Development of predisposition, injury, response, organ failure model for predicting acute kidney injury in acute on chronic liver failure.

BACKGROUND AND AIM: There is limited data on predictors of acute kidney injury in acute on chronic liver failure. We developed a PIRO model (Predisposition, Injury, Response, Organ failure) for predicting acute kidney injury in a multicentric cohort of acute on chronic liver failure patients. PATIENTS AND METHODS: Data of 2360 patients from APASL-ACLF Research Consortium (AARC) was analysed. Multivariate logistic regression model (PIRO score) was developed from a derivation cohort (n=1363) which was validated in another prospective multicentric cohort of acute on chronic liver failure patients (n=997). RESULTS: Factors significant for P component were serum creatinine[(≥2 mg/dL)OR 4.52, 95% CI (3.67-5.30)], bilirubin [(<12 mg/dL,OR 1) vs (12-30 mg/dL,OR 1.45, 95% 1.1-2.63) vs (≥30 mg/dL,OR 2.6, 95% CI 1.3-5.2)], serum potassium [(<3 mmol/LOR-1) vs (3-4.9 mmol/L,OR 2.7, 95% CI 1.05-1.97) vs (≥5 mmol/L,OR 4.34, 95% CI 1.67-11.3)] and blood urea (OR 3.73, 95% CI 2.5-5.5); for I component nephrotoxic medications (OR-9.86, 95% CI 3.2-30.8); for R component,Systemic Inflammatory Response Syndrome,(OR-2.14, 95% CI 1.4-3.3); for O component, Circulatory failure (OR-3.5, 95% CI 2.2-5.5). The PIRO score predicted acute kidney injury with C-index of 0.95 and 0.96 in the derivation and validation cohort. The increasing PIRO score was also associated with mortality (P<.001) in both the derivation and validation cohorts. CONCLUSIONS: The PIRO model identifies and stratifies acute on chronic liver failure patients at risk of developing acute kidney injury. It reliably predicts mortality in these patients, underscoring the prognostic significance of acute kidney injury in patients with acute on chronic liver failure.

Addition of simvastatin to carvedilol non responders: A new pharmacological therapy for treatment of portal hypertension.

AIM: To determine whether addition of simvastatin could be an important pharmacological rescue therapy for carvedilol non-responders. METHODS: One hundred and two consecutive patients of cirrhosis of liver with significant portal hypertension were included. Hepatic venous pressure gradient (HVPG) was measured at the base line and after proper optimization of dose; chronic response was assessed at 3 mo. Carvedilol non-responders were given simvastatin 20 mg per day (increased to 40 mg per day at day 15). Carvedilol plus simvastatin was continued for 1 mo and hemodynamic response was again measured at 1 mo. RESULTS: A total of 102 patients with mean age of 58.3 ± 6.6 years were included. Mean baseline HVPG was 16.75 ± 2.12 mmHg and after optimization of dose and reassessment of HVPG at 3 mo, mean reduction of HVPG from baseline was 5.5 ± 1.7 mmHg and 2.8 ± 1.6 mmHg among responders and non-responders respectively (P < 0.001). Addition of simvastatin to carvedilol non-responders resulted in significant response in 16 patients (42.1%) and thus overall response with carvedilol and carvedilol plus simvastatin was seen in 78 patients (80%). Two patients were removed in chronic protocol study with carvedilol and three patients were removed in carvedilol plus simvastatin study due to side effects. CONCLUSION: Addition of simvastatin to carvedilol non-responders may prove to be an excellent rescue therapy in patients with portal hypertension.

Prevalence and prognostic significance of hyperkalemia in hospitalized patients with cirrhosis.

BACKGROUND: The prevalence and clinical significance of hyponatremia in cirrhotics have been well studied; however, there are limited data on hyperkalemia in cirrhotics. AIM: We evaluated the prevalence and prognostic significance of hyperkalemia in hospitalized patients with cirrhosis and developed a prognostic model incorporating potassium for prediction of liver-related death in these patients. METHODS: The training derivative cohort of patients was used for development of prognostic scores (Group A, n = 1160), which were validated in a large prospective cohort of cirrhotic patients. (Group B, n = 2681) of cirrhosis. RESULTS: Hyperkalemia was seen in 189 (14.1%) and 336 (12%) in Group A and Group B, respectively. Potassium showed a significant association that was direct with creatinine (P < 0.001) and urea (P < 0.001) and inverse with sodium (P < 0.001). Mortality was also significantly higher in patients with hyperkalemia (P = 0.0015, Hazard Ratio (HR) 1.3, 95% confidence interval 1.11-1.57). Combination of all these parameters into a single value predictor, that is, renal dysfunction index predicted mortality better than the individual components. Combining renal dysfunction index with other known prognostic markers (i.e. serum bilirubin, INR, albumin, hepatic encephalopathy, and ascites) in the "K" model predicted both short-term and long-term mortality with an excellent accuracy (Concordance-index 0.78 and 0.80 in training and validation cohorts, respectively). This was also superior to Model for End-stage Liver Disease, Model for End-stage liver disease sodium (MELDNa), and Child-Turcott-Pugh scores. CONCLUSIONS: Cirrhotics frequently have impaired potassium homeostasis, which has a prognostic significance. Serum potassium correlates directly with serum creatinine and urea and inversely with serum sodium. The model incorporating serum potassium developed from this study ("K"model) can predict death in advanced cirrhotics with an excellent accuracy.

After proper optimization of carvedilol dose, do different child classes of liver disease differ in terms of dose tolerance and response on a chronic basis?

BACKGROUND/AIMS: Literature regarding safe doses of carvedilol is limited, and safe doses across different Child classes of chronic liver disease are not clear. PATIENTS AND METHODS: A total of 102 consecutive cirrhotic patients with significant portal hypertension were included in this study. Hepatic venous pressure gradient was measured at baseline and 3 months after dose optimization. RESULTS: A total of 102 patients (63 males, 39 females) with a mean age of 58.3 ± 6.6 years were included. Among these patients, 42.2% had Child Class A, 31.9% had Class B, and 26.6% had Child Class C liver disease. The mean baseline hepatic venous pressure gradient was 16.75 ± 2.12 mmHg, and after dose optimization and reassessment of hepatic venous pressure gradient at 3 months, the mean reduction in the hepatic venous pressure gradient was 5.5 ± 1.7 mmHg and 2.8 ± 1.6 mmHg among responders and nonresponders respectively. The mean dose of carvedilol was higher in nonresponders (19.2 ± 5.7 mg) than responders (18.75 ± 5.1 mg). However, this difference was not statistically significant (P > 0.05). The univariate analysis determined that the absence of adverse events, the absence of ascites, and low baseline cardiac output were significantly associated with chronic response, whereas, the etiology, Child class, variceal size (large vs small), and gender were not. On multivariate analysis, the absence of any adverse event was determined to be an independent predictor of chronic response (OR 11.3, 95% CI; 1.9-67.8). CONCLUSION: The proper optimization of the dose of carvedilol, when administered chronically, may enable carvedilol treatment to achieve a greater response with minimum side effects among different Child classes of liver disease.

Extrahepatic portal vein obstruction and portal vein thrombosis in special situations: Need for a new classification.

Extrahepatic portal vein obstruction is a vascular disorder of liver, which results in obstruction and cavernomatous transformation of portal vein with or without the involvement of intrahepatic portal vein, splenic vein, or superior mesenteric vein. Portal vein obstruction due to chronic liver disease, neoplasm, or postsurgery is a separate entity and is not the same as extrahepatic portal vein obstruction. Patients with extrahepatic portal vein obstruction are generally young and belong mostly to Asian countries. It is therefore very important to define portal vein thrombosis as acute or chronic from management point of view. Portal vein thrombosis in certain situations such as liver transplant and postsurgical/liver transplant period is an evolving area and needs extensive research. There is a need for a new classification, which includes all areas of the entity. In the current review, the most recent literature of extrahepatic portal vein obstruction is reviewed and summarized.

Clinical course, laboratory parameters and outcome of TTP pediatric patients presenting with posterior reversible encephalopathy syndrome.

AIM: The clinical course and outcome of children with thrombotic thrombocytopenic purpura and posterior reversible encephalopathy has not been observed and studied till date. The aim of the present study was to know the clinical course and outcome of children with thrombotic thrombocytopenic purpura and posterior reversible encephalopathy. Results from our observation invite potential insight for further research on this subject. METHODS: From January 2005 to February 2013, seven children diagnosed with thrombotic thrombocytopenic purpura and posterior reversible encephalopathy syndromes were admitted in a tertiary care hospital in Srinagar, Kashmir. The demographic parameters, clinical characteristics and laboratory data were noted. The outcome was defined in the form of complete recovery or death. Thrombotic thrombocytopenic purpura was diagnosed on clinical grounds, laboratory parameters and renal biopsy. The diagnosis was established after an expert opinion from a hematologist. Posterior reversible encephalopathy syndrome was defined on neuroimaging. RESULTS: The common clinical parameters which were shared by all the patients were hypertension and altered sensorium. Four (57.1%) patients showed clinical deterioration and died within one week of admission even after intensive management. Three (42.8%) patients improved clinically and recovered fully and were discharged in stable clinical condition. Repeat imaging on discharge was normal. CONCLUSION: This series of seven pediatric patients is the first series on this subject. The presence of posterior reversible encephalopathy syndrome in pediatric patients with thrombotic thrombocytopenic purpura complicates the clinical course and worsens the prognosis.

Gastric varices: Classification, endoscopic and ultrasonographic management.

Gastric varices (GV) are responsible for 10-30% of all variceal hemorrhage. However, they tend to bleed more severely with higher mortality. Around 35-90% rebleed after spontaneous hemostasis. Approximately 50% of patients with cirrhosis of liver harbor gastroesophageal varices. In this review, new treatment modalities in the form of endoscopic treatment options and interventional radiological procedures have been discussed besides discussion on classification and pathophysiology of GV.

Serum ferritin predicts early mortality in patients with decompensated cirrhosis.

BACKGROUND & AIMS: Serum ferritin is a known marker of hepatic necro-inflammation and has been studied to predict 1 year mortality and post-transplant survival in decompensated cirrhotics. However, there are no studies evaluating ferritin as a predictor of early mortality. We investigated whether serum ferritin levels could predict 15 day and 30 day mortality in patients with decompensated cirrhosis. METHODS: 318 patients with decompensated cirrhosis were included. RESULTS: Patients of decompensated cirrhosis [257 males, mean age of 51 [±13]years, were followed for a median of 31 days. Serum ferritin levels were significantly different between survivors and non-survivors [p<0.001] and showed significant correlation with MELD score [p<0.001], CTP score [p<0.001], leucocyte counts [TLC] [p<0.001], serum sodium [p<0.001], ACLF grades [p=0.005], spontaneous bacterial peritonitis [SBP] [p=0.02], hepatic encephalopathy [HE] [p<0.001] and hepatorenal syndrome [HRS] [p=0.012]. Serum ferritin, etiology, MELD, HE, CTP score, sodium, TLC, and ACLF grades were significant predictors of mortality on univariate analysis. Ferritin [p=0.04, HR 1.66 95% CI (1.02-2.73)] was a significant predictor of early mortality on multivariate analysis along with HE [p=0.006, HR 3.47 95% CI (2.13-8.41)] (Model 1), TLC [p=0.02, HR 1.81 95% CI (1.06-3.07)] (Model 2), ACLF grades [p=0.018, HR 2.013,95% CI (1.126-3.60)], and CTP score [p<0.0001, HR 1.36 95% CI (1.17-1.59)] (Model 3). CONCLUSION: Serum ferritin levels correlate with severity of hepatic decompensation and are associated with early liver related death independent of the MELD score in hospitalized patients with decompensated cirrhosis. This could also have a potential therapeutic implication.

Acute-on-chronic liver failure: consensus recommendations of the Asian Pacific Association for the Study of the Liver (APASL) 2014.

The first consensus report of the working party of the Asian Pacific Association for the Study of the Liver (APASL) set up in 2004 on acute-on-chronic liver failure (ACLF) was published in 2009. Due to the rapid advancements in the knowledge and available information, a consortium of members from countries across Asia Pacific, "APASL ACLF Research Consortium (AARC)," was formed in 2012. A large cohort of retrospective and prospective data of ACLF patients was collated and followed up in this data base. The current ACLF definition was reassessed based on the new AARC data base. These initiatives were concluded on a 2-day meeting in February 2014 at New Delhi and led to the development of the final AARC consensus. Only those statements which were based on the evidence and were unanimously recommended were accepted. These statements were circulated again to all the experts and subsequently presented at the annual conference of the APASL at Brisbane, on March 14, 2014. The suggestions from the delegates were analyzed by the expert panel, and the modifications in the consensus were made. The final consensus and guidelines document was prepared. After detailed deliberations and data analysis, the original proposed definition was found to withstand the test of time and identify a homogenous group of patients presenting with liver failure. Based on the AARC data, liver failure grading, and its impact on the "Golden therapeutic Window," extra-hepatic organ failure and development of sepsis were analyzed. New management options including the algorithms for the management of coagulation disorders, renal replacement therapy, sepsis, variceal bleed, antivirals, and criteria for liver transplantation for ACLF patients were proposed. The final consensus statements along with the relevant background information are presented here.

Cirrhosis histology and Laennec staging system correlate with high portal pressure.

AIMS: To correlate cirrhosis histology and Laennec fibrosis scoring with portal pressure, as determined by hepatic venous pressure gradient (HVPG). METHODS AND RESULTS: One hundred and four patients with biopsy-proven cirrhosis and known HVPG were included in the study. Semiquantitative scoring of 12 histological parameters and quantitative assessment by morphometry for septal thickness and nodule diameter and image analysis for fibrosis were performed. Laennec histological subgrading and clinical staging of cirrhosis were also performed. There were significant positive correlations between HVPG and Laennec histological grade of cirrhosis (P < 0.001), micronodularity (P < 0.001), the presence of thick fibrous septa (P = 0.015), the amount of collagen in the space of Disse (P < 0.001), and the extent of fibrosis by image analysis (P = 0.003). Multivariate analysis, to predict high HVPG (≥16 mmHg), showed that degree of collagen in the space of Disse [P = 0.007, odds ratio (OR) 19.3], histological grade of cirrhosis (P = 0.017, OR 3.9) and micronodularity (P = 0.02, OR 3.5) independently predicted high HVPG. CONCLUSIONS: Histological subclassification of cirrhosis, collagen in the space of Disse and micronodularity are independent predictors of high portal pressure. The Laennec histological subclassification of cirrhosis correlates well with clinical severity of cirrhosis, and can provide useful prognostic information.