Improving the Diagnostic Criteria for Primary Liver Graft Nonfunction in Adults Utilizing Standard and Transportable Laboratory Parameters: An Outcome-Based Analysis.

Current diagnostic criteria for primary nonfunction (PNF) of liver grafts are based on clinical experience rather than statistical methods. A retrospective, single-center study was conducted of all adults (n = 1286) who underwent primary liver transplant (LT) 2000-2008 in our center. Laboratory variables during the first post LT week were analyzed. Forty-two patients (3.7%) had 2-week graft failure. Transplant albumin, day-1 aspartate aminotransferase (AST), day-1 lactate, day-3 bilirubin, day-3 international normalized ratio (INR), and day-7 AST were independently associated with PNF on multivariate logistic regression. PNF score =(0.000280*D1AST)+ (0.361*D1 Lactate)+(0.00884*D3 Bilirubin)+(0.940*D3 INR)+(0.00153*D7 AST)-(0.0972*TxAlbumin)-4.5503. Receiver operating curve analysis showed the model area under receiver operating curve (AUROC) of 0.912 (0.889-0.932) was superior to the current United Kingdom (UK) PNF criteria of 0.669 (0.634-0.704, p < 0.0001). When applied to a validation cohort (n = 386, 34.4% patients), the model had AUROC of 0.831 (0.789-0.867) compared to the UK early graft dysfunction criteria of 0.674 (0.624-0.721). The new model performed well after exclusion of patients with marginal grafts and when modified to include variables from the first three post-LT days only (AUROC of 0.818, 0.776-0.856, p = 0.001). This model is superior to the current UK PNF criteria and is based on statistical methods. The model is also applicable to recipients of all types of grafts (marginal and nonmarginal).

The severity of circulating neutrophil dysfunction in patients with cirrhosis is associated with 90-day and 1-year mortality.

BACKGROUND: Patients with cirrhosis are susceptible to sepsis, pre-disposing to the development of encephalopathy, bleeding and organ dysfunction with associated high mortality. AIM: To characterise circulating neutrophil function in a cirrhotic cohort as a determinant of 90-day and 1-year mortality. METHODS: Sixty-two patients with cirrhosis [49 stable (Child-Pugh A/B/C = 24%/39%/37%); 13 acute-on-chronic liver failure] were prospectively studied and compared with 11 healthy controls. Neutrophil function was evaluated at baseline and repeated at critical points during the course of the patient's illness until death/transplantation. Neutrophil phenotype was determined using fluorochrome-labelled antibodies to CD16/CD11b and assessed by flow cytometry. Neutrophil phagocytic activity (NPA) and capacity (NPC) were determined using FITC-labelled opsonised Escherichia coli. Oxidative burst (OB) was quantified by the percentage of neutrophils producing reactive oxygen species (ROS) and mean fluorescence intensity at rest, and after stimulation with E. coli. Physiological variables, biochemistry, microbiology and outcomes were collected. Plasma pro- and anti-inflammatory cytokine profiles were performed by ELISA. RESULTS: NPA/NPC was impaired in cirrhosis with the most significant dysfunction being observed in those with advanced disease and in those treated with propranolol. NPC predicted survival in stable cirrhosis [AUROC 0.83 (95% CI 0.68-0.97); P = 0.021] and differentiated survivors from nonsurvivors (90-day P = 0.01; 1 year P < 0.001). Resting OB ≥12% predicted 90-day mortality with 80% sensitivity and 71% specificity [AUROC 0.81 (95% CI 0.64-0.97); P = 0.026 and differentiated survivors from nonsurvivors; P = 0.015]. CONCLUSION: Circulating neutrophils in patients with cirrhosis are dysfunctional and predict the development of infection, organ dysfunction and survival at 90 days and 1 year.

Comparison of scoring systems and outcome of patients admitted to a liver intensive care unit of a tertiary referral centre with severe variceal bleeding.

BACKGROUND: Acute variceal haemorrhage (AVH) is associated with significant mortality. AIMS: To determine outcome and factors associated with hospital mortality (HM) in patients with AVH admitted to intensive care unit (ICU) and to compare outcomes of patients requiring transfer to a tertiary ICU (transfer group, TG) to a local in-patient group (LG). METHODS: A retrospective study of all adult patients (N = 177) admitted to ICU with AVH from 2000-2008 was performed. RESULTS: Median age was 48 years (16-80). Male represented 58%. Median MELD score was 16 (6-39), SOFA score was 8 (6-11). HM was higher in patients who had severe liver disease or critical illness measured by MELD, SOFA, APACHE II scores and number of failed organs (NFO), P < 0.05. Patients with day-1 lactate ≥ 2 mmol/L had increased HM (P < 0.001). MELD score performed as well as APACHE II, SOFA and NFO (P < 0.001) in predicting HM (AUROC = 0.84, 0.81, 0.79 and 0.82, respectively P > 0.05 for pair wise comparisons). Re-bleeding was associated with increased HM (56.9% vs. 31.6%, P = 0.002). The TG (n = 124) had less severe liver disease and critical illness and consequently had lower HM than local patients (32% vs. 57%, P = 0.002). TG patients with ≥2 endoscopies prior to transfer had increased 6-week mortality (P = 0.03). Time from bleeding to transfer ≥3 days was associated with re-bleeding (OR = 2.290, P = 0.043). CONCLUSIONS: MELD score was comparable to ICU prognostic models in predicting mortality. Blood lactate was also predictive of hospital mortality. Delays in referrals and repeated endoscopy were associated with increased re-bleeding and mortality in this group.

Predicting the development of acute kidney injury in liver cirrhosis--an analysis of glomerular filtration rate, proteinuria and kidney injury biomarkers.

BACKGROUND: The timely diagnosis of acute kidney injury (AKI) in liver cirrhosis is challenging. AIM: To evaluate whether quantification of glomerular filtration rate (GFR), proteinuria and kidney injury biomarkers can accurately predict the development of AKI. METHODS: A prospective cohort analysis of patients with cirrhosis was performed. Measures of baseline kidney function included serum creatinine, iohexol clearance and urine protein:creatinine ratio. Blood and urine samples were collected daily. A retrospective analysis of cystatin C GFR and neutrophil gelatinase-associated lipocalin (NGAL) measured 48 h prior to the diagnosis of AKI was undertaken to evaluate their ability to predict the development of AKI. RESULTS: Eighteen of the 34 cirrhosis patients studied developed AKI. A GFR <60 mL/min/1.73 m(2) was identified in 56% with Iohexol clearance compared to 8% using the four-variable modified diet in renal disease formula (P < 0.0001). Prediction of AKI, 48 h prior to the development of AKI with cystatin C GFR and serum NGAL concentration were similar; area under the receiver operating curve (AUROC) values 0.74 (0.51-0.97), P = 0.04 and 0.72 (0.52-0.92), P = 0.02 respectively. The development of AKI was strongly predicted by urine protein:creatinine ratio above the cut-off of >30 (equivalent to 300 mg/day of proteinuria) sensitivity 82% (57-96) and specificity 80% (52-96), AUROC 0.86 (0.73-0.98), P ≤ 0.0001. [OR 21 (3-133), P ≤ 0.002]. CONCLUSIONS: In patients with liver cirrhosis a urine protein:creatinine ratio >30 predicts AKI. Iohexol clearance and cystatin C formulae identify a greater proportion of patients with a GFR <60 mL/min/1.73 m(2), which also predicts the development of AKI.

Infection and systemic inflammation, not ammonia, are associated with Grade 3/4 hepatic encephalopathy, but not mortality in cirrhosis.

BACKGROUND & AIMS: Patients with cirrhosis are prone to infection which is a frequent precipitant of hepatic encephalopathy (HE). Clinical studies have examined the importance of inflammation and infection in modulating the manifestation of symptoms of HE in acute liver failure and patients with cirrhosis and minimal/low grade HE. It would be logical to presume that this relationship persists in patients who develop severe HE in cirrhosis although this has not been examined to date. METHODS: We report the findings of a prospective audit of 100 consecutive patients with cirrhosis admitted between Jan 2000 and March 2008 to a liver Intensive Care Unit (ICU) where HE was the primary indication for admission (59% Grade 3; 41% Grade 4). Haematological and microbiological data were collected at ICU admission, and organ scores and outcomes were recorded. RESULTS: 46% of patients had positive cultures taken within ± 48h from admission to ICU [25% blood] and a further 22% were culture negative but had evidence of systemic inflammation (SIRS). SIRS score (p=0.03) and SOFA score (p=0.006) were significantly higher in those patients with Grade 4 HE, who were also less likely to survive (p<0.001). HE grade/coma score did not correlate with ammonia, biochemistry or MELD score. Fifty-two percent of patients survived their ICU stay while the remainder developed progressive multiorgan failure and died; 38% survived to discharge, and 16% were transplanted. CONCLUSIONS: These data support an association between infection/SIRS and not ammonia, in patients with cirrhosis that develop severe HE. The presence or absence of infection/SIRS did not determine survival.

Outcomes of severe pregnancy-related liver disease: refining the role of transplantation.

Severe liver disease in pregnancy is generally considered to have a favorable prognosis. The limited data available have not yielded disease-specific prognostic criteria or guidance on who should undergo liver transplantation (LT). We retrospectively evaluated 54 admissions with pregnancy-related liver disease to (1) evaluate if any admission parameters were associated with death and/or transplantation and (2) identify maternal complications. Eighteen had acute fatty liver of pregnancy and 32 had hypertension/eclampsia related disease. Seven patients (13%) died and four (7%) underwent LT. Survival rates were 43/48 if not listed for LT and 4/6 if listed. Of the four transplanted, three survived. Patients who died and/or underwent LT were more likely to have encephalopathy (p = 0.04) and hyperlactaemia (p = 0.03). Serum lactate was the best discriminant (ROC AUC 0.84). An admission lactate greater than 2.8mg/dL had 73% sensitivity and 75% specificity for predicting death or LT. The addition of encephalopathy to this parameter increased sensitivity and specificity to 90% and 86%, respectively. The King's College criteria were not effective in predicting outcome. This study confirms the overall favorable prognosis in pregnancy-related liver failure but indicates that elevated lactate levels in the presence of encephalopathy best identify patients at greatest risk of death or LT.

Admission levels and early changes in serum interleukin-10 are predictive of poor outcome in acute liver failure and decompensated cirrhosis.

BACKGROUND & AIM: Immunoparesis contributes to prognosis in acute liver failure (ALF) and decompensated cirrhosis, a phenomenon thought to be mediated by the anti-inflammatory cytokine interleukin (IL)-10. We investigated the prognostic value of admission IL-10 levels and their evolution during the early phase of treatment in intensive care, in comparison to the pro-inflammatory cytokines IL-6 and tumour necrosis factor (TNF)-alpha. METHODS: We measured these cytokines within 48 h of admission in 51 ALF and 39 decompensated cirrhosis patients admitted to intensive care, and obtained follow-up measurement a median of 2 days later in 35 patients. RESULTS: Levels of all cytokines were higher in those with a poor outcome. IL-10 performed as well as TNF-alpha and IL-6 in the whole cohort (area under receiver operator curve 0.73 vs 0.66 and 0.72). However IL-10 outperfomed pro-inflammatory cytokines in the subgroups with ALF (0.80 vs 0.63 and 0.70) and acetaminophen-induced ALF (0.92 vs 0.67 and 0.81). Levels of all cytokines rose significantly in non-surviving patients (n=15); IL-10 by a factor of 2, TNF-alpha by 2.6 and IL-6 by 1.13. No significant changes were seen in the surviving patients. In ALF, IL-10 was an independent predictor of outcome in multivariate analysis. CONCLUSION: The magnitude of the compensatory anti-inflammatory response at admission, and its development during the early phase of treatment, predicts outcome as well as the pro-inflammatory response in acute hepatic syndromes and supports a vital role for this immunological phenomenon in the outcome of these patients.

Multiple organ failure and severe bone marrow dysfunction in two 18 year-old Caucasian patients: Epstein-Barr virus and the haemophagocytic syndrome.

Haemophagocytic lymphohistiocytosis secondary to viral infection is an unusual but well recognised cause of bone marrow dysfunction and multiple organ failure in young patients. Two 18 year-old patients were admitted to a tertiary liver unit with features of acute liver failure, cardio-respiratory collapse and pancytopenia. Serological tests and bone marrow examination with in-situ hybridisation revealed severe acquired haemophagocytic lymphohistiocytosis secondary to acute Epstein-Barr virus infection. Both patients died despite full supportive therapy; the first due to pulmonary haemorrhage, the second due to acute respiratory distress syndrome refractory to high frequency oscillatory ventilation. The clinical spectrum, diagnostic features and current evidence based recommendations for treatment of this condition are explored. The diagnosis of haemophagocytic lymphohistiocytosis should be considered in young patients with marked bone marrow dysfunction and multiple organ failure. Further research into appropriate therapy for patients with acute severe forms of the disease who require intensive organ support is required.

Hepatic function and non-invasive hepatosplanchnic monitoring in patients with abdominal hypertension.

A better understanding of intra-abdominal hypertension with relation to the liver is vital to the management of all forms of liver pathophysiology. Supporting good hepatic function within the critically ill patient is important not only in maintaining synthetic function, but also in avoiding the multi-organ complications of liver dysfunction. The resulting reduction in hepato-splanchnic blood flow (HSBF) observed with increasing intra-abdominal pressure has been clearly documented and seen to be exaggerated in animals with established liver disease. Unfortunately the tools required to measure this, remain difficult to apply routinely in the clinical setting and as such goal directed therapy to specifically improve the hepatosplanchnic circulation remains elusive. Given the documented effects of lAP on HSBF and the relatively high incidence of intra-abdominal hypertension and the abdominal compartment syndrome within "liver patients" as a whole, close attention to IAP and timely correction by appropriate medical or surgical means would appear to be essential.

Hepatic function and non-invasive hepatosplanchnic monitoring in patients with abdominal hypertension.

A better understanding of intra-abdominal hypertension with relation to the liver is vital to the management of all forms of liver pathophysiology. Supporting good hepatic function within the critically ill patient is important not only in maintaining synthetic function, but also in avoiding the multi-organ complications of liver dysfunction. The resulting reduction in hepato-splanchnic blood flow (HSBF) observed with increasing intra-abdominal pressure has been clearly documented and seen to be exaggerated in animals with established liver disease. Unfortunately the tools required to measure this, remain difficult to apply routinely in the clinical setting and as such goal directed therapy to specifically improve the hepatosplanchnic circulation remains elusive. Given the documented effects of IAP on HSBF and the relatively high incidence of intra-abdominal hypertension and the abdominal compartment syndrome within "liver patients" as a whole, close attention to IAP and timely correction by appropriate medical or surgical means would appear to be essential.

Myeloma associated amyloidosis presenting as subacute liver failure.

Multiple myeloma related amyloidosis is rare and its presentation with subacute liver failure (SALF) has not been reported. A case is described of a 46 year old woman presenting with a six week history of nausea, abdominal pain, and jaundice. Routine tests failed to establish a cause. Computed tomography showed a small volume liver consistent with SALF. Emergency liver transplantation was not undertaken because of the suspicion of underlying malignancy. At necropsy, liver biopsy showed amyloid deposition and bone marrow biopsy showed multiple myeloma. Thus, amyloidosis should be added to the list of potential causes of SALF.

Effects of serum from patients with acute liver failure due to paracetamol overdose on human hepatocytes in vitro.

OBJECTIVE: Our goal was to investigate the effects of serum from patients with acute liver failure due to paracetamol (acetaminophen) overdose on the function of human hepatocytes in vitro. METHODS: Freshly isolated human hepatocytes plated on collagen-coated culture plates were, incubated (24 hours 37 degrees C) in medium containing pooled human sera (0%-80%) obtained from normal individuals or from patients with acute liver failure due to paracetamol overdose. The effects of the sera on cell function were assessed using MTT, [14C]-leucine incorporation, and cytochrome P450 (CYP1A1/2) activity assays. RESULTS: The overall cellular metabolic activity was significantly greater at all concentrations after exposure to acute liver failure serum compared to normal serum. There were no significant differences in the decreases produced by pooled acute liver failure and normal sera at concentrations up to 80% on the [14C]-leucine incorporation or CYP1A1/2 activity. CONCLUSION: The overall cell function/activity of human hepatocytes was not impaired in vitro on exposure to serum from patients with acute liver failure due to paracetamol overdose.

Liver and intestinal lactate metabolism in patients with acute hepatic failure undergoing liver transplantation.

OBJECTIVE: To determine the relative contribution of the gastrointestinal tract and the liver in lactate metabolism in patients with acute liver failure (ALF) and the effect of liver transplantation on this. We hypothesized that the liver and gut are net producers of lactate in ALF and that this is reversed after liver transplantation. SETTING: A university-affiliated specialist liver transplant operating theater. SUBJECTS: Eleven patients with ALF undergoing liver transplantation. MEASUREMENTS AND INTERVENTIONS: After ethical approval, 11 patients with ALF listed for orthotopic hepatic transplantation were studied. Whole blood was analyzed for lactate concentration from radial artery (RA) catheter, portal vein (PV), and hepatic vein (HV) during the dissection phase and was repeated postreperfusion of the liver graft. Gradients across the gut and the liver were calculated to see if there was net production or consumption. RESULTS: HV lactate was significantly higher than arterial (p =.028) in patients with ALF before liver transplantation, suggesting splanchnic production of lactate. Total splanchnic lactate gradient (HV-RA) is positive in ALF. Both the gut (PV-RA) and the liver (HV-PV) were net producers of lactate. After liver transplantation, hepatic venous lactate falls below arterial levels but not significantly. The gradient across the gut (PV-RA) remained positive, but the transhepatic gradient (HV-PV) became significantly negative, showing consumption by the graft (p =.021). The magnitude of lactate consumption after transplantation correlated positively with portal venous lactate concentration (p =.029) and inversely with graft cold ischemic time (p =.007). CONCLUSION: The liver is a net producer of lactate in patients with ALF and an elevated whole blood lactate. After liver transplantation, the graft becomes a consumer of lactate as shown by the negative lactate gradient. The degree of consumption is dependent on portal venous lactate concentration and cold ischemic time.

Perioperative management of liver transplantation patients.

Perioperative care involves many disciplines, each of which contributes in important ways. Changes in liver-transplantation care during the last 40 years can be attributed to the accumulation of improvements, discoveries, and technologic improvements across different disciplines. Here we review some of the articles that were published during the last year that relate to these advances.

Temporal changes in insulin sensitivity following the development of acute liver failure secondary to acetaminophen.

Insulin resistance in chronic liver disease (CLD) is well documented. This study investigated whether similar changes occur in acute liver failure (ALF). Patients with ALF (n = 10) were recruited within 72 hours of their peak prothrombin time (range 42-120 seconds). All patients were ventilated for encephalopathy (grade III-IV). Peripheral and endogenous insulin sensitivity were assessed by a hyperinsulinemic euglycemic clamp (Human Actrapid 1.5 mU/min/kg) with an infusion of D-[6,6-(2)H(2)] glucose. The clamp was performed on day 0 and then on day 7 and day 14. During the insulin infusion, the mean total peripheral glucose uptake (area under the curve [AUC]) was 1,422 (SD, 1,253), 2,244 (SD, 1,392), and 4,500 (SD, 1,120) micromol/kg on days 0, 7, and 14, respectively. Significant changes occurred from day 0 to 14 (day 14-day 0: 3,078 [95% CI, 1,798 to 4,359]; P =.001) and day 7 to 14 (day 14-day 7: 2,256 [95% CI, 923 to 3,589]; P =.001). No significant difference in endogenous glucose production was demonstrated over time. Mean peripheral insulin sensitivity altered over time, increasing from 0.09 (SD, 0.09) micromol/kg/min/mU/L on day 0 to 0.24 (SD, 0.16) on day 7 and 0.5 (SD, 0.1) on day 14. Significant changes occurred between days 0, 7, and 14 (day 7-day 0: 0.15 [95% CI, 0.04 to 0.26], P =.006; day 14-day 0: 0.4 [95% CI, 0.28 to 0.5], P =.001; day 14-day 7: 0.2 [95% CI, 0.12 to 0.38], P =.001). This study demonstrates that in ALF, impaired peripheral uptake of glucose occurs, peripheral insulin sensitivity being restored at 2 weeks in subjects who survived.

A prospective study of gastric mucosal ischaemia in paracetamol-induced acute liver failure.

OBJECTIVE: To evaluate the time course of changes in the gastric mucosal pH (pHi) and the gastric mucosal to arterial CO2 gap (CO2 gap) following paracetamol-induced acute liver failure and to relate these variables to the severity of illness. DESIGN: Clinical prospective study. SETTING: A liver intensive care unit in a university teaching hospital. PATIENTS: Twenty-three patients with paracetamol-induced acute liver failure. INTERVENTIONS: Gastric tonometer placement. MEASUREMENTS AND MAIN RESULTS: Daily assessment of pHi and CO2 gap, the systemic organ failure assessment (SOFA) score for up to 9 days post-paracetamol ingestion. Both pHi and CO2 gap were within the normal range on entry into the study. The CO2 gap showed increases from the normal range on days 5-7 post-ingestion (P<0.01) and increases from study entry on days 4, 7, and 8 post-ingestion (P< 0.01). The pHi showed decreases from the normal range on days 4, 6, 7 and 9 post-ingestion (P< 0.01) and decreases from study entry on days 4, 5, 7, and 9 post-ingestion (P<0.01). There was no correlation found between pHi, CO2 gap, and the SOFA score. CONCLUSIONS: Paracetamol-induced acute liver failure is associated with increases in the CO2 gap and decreases in pHi between 4 to 9 days post-paracetamol ingestion. This may reflect changes in mesenteric blood flow related to hepatic regeneration. These changes may be in part responsible for some of the morbidity seen with this condition.

Subclinical seizure activity and prophylactic phenytoin infusion in acute liver failure: a controlled clinical trial.

Subclinical seizure activity in the patient with encephalopathy and on ventilation with acute liver failure (ALF) is a poorly recognized entity. Its importance lies in the likely exacerbation of cerebral hypoxia and the contribution of such seizure activity to the development of cerebral edema. The aim of the present study was to document the frequency of subclinical seizure activity in a cohort of patients with ALF by using a cerebral function and activity monitor that allows continuous recording of electroencephalogram activity at the bedside and to determine whether the prophylactic administration of the antiepileptic agent phenytoin would reduce its occurrence. Forty-two patients were enrolled in a controlled clinical trial: 20 patients were given phenytoin and 22 acted as controls. Subclinical seizure activity was recorded in 3 and 10 patients, respectively, of the treated and control groups. Pupillary abnormalities indicative of seizure activity and/or raised intracranial pressure (ICP) were also seen less frequently in the phenytoin-treated group compared with the controls (5 and 11 patients, respectively). Autopsy examinations available in 19 patients showed signs of cerebral edema in only 2 (22%) of the phenytoin-treated patients compared with 7 (70%) of the controls (P <.033). Based on these findings, we recommend that patients with ALF, on reaching the stage of grade III or IV encephalopathy, should be routinely monitored for subclinical seizure activity. In this study, prophylaxis with phenytoin reduced the frequency of such seizure activity and its effects, and proved to be safe with the regimen used.

Temporary extracorporeal liver support for severe acute alcoholic hepatitis using the BioLogic-DT.

Patients with severe acute alcoholic hepatitis develop multiple organ failure which is associated with production of inflammatory cytokines and a poor prognosis. The aim of the present pilot study was to evaluate the effects of the BioLogic-DT sorption-suspension dialyser in patients with severe acute alcoholic hepatitis. Ten patients with encephalopathy (grade II-IV) were entered into the study, 5 received treatment with the BioLogic-DT for 6 hours daily for 3 days and 5 received conventional treatment as controls. The system was biocompatible with no adverse effects on blood pressure or platelet counts, factor V, fibrinogen or antithrombin III. No bleeding episodes were observed even with the use of small doses of heparin. After 3 days, blood ammonia was lower in the BioLogic-DT treated patients than in the controls, although blood lactate was higher. There were slight increases in plasma TNF and IL-8 during treatment over and above the higher levels present initially, possibly as a result of activation of white cells in the extracorporeal circuit. The further development of the BioLogic-DT dialyser with the addition of a plasma treatment module capable of removing cytokines would be worth evaluating in acute alcoholic hepatitis.