The natural history of nonalcoholic fatty liver disease with advanced fibrosis or cirrhosis: an international collaborative study

Information on the long-term prognosis of nonalcoholic fatty liver disease (NAFLD) is limited. We sought to describe the long-term morbidity and mortality of patients with NAFLD with advanced fibrosis or cirrhosis by prospectively studying 247 such patients from four international centers (in Australia, USA, UK and Italy). Their natural history was then compared with 264 patients with HCV infection who were either na?ve or non-responders to treatment. Both cohorts were Child-Pugh class A and had advanced fibrosis (stage 3) or cirrhosis (stage 4) confirmed by liver biopsy at enrollment. In the NAFLD cohort, followed up for a mean of 85.6 months (range, 6-297), there were 48 (19.4%) liver-related complications and 33 (13.4%) deaths or liver transplants. In the HCV cohort, followed up for 74.9 months (mean; range, 6-238), there were 47 (16.7%) liver-related complications and 25 (9.4%) deaths or liver transplants. When adjusting for baseline differences in age and gender, the cumulative incidence of liver-related complications was lower in the NAFLD than the HCV cohort (P = 0.03), including incident hepatocellular cancer (6 versus 18; P = 0.03), but that of cardiovascular events (P = 0.17) and overall mortality (P = 0.6) were similar in both groups. In the NAFLD cohort, platelet count, stage 4 fibrosis, lowered platelet count, and lowered serum cholesterol and alanine aminotransferase (ALT) levels were associated with liver-related complications; an aspartate aminotransferase/ALT ratio >1 and older age were associated with overall mortality, and higher serum bilirubin levels and stage 4 fibrosis were associated with liver-related mortality. CONCLUSIONS: Patients with NAFLD with advanced fibrosis or cirrhosis have lower rates of liver-related complications and hepatocellular cancer than corresponding patients with HCV infection, but similar overall mortality. Some clinical and laboratory features predict liver-related complications and other outcomes in patients with NAFLD.     

Circulating microRNAs as potential markers of human drug-induced liver injury

New biomarkers of liver injury are required in the clinic and in preclinical pharmaceutical evaluation. Previous studies demonstrate that two liver-enriched microRNAs (miR-122 and miR-192) are promising biomarkers of acetaminophen-induced acute liver injury (APAP-ALI) in mice. We have examined these molecules, for the first time, in humans with APAP poisoning. Serum miR-122 and miR-192 were substantially higher in APAP-ALI patients, compared to healthy controls (median ΔΔCt [25th, 75th percentile]) (miR-122: 1,265 [491, 4,270] versus 12.1 [7.0, 26.9], P < 0.0001; miR-192: 6.9 [2.0, 29.2] versus 0.44 [0.30, 0.69], P < 0.0001). A heart-enriched miR-1 showed no difference between APAP-ALI patients and controls, whereas miR-218 (brain-enriched) was slightly higher in the APAP-ALI cohort (0.17 [0.07, 0.50] versus 0.07 [0.04, 0.12]; P = 0.01). In chronic kidney disease (CKD) patients, miR-122 and -192 were modestly higher, compared to controls (miR-122: 32.0 [21.1, 40.9] versus 12.1 [7.0, 26.9], P = 0.006; miR-192: 1.2 [0.74, 1.9] versus 0.44 [0.30, 0.69], P = 0.005), but miR-122 and -192 were substantially higher in APAP-ALI patients than CKD patients (miR-122: P < 0.0001; miR-192: P < 0.0004). miR-122 correlated with peak ALT levels in the APAP-ALI cohort (Pearson R = 0.46, P = 0.0005), but not with prothrombin time. miR-122 was also raised alongside peak ALT levels in a group of patients with non-APAP ALI. Day 1 serum miR-122 levels were almost 2-fold higher in APAP-ALI patients who satisfied King's College Criteria (KCC), compared to those who did not satisfy KCC, although this did not reach statistical significance (P = 0.15). CONCLUSION: This work provides the first evidence for the potential use of miRNAs as biomarkers of human drug-induced liver injury.     

Multivessel intervention and placement of a percutaneous right ventricular assist device in a patient with acute myocardial infarction complicated by cardiac arrest

We present a case of a 66-year-old male who presented with ST elevation myocardial infarction and complicated by cardiac arrest. The patient underwent emergent multivessel revascularization. However, the patient developed right ventricular failure with persistent and recalcitrant hemodynamic instability. Placement of a TandemHeart? right ventricular assist device? (Cardiac Assist, Pittsburgh, Pennsylvania) was undertaken to allow for right ventricular recovery. The device was removed after several days and the patient has had no further events one year after arrest.     

Organ failure: central nervous system

Central nervous system (CNS) failure represents a spectrum of disease ranging from mild neurological impairment that may have motor, sensory, visual, speech, cognitive manifestations, or a combination thereof, to comatose states and brain death. This article summarizes the common causes of CNS failure and analyzes the role of clinical, radiological, laboratory, and other ancillary testing in establishing the underlying diagnosis and assessing severity of CNS failure in each condition; we also comment on various treatment options for each of the causes of CNS failure.     

Linagliptin: a novel xanthine-based dipeptidyl peptidase-4 inhibitor for treatment of type II diabetes mellitus

Type 2 diabetes mellitus causes significant morbidity and mortality on account of its progressive nature and results in considerable burden on healthcare resources. Current treatment strategies have only limited long-term efficacy and tolerability given the progressive nature of the disease leading to inadequate glycemic control and are also associated with undesirable side effects such as weight gain, hypoglycemia and gastrointestinal distress. In the light of these existing limitations, exploring new treatment targets and new therapies have become the need of the hour at present. The incretin pathway, in particular, glucagon-like peptide (GLP-1), plays an important pathological role in the development of type 2 diabetes mellitus, and treatments targeting the incretin system have recently generated surmount interest. These can mainly be categorized into two broad classes; GLP-1 agonists/analogs (exenatide, liraglutide), and dipeptidyl peptidase- 4 inhibitors (sitagliptin, vildagliptin). The gliptins act by prolonging the action of incretins, the gut hormones which can boost insulin levels. Linagliptin is the latest dipeptidyl peptidase-4 inhibitor to complete pivotal phase III trials, which have demonstrated its superiority to its competitors based on its low therapeutic dose, long-lasting inhibition of DPP-4 activity and a good safety/tolerability profile. One of the unique characteristics of linagliptin is its primarily non-renal route of excretion. The drug has recently been approved by the US Food and Drug Administration and has been portrayed as a promising treatment option for patients in whom metformin and the other DPP-4 inhibitors are either contraindicated or require dose adjustment because of moderate to severe renal impairment.     

Comparison of Framingham,PROCAM, SCORE,and Diamond Forrester to predict coronary atherosclerosis and cardiovascular events

Background  

Cardiologists are often confronted with patients presenting with chest pain, in whom clinical risk profiling is required. We studied four frequently used risk scores in their ability to predict for coronary artery disease (CAD) and major adverse cardiovascular events in patients presenting with stable chest pain at the cardiology outpatient clinic.