Janice S Davidson

The systemic inflammatory response syndrome is predictive of renal dysfunction in patients with non-paracetamol-induced acute liver failure

Background: Although renal dysfunction is a common complication of acute liver failure (ALF) with significant prognostic implications, the pathophysiological mechanisms remain unclear. The current hypothesis suggests that the renal dysfunction may mirror the hepatorenal syndrome of cirrhosis. However, ALF has distinct clinical characteristics and the circulatory derangement may be more comparable with sepsis. Objectives: To examine the relationship between the systemic inflammatory response syndrome (SIRS) and renal dysfunction in ALF, and to identify additional risk factors for renal dysfunction. Methods: A single-centre retrospective study of 308 patients with ALF was carried out. Renal dysfunction was defined according to the RIFLE criteria for acute kidney injury. Results: 67% of patients developed renal dysfunction. On univariate analysis, renal dysfunction patients were more likely to be hypothermic (p = 0.010), had a faster heart rate (p<0.001), a higher white cell count (p = 0.001) and a lower PaCO2 (p = 0.033). 78% of renal dysfunction patients and 53% of non-renal dysfunction patients had SIRS (p<0.001). On multivariate analysis, the risk factors for renal dysfunction were age (p = 0.024), fulfilled Kings College Hospital prognostic criteria (p<0.001), hypotension (p<0.001), paracetamol-induced ALF (p<0.001), infection (p = 0.077) and SIRS (p = 0.017). SIRS remained an independent predictor of renal dysfunction in the subgroup of patients with non-paracetamol-induced ALF (n = 91, p = 0.001). In contrast, in patients with paracetamol-induced ALF (n = 217), no relationship between SIRS and renal dysfunction was demonstrated (p = 0.373). Conclusion: SIRS is strongly associated with the development of renal dysfunction in patients with non-paracetamol-induced ALF. It is proposed that the systemic inflammatory cascade plays a key role in its pathogenesis.

Staggered overdose pattern and delay to hospital presentation are associated with adverse outcomes following paracetamol-induced hepatotoxicity

AIMS Paracetamol (acetaminophen) poisoning remains the major cause of severe acute hepatotoxicity in the UK. In this large single centre cohort study we examined the clinical impact of staggered overdoses and delayed presentation following paracetamol overdose. RESULTS Between 1992 and 2008, 663 patients were admitted with paracetamol-induced severe liver injury, of whom 161 (24.3%) had taken a staggered overdose. Staggered overdose patients were significantly older and more likely to abuse alcohol than single time point overdose patients. Relief of pain (58.2%) was the commonest rationale for repeated supratherapeutic ingestion. Despite lower total ingested paracetamol doses and lower admission serum alanine aminotransferase concentrations, staggered overdose patients were more likely to be encephalopathic on admission, require renal replacement therapy or mechanical ventilation and had higher mortality rates compared with single time point overdoses (37.3% vs. 27.8%, P= 0.025), although this overdose pattern did not independently predict death. The Kings College poor prognostic criteria had reduced sensitivity (77.6, 95% CI 70.8, 81.5) for this pattern of overdose. Of the 396/450 (88.0%) single time point overdoses in whom accurate timings could be obtained, 178 (44.9%) presented to medical services >24 h following overdose. Delayed presentation beyond 24 h post overdose was independently associated with death/liver transplantation (OR 2.25, 95% CI 1.23, 4.12, P= 0.009). CONCLUSIONS Both delayed presentation and staggered overdose pattern are associated with adverse outcomes following paracetamol overdose. These patients are at increased risk of developing multi-organ failure and should be considered for early transfer to specialist liver centres.

Overdose pattern and outcome in paracetamol-induced acute severe hepatotoxicity

AIMS Paracetamol (acetaminophen) hepatotoxicity is the commonest cause of acute liver failure (ALF) in the UK. Conflicting data regarding the outcomes of paracetamol-induced ALF resulting from different overdose patterns are reported. METHODS Using prospectively defined criteria, we have analysed the impact of overdose pattern upon outcome in a cohort of 938 acute severe liver injury patients admitted to the Scottish Liver Transplantation Unit. RESULTS Between 1992 and 2008, 663 patients were admitted with paracetamol-induced acute severe liver injury. Of these patients, 500 (75.4%) had taken an intentional paracetamol overdose, whilst 110 (16.6%) had taken an unintentional overdose. No clear overdose pattern could be determined in 53 (8.0%). Unintentional overdose patients were significantly older, more likely to abuse alcohol, and more commonly overdosed on compound narcotic/paracetamol analgesics compared with intentional overdose patients. Unintentional overdoses had significantly lower admission paracetamol and alanine aminotransferase concentrations compared with intentional overdoses. However, unintentional overdoses had greater organ dysfunction at admission, and subsequently higher mortality (unintentional 42/110 (38.2%), intentional 128/500 (25.6%), P < 0.001). The Kings College poor prognostic criteria had reduced sensitivity in unintentional overdoses (77.8%, 95% confidence intervals (CI) 62.9, 88.8) compared with intentional overdoses (89.9%, 95% CI 83.4, 94.5). Unintentional overdose was independently predictive of death or liver transplantation on multivariate analysis (odds ratio 1.91 (95% CI 1.07, 3.43), P = 0.032). CONCLUSIONS Unintentional paracetamol overdose is associated with increased mortality compared with intentional paracetamol overdose, despite lower admission paracetamol concentrations. Alternative prognostic criteria may be required for unintentional paracetamol overdoses.

A biochemical prognostic model of outcome in paracetamol-induced acute liver injury.

Background. The aim of this study was to develop a prognostic model of outcome for patients with paracetamol induced acute liver injury based on admission parameters Methods. We used a cohort of 97 patients admitted to the Scottish Liver Transplant Unit between 1997 and 1998 to identify biochemical prognostic markers of outcome and thus create a prognostic model. Blood samples were taken on admission for analysis. The model was subsequently validated by testing it on a second cohort of 86 patients admitted between 1999 and 2000. Results. The following were identified as independent variables of poor prognosis (death/ transplant); phenylalanine, pyruvate, alanine, acetate, calcium, haemoglobin and lactate. A prognostic model was then constructed by stepwise forward logistic regression analysis: (400 × Pyruvate mmols/L) + (50 × Phenylalanine (mmols/L) – (4 × Hemoglobin (g/dL). A value of <16 had an accuracy of 93% in predicting death correctly. When applied to the validation cohort this model had a positive predictive value of 91%, a negative predictive value of 94%, a sensitivity of 91%, and a specificity of 94%. On the same population overall, the positive and negative predictive value of the Kings criteria were 94% and 93% respectively, whereas their sensitivity and specificity were 88% and 96% respectively. Conclusions. Using admission characteristics our model is able to identify patients who die from paracetamol overdose fulminant hepatic failure as accurately as Kings College criteria, but at a much earlier stage in their condition.

The systemic inflammatory response syndrome (SIRS) and sequential organ failure assessment (SOFA) scores are effective triage markers following paracetamol overdose

Aliment Pharmacol Ther 2011; 34: 219–228

Hepatitis E virus in patients with acute severe liver injury

AIM To examine the incidence of hepatitis E (HepE) in individuals with acute liver injury severe enough to warrant treatment at a transplant unit. METHODS Hepatitis E virus (HEV) is an emerging pathogen in developed countries causing severe illness, particularly in immunocompromised patients or those with underlying chronic liver disease. HepE infection is often under diagnosed, as clinicians can be reluctant to test patients who have not travelled to regions traditionally considered hyperendemic for HepE. There are few data regarding the significance of HEV in patients with very severe acute liver injury in developed countries. Eighty patients with acute severe liver injury attending the Scottish Liver Transplant unit were tested for HEV and anti-HEV IgG and IgM. Severe acute liver injury was defined as a sudden deterioration in liver function confirmed by abnormal liver function tests and coagulopathy or presence of hepatic encephalopathy. Eighty percent of these patients were diagnosed with paracetomol overdose. No patients had a history of chronic or decompensated chronic liver disease at time of sampling. IgG positive samples were quantified against the World Health Organization anti-HEV IgG standard. Samples were screened for HEV viral RNA by quantitative reverse transcription polymerase chain reaction. RESULTS Four cases of hepatitis E were identified. Three of the four cases were only diagnosed on retrospective testing and were initially erroneously ascribed to drug-induced liver injury and decompensated chronic liver disease, with the cause of the decompensation uncertain. One case was caused by HEV genotype 1 in a traveller returning from Asia, the other three were autochthonous and diagnosed on retrospective testing. In two of these cases (where RNA was detected) HEV was found to be genotype 3, the most prevalent genotype in developed countries. Three patients survived, two of whom had been misdiagnosed as having drug induced liver injury. The fourth patient died from sepsis and liver failure precipitated as a result of hepatitis E infection and previously undiagnosed cirrhosis. Histopathology data to date is limited to mainly that seen for endemic HepE. All patients, with the exception of patient 1, demonstrated characteristics of HepE infection, as seen in previously described locally acquired cases. CONCLUSION In patients with acute severe liver injury, HEV testing should be part of the initial diagnostic investigation algorithm irrespective of suspected initial diagnosis, age or travel history.

The sequential organ failure assessment (SOFA) score is an effective triage marker following staggered paracetamol (acetaminophen) overdose

The sequential organ failure assessment (SOFA) score is an effective triage marker following single time point paracetamol (acetaminophen) overdose, but has not been evaluated following staggered (multiple supratherapeutic doses over >8 h, resulting in cumulative dose of >4 g/day) overdoses.

Serum phosphate is not a reliable early predictor of outcome in paracetamol induced hepatotoxicity

We read with interest the recent study by Chung, Sitrin, Te regarding serum phosphate (PO4) levels as a predictor of clinical outcome in fulminant hepatic failure.1 This study did not specify the timing of serum PO4 measurement and concluded better prognosis in low serum PO4 patients. A similar prospective study by Schmidt and Dalhoff2 investigated the outcome in paracetamol poisoning, which is the most common cause of acute liver failure in North America and Europe. This study concluded that a PO4 concentration of 1.2 mmol/L at 48 to 96 hours after overdose was highly specific and sensitive and had a greater overall predictive value than King’s College Hospital criteria.3 We carried out a retrospective analysis in our cohort of patients with paracetamol poisoning referred to the Scottish Liver Transplant Unit during the period 1992 to 2002. Four hundred fifty-four patients were referred with paracetamol-induced hepatotoxicity within the 10year period. We selected 117 patients with both the time from paracetamol ingestion to N-acetyl cysteine administration and at least one PO4 measurement available at 48 to 96 hours postoverdose. The median time from ingestion to hospital admission was 24 hours (range, 5–96 hours) and all patients were given intravenous N-acetyl cysteine upon arrival at the hospital. There were 58 (49.6%) spontaneous survivors who did not fulfil the KCH criteria. Fifty-nine (50.4%) patients met the KCH criteria of whom 11 were transplanted and the other 48 died without a liver transplant. Out of 117 patients, 38 patients had PO4 measurements on both day 2 (48 to 72 hours postoverdose) and day 3 (72 to 96 hours postoverdose), 36 patients had PO4 measurement available only on day 2, and 43 patients only on day 3. A corresponding serum creatinine was also recorded. Phosphate concentrations were significantly higher in nonsurvivors or transplanted patients than survivors on day 2 (1.32 1.06 mmol/L vs. 0.66 0.26 mmol/L, respectively; Mann-Whitney: P 0.001) but were not significantly higher on day 3 (0.98 0.81 mmol/L vs. 0.64 0.38 mmol//L, respectively; MannWhitney: P 0.16). The discriminant PO4 value of 1.2 mmol/L reported by Schmidt and Dalhoff was found to have a poor negative predictive value as 66.7% (22/33) of measureFigure 1. Serum phosphate (PO4) levels on days 2 and 3, according to King’s College Hospital (KCH) criteria. Dotted lines indicate 1.2 mmol/L. A: Day 2 post overdose. B: Day 3 post overdose.

Chronic kidney disease after liver transplantation for acute liver failure is not associated with perioperative renal dysfunction

Renal dysfunction of acute liver failure (ALF) may have distinct pathophysiological mechanisms to hepatorenal syndrome of cirrhosis. Yet, the impact of perioperative renal function on posttransplant renal outcomes in ALF patients specifically has not been established. The aims of this study were ( 1) to describe the incidence and risk factors for chronic renal dysfunction following liver transplantation for ALF and ( 2) to compare renal outcomes with age–sex‐matched patients transplanted for chronic liver disease. This was a single‐center study of 101 patients transplanted for ALF. Fifty‐three‐and‐a‐half percent had pretransplant acute kidney injury and 64.9% required perioperative renal replacement therapy. After transplantation the 5‐year cumulative incidence of chronic kidney disease (eGFR <60 mL/min/1.73 m2) was 41.5%. There was no association between perioperative acute kidney injury (p = 0.288) or renal replacement therapy (p = 0.134) and chronic kidney disease. Instead, the independent predictors of chronic kidney disease were older age (p = 0.019), female gender (p = 0.049), hypertension (p = 0.031), cyclosporine (p = 0.027) and nonacetaminophen‐induced ALF (p = 0.039). Despite marked differences in the perioperative clinical condition and survival of patients transplanted for ALF and chronic liver disease, renal outcomes were the same. In conclusion, in patients transplanted for ALF the severity of perioperative renal injury does not predict posttransplant chronic renal dysfunction.

Reduced fibrosis in recurrent HCV with tacrolimus, azathioprine and steroids versus tacrolimus: randomised trial long term outcomes

Objective Early results of a randomised trial showed reduced fibrosis due to recurrent HCV hepatitis with tacrolimus triple therapy (TT) versus monotherapy (MT) following transplantation for HCV cirrhosis. We evaluated the clinical outcomes after a median 8 years of follow-up, including differences in fibrosis assessed by collagen proportionate area (CPA). Design 103 consecutive liver transplant recipients with HCV cirrhosis receiving cadaveric grafts were randomised to tacrolimus MT (n=54) or TT (n=49) with daily tacrolimus (0.1 mg/kg divided dose), azathioprine (1 mg/kg) and prednisolone (20 mg), the last tailing off to zero by 6 months. Both groups had serial transjugular biopsies with hepatic venous pressure gradient (HVPG) measurement. Time to reach Ishak stage 4 was the predetermined endpoint. CPA was measured in all biopsies. Factors associated with HCV recurrence were evaluated. Clinical decompensation was the first occurrence of ascites/hydrothorax, variceal bleeding or encephalopathy. Results No significant preoperative, peri-operative or postoperative differences between groups were found. During 96 months median follow-up, stage 4 fibrosis was reached in 19 MT/11 TT with slower fibrosis progression in TT (p=0.009). CPA at last biopsy was 12% in MT and 8% in TT patients (p=0.004). 14 MT/ three TT patients reached HVPG≥10 mm Hg (p=0.002); 10 MT/three TT patients, decompensated. Multivariately, allocated MT (p=0.047, OR 3.23, 95% CI 1.01 to 10.3) was independently associated with decompensation: 14 MT/ seven TT died, and five MT/ four TT were retransplanted. Conclusions Long term immunosuppression with tacrolimus, azathioprine and short term prednisolone in HCV cirrhosis recipients resulted in slower progression to severe fibrosis assessed by Ishak stage and CPA, less portal hypertension and decompensation, compared with tacrolimus alone. ISRCTN94834276 —Randomised study for immunosuppression regimen in liver transplantation.