD score greater than or equal to 17 (p<0.0001). When stratified according to BRS (less than, or greater than or equal to 6 ms/mm Hg), mortality was significantly higher in patients with more severe impairment (<6 ms/mm Hg) than with preserved BRS (33% vs 12.5%, p=0.0034) despite no significant difference in Child-Pugh score, MELD, systemic haemodynamics, HVPG or length of follow-up. Patients with impaired BRS had significantly higher probability of variceal bleeding, and were more likely to have ascites (24% vs 0%). Conclusion BRS is not related to liver disease severity as assessed by Child-Pugh or MELD but a significant inverse correlation exists between BRS and HVPG. Compared to patients with preserved BRS, patients with significant impairment of BRS have a higher mortality, a higher probability of variceal bleeding and are more likely to have ascites. Impairment of BRS appears to be a poor prognostic factor independent of liver disease severity or portal pressure, possibly relating to a failure to respond to the haemodynamic challenges associated with complications in cirrhosis.

PTU-066 Non-invasive assessment of systemic haemodynamics to determine variceal bleeding risk in cirrhotic patients: Abstract PTU-066

Introduction Variceal bleeding is one of the most severe complications of portal hypertension. Universal endoscopic variceal screening is recommended and primary prophylaxis given based on oesophageal variceal size. Risk of bleeding also relates to other factors such as portal pressure, liver disease severity, and red wale markings at endoscopy. Currently there is no non-invasive way of measuring portal pressure or bleeding risk. The aim of this study was to evaluate whether non-invasive assessment of systemic haemodynamics in cirrhosis can identify bleeding risk in portal hypertension. Methods We studied 29 cirrhotic patients. Systemic haemodynamics and baroreceptor sensitivity (BRS) were assessed non-invasively using the Finometer® (TNO instruments, Amsterdam), and analysed with Beatscope® software. Spontaneous BRS was assessed by studying the relationship between inter-beat variability and beat-to-beat changes in systolic blood pressure. Portal pressure was assessed by measurement of the hepatic venous pressure gradient (HVPG). Gastroscopy assessed variceal size, Japanese score and 1-year probability of bleeding according to the NIEC index. Results 69% male, median age 47 (42–55) years, Child-Pugh (CP) score 6 (Class A 18, Class B 10, Class C 1) and MELD 10 (8–13). 90% alcoholic cirrhosis, 66% abstinent. HVPG correlated positively with variceal size (r=0.64, p<0.001), and all measures of variceal bleeding risk (Abstract 066). Significant positive correlations were seen with CI, HR and SVR and variceal bleeding risk, while a significant negative correlation was seen with BRS and bleeding risk. HVPG correlated positively with both CI (r=0.53, p=0.005) and HR (r=0.62, p<0.001) and negatively correlated with BRS (r=−0.69, p<0.001). BRS correlated negatively with HR (r=−0.56, p=0.002). Abstract PTU-066 Japanese score NIEC score 1 year probability of bleeding Child-Pugh score Cardiac output l/min r=0.38, p=0.042 r=0.46, p=0.012 r=0.49, p=0.006 r=0.31, p=0.103 Cardiac index l/min/m2 r=0.50, p=0.006 r=0.53, p=0.003 r=0.52, p=0.004 r=0.36, p=0.055 Peripheral vascular resistance MU r=−0.26, p=0.165 r=−0.32, p=0.093 r=−0.36, p=0.053 r=−0.18, p=0.355 Heart rate bpm r=0.27, p=0.160 r=0.39, p=0.038 r=0.35, p=0.065 r=0.37, p=0.048 BRS ms/mm Hg r=−0.41, p=0.026 r=−0.33, p=0.077 r=−0.43, p=0.020 r=−0.18, p=0.338 HVPG mm Hg r=0.61, p<0.001 r=0.65, p<0.001 r=0.72, p<0.001 r=0.58, p=0.005 Child-Pugh score r=0.49, p=0.008 r=0.75, p<0.001 r=0.72, p<0.001 Conclusion Non-invasive assessment of systemic haemodynamics in cirrhosis may be useful in predicting HVPG and bleeding risk from oesophageal varices. This study highlights that other factors such as baroreceptor sensitivity are important in determining portal pressure and bleeding risk and may open up potential new treatment options.