Raza Malik

Survival in infection-related acute-on-chronic liver failure is defined by extrahepatic organ failures

Infections worsen survival in cirrhosis; however, simple predictors of survival in infection‐related acute‐on‐chronic liver failure (I‐ACLF) derived from multicenter studies are required in order to improve prognostication and resource allocation. Using the North American Consortium for Study of End‐stage Liver Disease (NACSELD) database, data from 18 centers were collected for survival analysis of prospectively enrolled cirrhosis patients hospitalized with an infection. We defined organ failures as 1) shock, 2) grade III/IV hepatic encephalopathy (HE), 3) need for dialysis and mechanical ventilation. Determinants of survival with these organ failures were analyzed. In all, 507 patients were included (55 years, 52% hepatitis C virus [HCV], 15.8% nosocomial infection, 96% Child score ≥7) and 30‐day evaluations were available in 453 patients. Urinary tract infection (UTI) (28.5%), and spontaneous bacterial peritonitis (SBP) (22.5%) were the most prevalent infections. During hospitalization, 55.7% developed HE, 17.6% shock, 15.1% required renal replacement, and 15.8% needed ventilation; 23% died within 30 days and 21.6% developed second infections. Admitted patients developed none (38.4%), one (37.3%), two (10.4%), three (10%), or four (4%) organ failures. The 30‐day survival worsened with a higher number of extrahepatic organ failures, none (92%), one (72.6%), two (51.3%), three (36%), and all four (23%). I‐ACLF was defined as ≥2 organ failures given the significant change in survival probability associated at this cutoff. Baseline independent predictors for development of ACLF were nosocomial infections, Model for Endstage Liver Disease (MELD) score, low mean arterial pressure (MAP), and non‐SBP infections. Independent predictors of poor 30‐day survival were I‐ACLF, second infections, and admission values of high MELD, low MAP, high white blood count, and low albumin. Conclusion: Using multicenter study data in hospitalized decompensated infected cirrhosis patients, I‐ACLF defined by the presence of two or more organ failures using simple definitions is predictive of poor survival. (Hepatology 2014;60:250–256)

New Consensus Definition of Acute Kidney Injury Accurately Predicts 30-Day Mortality in Patients With Cirrhosis and Infection

BACKGROUND & AIMS Participants at a consensus conference proposed defining cirrhosis-associated acute kidney injury (AKI) based on a >50% increase in serum creatinine level from the stable baseline value in <6 months or an increase of ≥ 0.3 mg/dL in <48 hours. We performed a prospective study to evaluate the ability of these criteria to predict mortality within 30 days of hospitalization among patients with cirrhosis and infection. METHODS We followed up 337 patients with cirrhosis who were admitted to the hospital with an infection or developed an infection during hospitalization (56% men; 56 ± 10 years of age; Model for End-Stage Liver Disease [MELD] score, 20 ± 8) at 12 centers in North America. We compared data on 30-day mortality, length of stay in the hospital, and organ failure between patients with and without AKI. RESULTS In total, based on the consensus criteria, 166 patients (49%) developed AKI during hospitalization. Patients who developed AKI were admitted with higher Child-Pugh scores than those who did not develop AKI (11.0 ± 2.1 vs 9.6 ± 2.1; P < .0001) as well as higher MELD scores (23 ± 8 vs 17 ± 7; P < .0001) and lower mean arterial pressure (81 ± 16 vs 85 ± 15 mm Hg; P < .01). Higher percentages of patients with AKI died within 30 days of hospitalization (34% vs 7%), were transferred to the intensive care unit (46% vs 20%), required ventilation (27% vs 6%), or went into shock (31% vs 8%); patients with AKI also had longer stays in the hospital (17.8 ± 19.8 vs 13.3 ± 31.8 days) (all P < .001). Of the AKI episodes, 56% were transient, 28% were persistent, and 16% resulted in dialysis. Mortality was higher among those without renal recovery (80%) compared with partial (40%) or complete recovery (15%) or those who did not develop AKI (7%; P < .0001). CONCLUSIONS Among patients with cirrhosis, 30-day mortality is 10-fold higher among those with irreversible AKI than those without AKI. The consensus definition of AKI accurately predicts 30-day mortality, length of hospital stay, and organ failure.

The role of non-parenchymal cells in liver growth

The main non-parenchymal cells of the liver, Kupffer cells, sinusoidal endothelial cells and stellate cells, participate in liver growth with respect to both their own proliferation, and effects on hepatocyte proliferation. In the well-characterised paradigm of 70% partial hepatectomy, they undergo DNA synthesis and cell division 20-24h later than the hepatocyte population. They exert both positive and negative influences on hepatocyte proliferation, including provision of an extracellular matrix-bound reservoir of hepatocyte growth factor that is activated after damage; priming of hepatocytes for DNA synthesis through rapid generation of TNF-alpha and IL-6; and generation of factors at later time points that curb hepatocyte DNA synthesis (IL-1, TGF-beta) and initiate reconstruction and reformation of matrix proteins.

Original ResearchFull Report: Clinical—LiverNew Consensus Definition of Acute Kidney Injury Accurately Predicts 30-Day Mortality in Patients With Cirrhosis and Infection

BACKGROUND & AIMS Participants at a consensus conference proposed defining cirrhosis-associated acute kidney injury (AKI) based on a >50% increase in serum creatinine level from the stable baseline value in <6 months or an increase of ≥ 0.3 mg/dL in <48 hours. We performed a prospective study to evaluate the ability of these criteria to predict mortality within 30 days of hospitalization among patients with cirrhosis and infection. METHODS We followed up 337 patients with cirrhosis who were admitted to the hospital with an infection or developed an infection during hospitalization (56% men; 56 ± 10 years of age; Model for End-Stage Liver Disease [MELD] score, 20 ± 8) at 12 centers in North America. We compared data on 30-day mortality, length of stay in the hospital, and organ failure between patients with and without AKI. RESULTS In total, based on the consensus criteria, 166 patients (49%) developed AKI during hospitalization. Patients who developed AKI were admitted with higher Child-Pugh scores than those who did not develop AKI (11.0 ± 2.1 vs 9.6 ± 2.1; P < .0001) as well as higher MELD scores (23 ± 8 vs 17 ± 7; P < .0001) and lower mean arterial pressure (81 ± 16 vs 85 ± 15 mm Hg; P < .01). Higher percentages of patients with AKI died within 30 days of hospitalization (34% vs 7%), were transferred to the intensive care unit (46% vs 20%), required ventilation (27% vs 6%), or went into shock (31% vs 8%); patients with AKI also had longer stays in the hospital (17.8 ± 19.8 vs 13.3 ± 31.8 days) (all P < .001). Of the AKI episodes, 56% were transient, 28% were persistent, and 16% resulted in dialysis. Mortality was higher among those without renal recovery (80%) compared with partial (40%) or complete recovery (15%) or those who did not develop AKI (7%; P < .0001). CONCLUSIONS Among patients with cirrhosis, 30-day mortality is 10-fold higher among those with irreversible AKI than those without AKI. The consensus definition of AKI accurately predicts 30-day mortality, length of hospital stay, and organ failure.

The clinical utility of biomarkers and the nonalcoholic steatohepatitis CRN liver biopsy scoring system in patients with nonalcoholic fatty liver disease

Background and Aims:  We identified patients with nonalcoholic fatty liver disease (NAFLD) to determine the predictive value of serum markers to diagnose histological steatohepatitis (NASH).

Infection and inflammation in liver failure: Two sides of the same coin

Acute deterioration in the clinical condition of a cirrhotic patient due to the effects of a precipitating illness leading to hospital admission is associated with widely variable clinical outcomes. A proportion of patients makes an appropriate response to treatment of the precipitating event and can be discharged relatively quickly from hospital. There are a second group of patients, who despite treatment of the precipitating event progress to organ dysfunction, developing complications of cirrhosis and this is the group that is associated with high mortality rates and is referred to broadly as ‘Acute on Chronic Liver Failure’ (ACLF) [1]. The underlying mechanisms that determine which patient will recover and which patient will progress to multiple organ dysfunction despite similar precipitating events is not clear. The paper by Cazzaniga et al. in the present issue of the Journal addresses this important question and suggests that a systemic inflammatory response may be important in determining outcomes [2].

Long-term Use of Antibiotics and Proton-Pump Inhibitors Predict Development of Infections in Patients with Cirrhosis

BACKGROUND & AIMS Bacterial infections, particularly repeated infections, are significant causes of morbidity and mortality among patients with cirrhosis. We investigated and characterized risk factors for repeat infections in these patients. METHODS In a prospective study, we collected data from 188 patients hospitalized with cirrhosis and infections and enrolled in the North American Consortium for the Study of End-Stage Liver Disease (12 centers). Patients were followed up for 6 months after hospital discharge and data were analyzed on type of infections and factors associated with subsequent infections. RESULTS Six months after hospital discharge, 14% of subjects had received liver transplants, 27% died, and 59% were alive without liver transplantation. After discharge, 45% had subsequent infections, but only 26% of the subsequent infections occurred at the same site. Compared with patients not re-infected, patients with repeat infections were older and a higher proportion used proton pump inhibitors (PPIs) (P = .006), rifaximin (P < .001), or prophylactic therapy for spontaneous bacterial peritonitis (SBP) (P < .001). Logistic regression showed that SBP prophylaxis (odds ratio [OR], 3.44; 95% confidence interval [CI], 1.56-7.63), PPI use (OR, 2.94; 95% CI, 1.39-6.20), SBP at hospital admission (OR, 0.37; 95% CI, 0.15-0.91), and age (OR, 1.06; 95% CI, 1.02-1.11) were independent predictors of subsequent infections. CONCLUSIONS Patients hospitalized with cirrhosis and infections are at high risk for subsequent infections, mostly at different sites, within 6 months of index infection resolution. Those at highest risk include previously infected older patients receiving PPIs and/or SBP prophylaxis, although these associations do not prove that these factors cause the infections. New strategies are needed to prevent infections in patients with cirrhosis.

Comparison of transient elastography, serum markers and clinical signs for the diagnosis of compensated cirrhosis.

Background and Aims:  Non‐invasive diagnosis of compensated cirrhosis is important. We therefore compared liver stiffness by transient elastography, APRI score, AST/ALT ratio, hyaluronic acid and clinical signs to determine which modality performed best at identifying compensated cirrhosis.

Exogenous Thyroid Hormone Induces Liver Enlargement, Whilst Maintaining Regenerative Potential—A Study Relevant to Donor Preconditioning

We have investigated thyroid hormone‐ (T3) induced liver cell hyperplasia in rats to explore the potential utility of primary mitogens within the clinical context of donor conditioning prior to living‐related transplantation. A single injection of T3 induced a semi‐synchronized proliferative response in hepatocytes, resulting at 10 days in a peak increase in liver mass, liver/body mass ratio, total DNA and total protein. Importantly, the hyperplastic liver induced by T3 exhibits a commensurate increase in metabolic capacity, as assessed by enhanced galactose elimination capacity. Furthermore, when the liver mass had been increased by an injection of T3 given 10 days previously and 70% partial hepatectomy performed, there was a larger remnant liver mass, liver/body mass ratio, total DNA and total protein content 24 h after surgery, compared with animals given a control injection. Interestingly, the regenerative response to surgery was the same in both groups, indicating that prior T3 conditioning did not impair the regenerative response of the liver. Using more stringent conditions to test hepatic functional reserve, following 90% hepatectomy, there was a greater (57%) survival in animals pre‐treated with T3 compared to 14% in controls.

Coagulopathy in cirrhosis – The role of the platelet in hemostasis

Division of Gastroenterology and Hepatology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA *Corresponding author. Address: Division of Gastroenterology and Hepatology, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Avenue Boston, MA 02215, USA. Tel.: +1 617 632 1063; Fax.: +1 617 632 1065. *E-mail address: rmalik@bidmc.harvard.edu (R. Malik)