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).

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.

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.

Primary restrictive cardiomyopathy: clinical and pathologic characteristics.

Twenty-four patients with restrictive cardiomyopathy were identified at St. Thomas' Hospital during a 17-year period. All had endomyocardial biopsy, but in two patients the biopsy specimens were small and nondiagnostic. Seven patients had amyloidosis and five had other specific heart muscle diseases. The remaining 10 patients with primary restrictive cardiomyopathy had myocyte hypertrophy or interstitial fibrosis, or both. Patients with primary restrictive cardiomyopathy presented earlier but survived longer after presentation than did those with amyloidosis. In each group, survival after cardiac catheterization was related to cardiac index but not to filling pressures. Primary restrictive cardiomyopathy was associated with complete heart block in four patients, two of whom had skeletal myopathy. One had a family history of dominantly inherited skeletal myopathy. Primary restrictive cardiomyopathy was present in a mother and daughter. Two other patients had a family history of heart failure, sudden death or complete heart block, alone or in combination, at a young age. Restrictive hemodynamics and complete heart block were present in patients even in the absence of significant fibrosis. The data suggest that primary restrictive cardiomyopathy may be a distinct myopathy with dominant inheritance and incomplete penetrance that is expressed morphologically as myocyte hypertrophy and interstitial fibrosis. Skeletal myopathy may be associated with the cardiomyopathy.

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.

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.

Use of extracorporeal liver assist device and auxiliary liver transplantation in fulminant hepatic failure.

The case history of a 14-year-old boy with fulminant hepatic failure secondary to non-A, non-B hepatitis who fulfilled selection criteria for orthotopic liver transplantation is described. Two forms of liver support were used (extracorporeal liver assist device and an auxiliary partial orthotopic liver transplantation) to provide additional time to allow spontaneous recovery to occur. During the 66 h of extracorporeal haemoperfusion through the device, haemodynamic stability was maintained along with improvements in serum bilirubin (555 to 381 mumol/l), and international normalized ratio (INR) (3.7 to 2.9). Deterioration in these parameters was observed following cessation of treatment and 10 h later, after a donor liver had become available, an auxiliary transplant was performed. Clinical recovery, though initially slow, was eventually complete, with histopathological and scintigraphic evidence of full liver regeneration at 3 months. Withdrawal of his immunosuppressive drugs began at 6 months and was complete by 14 months after auxiliary transplantation. He has since remained well with normal liver function tests. Temporary liver support may provide additional time for spontaneous recovery of the native liver to occur in selected cases of fulminant hepatic failure, even when criteria are fulfilled for orthotopic liver grafting.

N-acetylcysteine infusion in viral myocarditis: a case report.

N-acetylcysteine improves survival in established acute liver failure following paracetamol overdose by reducing the incidence of multiorgan failure. These benefits are thought to be related to decreased tissue hypoxia by the enhancement of both oxygen delivery and oxygen extraction. Similar findings have been recorded in critically ill patients from an alternative aetiology. The cardiovascular properties of N-acetylcysteine are to increase stroke volume index, and thus cardiac output, although there is no effect on cardiac output in normal subjects. N-acetylcysteine is known to improve myocardial contraction in a hamster model of chronic myocardial ischaemia, but such effects have not previously been described in humans. We report the beneficial circulatory effect of N-acetylcysteine in a patient with marked left ventricular dysfunction secondary to acute viral myocarditis.

Evaluation of the BioLogic-DT sorbent-suspension dialyser in patients with fulminant hepatic failure.

The BioLogic-DT sorbent suspension dialyser was developed to remove toxic substances from the blood of patients with liver failure. In the present study a randomised controlled trial was carried out in 10 patients with fulminant hepatic failure who had developed grade 4 encephalopathy to evaluate the safety and biocompatibility of the dialyser in such severely ill patients. A total of 18 treatments were performed in 5 patients. Haemodynamic stability was maintained throughout. There was a significant loss of platelets (163 +/- 34 to 101 +/- 13 x 10(9)/l) and decrease in plasma fibrinogen (0.53 +/- 0.09 to 0.31 +/- 0.08 g/l) with a rise in blood activated clotting time (190 +/- 17 to 223 +/- 22 sec)--not seen in the controls--, which was a result of the dialysis being carried out without the use of heparin as anticoagulant. Removal of metabolites by treatment was limited, with no significant effect on blood ammonia level and further developments of the system will be needed for this very sick group of patients.

Effect of ELAD liver support on plasma HGF and TGF-beta 1 in acute liver failure.

The aim of this study was to investigate the effects of treatment with the extracorporeal liver assist device (ELAD) in patients with acute liver failure (ALF) on plasma hepatocyte growth factor (HGF), the most potent growth factor, and transforming growth factor-beta 1 (TGF-beta 1), an inhibitory factor for liver regeneration. Initial plasma HGF, measured by ELISA, was significantly increased in the ALF patients (7.86 +/- SEM 1.76 ng/ml) compared with normal subjects (0.10 +/- 0.02 ng/ml, p < 0.001). After 6 hours of ELAD haemoperfusion, plasma HGF increased further (30.5 +/- 6.19 ng/ml, p < 0.001), with a subsequent decrease towards the initial value by 48 hours. Initial plasma levels of TGF-beta 1 determined by ELISA were significantly increased in the ALF patients (43.4 +/- 5.9 ng/ml) compared with normal subjects (25.1 +/- 2.3 ng/ml, p < 0.01), but there was no change in plasma TGF-beta 1 during the study period in either the ELAD or control ALF group. As HGF is a heparin-binding growth factor and similar changes in HGF were observed during CVVHD, one possible explanation is that heparin administered as anticoagulant for extracorporeal circulation is involved in the effects observed on HGF.

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.

Intravenous acetylcysteine in paracetamol induced fulminant hepatic failure: a prospective controlled trial.

OBJECTIVE: To see whether intravenous acetylcysteine would improve outcome in patients with fulminant hepatic failure after paracetamol overdose. DESIGN: A prospective randomised controlled study. SETTING: The Institute of Liver Studies, King's College Hospital, London. PATIENTS: 50 consecutive patients (21 male) aged 16-60 with fulminant hepatic failure after paracetamol overdose who had not previously received acetylcysteine. INTERVENTIONS: Conventional intensive liver care plus either acetylcysteine (25 patients) in the same dose regimen as used early after a paracetamol overdose, except that the infusion was continued until recovery from encephalopathy or death, or an equivalent volume of 5% dextrose (25 patients). MAIN OUTCOME MEASURES: Survival; incidence of cerebral oedema, renal failure, and hypotension requiring inotropic support; liver function as assessed by prolongation of the prothrombin time; and degree of encephalopathy. RESULTS: The rate of survival was significantly higher in the acetylcysteine treated group than in the controls (48% (12/25 patients) v 20% (5/25); p = 0.037, 95% confidence interval for difference in proportions surviving 3% to 53%). Acetylcysteine treated patients had a lower incidence of cerebral oedema (40% (10/25) v 68% (17/25); p = 0.047, 95% confidence interval for difference in incidence 2% to 54%), and fewer developed hypotension requiring inotropic support (48% (12/25) v 80% (20/25); p = 0.018, 95% confidence interval 7% to 57%). Rates of deterioration and recovery of liver function, however, were similar in the two groups. No adverse reactions to acetylcysteine were seen. CONCLUSIONS: Acetylcysteine is safe and effective in fulminant hepatic failure after paracetamol overdose.

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.