Timothy J.S. Cross

Outcome after wait-listing for emergency liver transplantation in acute liver failure: A single centre experience

BACKGROUND/AIMS Though emergency liver transplantation (ELT) is an established treatment for severe acute liver failure (ALF), outcomes are inferior to elective surgery. Despite prioritization, many patients deteriorate, becoming unsuitable for ELT. METHODS We examined a single-centre experience of 310 adult patients with ALF registered for ELT over a 10-year period to determine factors associated with failure to transplant, and in those patients undergoing ELT, those associated with 90-day mortality. RESULTS One hundred and thirty-two (43%) patients had ALF resulting from paracetamol and 178 (57%) from non-paracetamol causes. Seventy-four patients (24%) did not undergo surgery; 92% of these died. Failure to transplant was more likely in patients requiring vasopressors at listing (hazard ratio 1.9 (95% CI 1.1-3.6)) paracetamol aetiology (2.5 (1.4-4.6)) but less likely in blood group A (0.5 (0.3-0.9)). Post-ELT survival at 90-days and one-year increased from 66% and 63% in 1994-1999 to 81% and 79% in 2000-2004 (p<0.01). Four variables were associated with post-ELT mortality; age >45 years (3 (1.7-5.3)), vasopressor requirement (2.2 (1.3-3.8), transplantation before 2000 (1.9 (1.1-3.3)) and use of high-risk grafts (2.3 (1.3-4.2). CONCLUSIONS The data indicate improved outcomes in the later era, despite higher level patient dependency and greater use of high-risk grafts, through improved graft/recipient matching.

Liver transplantation in patients over 60 and 65 years: An evaluation of long‐term outcomes and survival

With increased demand for liver transplantation (LT), outcomes of older recipients have been subjected to greater scrutiny, as previous studies have demonstrated poorer survival outcomes. Outcomes of 77 patients aged > 65 yr (group 1) who underwent transplantation between 1988 and 2003 at Kings College Hospital, London, were compared with all recipients aged between 60 and 64 yr (group 2, n = 137) and 202 time‐matched control patients with chronic liver disease aged between 18‐59 yr (group 3). Patient survival at 30‐days for groups 1, 2, and 3 were 99%, 94%, and 94%, respectively (P = not significant [NS]). At 1‐yr, survival in the 3 groups was 82%, 86%, and 83%, respectively (P = NS), and at 5‐yr patient survival was comparable (73%, 80%, and 78%, respectively) (P = NS). Episodes of acute cellular rejection (ACR) were fewer in the older cohorts (43% vs. 45% vs. 61%, P = 0.0016), although there was no significant difference identified in the numbers of patients in each group who experienced ACR (P = 0.16). A similar but nonsignificant trend was identified for rates of chronic rejection among the groups. In conclusion, these data suggest that survival of patients over 60 and 65 yr undergoing LT is satisfactory, at least in the first 5‐yr posttransplantation. In addition, patients over 65 yr experience less rejection, with good graft survival. Thus, LT should not be denied to patients >65 yr on the basis of age alone, once a comprehensive screen for comorbidity has been undertaken. Liver Transpl 13:1382–1388. 2007.

Predictors of bacteraemia and mortality in patients with acute liver failure

PurposeTo determine what physiological and biochemical factors predict development of bacteraemia and mortality in patients with acute liver failure (ALF).MethodsRetrospective analysis of 206 ALF patients admitted to a specialist liver intensive therapy unit (LITU) from January 2003 to July 2005 (data collected prospectively).ResultsA total of 206 patients were defined with ALF: 72 (35%) suffered bacteraemia (BAClf) and 134 (65%) did not (NBAClf). Gram positive organisms were observed in 44% of isolates, gram negatives in 52% and fungaemia in 4%. Median time to first bacteraemia was 10 (7–16) days. On admission, BAClf patients had higher SIRS scores and degrees of hepatic encephalopathy (HE). During their LITU course, BAClf patients had significantly increased requirements for renal replacement therapy (RRT), mechanical ventilation, and longer median LITU stay. Multivariate analysis (logistical regression) demonstrated significant predictors of bacteraemia on admission were HE grade >2 (Odds Ratio 1.6) and SIRS score >1 (OR 2.7). In all patients, independent predictors of mortality (logistical) were age (OR 1.41), maximum HE grade pre-intubation (1.76), Lactate (1.14) and Acute Physiology and Chronic Health Evaluation II score (APACHEII) (1.09), but not bacteraemia. Transplantation was protective (OR 0.20).ConclusionIn this study, severity of hepatic encephalopathy and SIRS score >1 were predictive of bacteraemia. APACHEII was independently predictive of mortality in all ALF patients but not bacteraemia.

The impact of hepatic steatosis on the natural history of chronic hepatitis C infection

Summary.  Since patients with hepatitis C virus (HCV) often have hepatic steatosis, this retrospective analysis aimed to assess whether steatosis influences fibrosis progression. We studied 112 HCV RNA positive subjects (median age 44, IQR 39–51 years), who had two liver biopsies performed (median biopsy interval 50, 34–74 months). Fibrosis was staged using the Ishak method and steatosis by the Kleiner system (<5% steatosis = S0, 5–33% = S1, 33–66% = S2, and >66% = S3). The subjects were untreated because they had mild fibrosis (n = 59), declined therapy (n = 48), or had co‐existing disease precluding treatment (n = 5). On first liver biopsy, 60 (54%) had S0, 34 (30%) had S1, 12 (11%) had S2, and 6 (5%) had S3. Steatosis was associated with genotype 3, odds ratio 4.8 (95% CI 1.3–16.7, P = 0.02). Twenty‐three patients (21%) had disease progression on the second biopsy, defined as an increase in Ishak score by ≥1 stage. On univariate analysis, fibrosis progression was associated with older age (P = 0.004), higher AST (P = 0.04), and steatosis (P = 0.005) but on multivariate analysis, only baseline steatosis was significant, odds ratio 14.3 (2.1–111.1, P = 0.006). Kaplan‐Meier analysis demonstrated that steatosis impacted on time to progression to both significant fibrosis (Ishak ≥F3) and cirrhosis (Ishak F5‐6) (P = 0.001 and P = 0.049, respectively). The finding that steatosis was significantly associated with fibrosis progression indicates that, independent of baseline fibrosis stage, patients should be considered for anti‐viral treatment if steatosis is present. Furthermore, strategies to reduce steatosis may have a beneficial effect on fibrosis progression and, therefore, patient outcome.

Prospective comparison of Fibroscan, King’s score and liver biopsy for the assessment of cirrhosis in chronic hepatitis C infection

Summary.  Historically, liver biopsy (LB) was the sole method to evaluate the severity of hepatic fibrosis in patients with chronic hepatitis C infection. However, LB is expensive and associated with a risk of severe complications. Therefore, noninvasive tests have been developed to assess the severity of liver fibrosis. The accuracy of Fibroscan (FS) and King’s score (KS) was evaluated individually and in combination using liver histology as the reference standard. One hundred and eighty‐seven patients were identified who had undergone a biopsy with a diagnosis of chronic hepatitis C virus (HCV) mono‐infection (HCV RNA‐positive by RT‐PCR), attending King’s College Hospital (n = 88) or the Royal Free Hospital (n = 99) (London) between May 2006 and December 2007. Liver fibrosis was scored using the Ishak method; significant fibrosis was defined as Ishak fibrosis stage F3–F6, and cirrhosis defined as Ishak fibrosis F5–F6. The diagnostic accuracy of each test was assessed by area under receiver operator characteristic curves (AUROC). Median age was 49 years (43–54) and 115 (61%) were male. The AUROC for FS, KS and FS + KS for the diagnosis of Ishak F3–F6 were 0.83, 0.82 and 0.85, respectively and for the diagnosis of cirrhosis (≥F5) were 0.96, 0.89 and 0.93, respectively. The negative predictive values for the diagnosis of cirrhosis using the optimal cut‐off results for fibrsocan (10.05 kPa), KS (24.3) and the two combined (26.1) were 98%, 91% and 94%, respectively. The noninvasive markers and, particularly, FS were effective tests for the prediction of cirrhosis in chronic hepatitis C. Both KS and FS also had clinical utility for the prediction of Ishak fibrosis stages F3–F6.

Actin‐free Gc globulin: A rapidly assessed biomarker of organ dysfunction in acute liver failure and cirrhosis

Reductions in serum levels of Gc globulin, a hepatically synthesized component of the extracellular actin scavenger system responsible for complexing circulating actin and attenuating intravascular microthrombus formation, are associated with poor outcome in acute liver failure. Clinically applicable assays of the important actin‐free fraction (Af‐Gc) have not been available until now. We measured actin‐free Gc globulin levels with a novel, rapid assay in 61 cases of acute liver failure (ALF) and in 91 patients with cirrhosis (40 of whom were clinically unstable with extrahepatic organ dysfunction), and studied associations with liver dysfunction, extrahepatic organ dysfunction, indices of disseminated coagulation, and outcome. Reductions in Af‐Gc levels mirrored hepatic dysfunction and organ dysfunction in both groups, and discriminated patients with poor prognosis from those with good prognosis in the ALF cohort. Levels were lowest in patients with ALF (10% of control values), but levels were also markedly reduced in both unstable (28%) and stable (44%) patients with cirrhosis. Associations with markers of disseminated intravascular coagulation were seen in both groups, most notably in the cirrhosis cohort, supporting a pathophysiological role for reduced Af‐Gc in the evolution of organ dysfunction. In acetaminophen‐induced ALF, Af‐Gc identified patients with poor prognosis as well as did the Acute Physiology and Chronic Health Evaluation (APACHE II) score (area under the receiver operating characteristic curve, 0.7), and in cirrhosis, Af‐Gc was an independent predictor of mortality by multifactorial analysis. In conclusion, the importance of Af‐Gc reductions in the development of multiple organ dysfunction in ALF and cirrhosis is highlighted, probably resulting from reduced hepatic production and peripheral exhaustion of this arm of the extracellular actin scavenger system. Liver Transpl 13:1254–1261, 2007.

A simple, noninvasive test for the diagnosis of liver fibrosis in patients with hepatitis C recurrence after liver transplantation

Summary.  Recurrent hepatitis C is a common cause of graft loss in patients undergoing liver transplantation, and serial protocol liver biopsies have been used to identify patients at risk of graft loss from rapid fibrosis progression. The aim of this study was to derive a simple noninvasive index to predict fibrosis in patients with recurrent hepatitis C post‐transplant. A retrospective study was performed assessing serial liver biopsies for post‐transplant chronic hepatitis C infection. One hundred eighty‐five patients were included in the analysis; median age 53 years (interquartile range 48–59) and 140 (76%) were male. Liver histology showed 53 (29%) had Ishak fibrosis stages F0/F1, 31 (17%) had F2, 29 (16%) had F3, 19 (10%) had F4 and 53 (29%) had F5/F6. The London Transplant Centres’ (LTC) score was derived combining aspartate aminotransferase (AST IU/L), time from liver transplant (TFLT months), international normalized ratio and platelets. Diagnostic accuracy of the LTC score was assessed using area under receiver‐operating characteristic (ROC) curves. The area under the ROC curve for moderate fibrosis (F ≥ 2) was 0.78 (95% CI, 0.70–0.86; P < 0.0001), for advanced fibrosis (F4–6) was 0.80 (95% CI, 0.72–0.87; P < 0.0001) and for cirrhosis was 0.80 (95% CI, 0.72–0.88; P < 0.0001). An optimal cut‐off value of 6.3 distinguished patients with no or mild fibrosis (F ≤ 1) odds ratio 10.8 (95% CI, 5.1–22.9); P < 0.0001), sensitivity 88%, specificity 60%, negative predictive value 67% and positive predictive value 84%. The LTC score can identify patients with Hepatitis C virus recurrence following liver transplant with a low risk of significant fibrosis, thus avoiding the need for protocol biopsy.

The importance of steatosis in chronic hepatitis C infection and its management: A review

Hepatitis C virus (HCV) infection is a major cause of chronic liver disease with approximately 180 million people infected worldwide. Hepatic steatosis is a frequent histological finding in chronic hepatitis C (CHC) infection and is 2‐ to 3‐fold more common than would be expected by chance alone. A high body mass index with excess visceral fat distribution is associated with steatosis in patients infected with HCV genotype 1 but not genotype 3, re‐enforcing the concept that in patients with CHC, some have “metabolic steatosis”, predominantly HCV genotype 1, and others “viral steatosis”, mainly HCV genotype 3. Accumulating evidence suggests that steatosis may contribute to progression of fibrosis in CHC. Hepatic insulin resistance appears to play a role through the pro‐fibrogenic effects of compensatory hyperinsulinemia. The aim of this review was to assess the effect host and viral factors play in steatosis development in patients with CHC infection and its possible relationship with hepatocellular carcinoma. The review examines the mechanisms by which CHC infection causes hepatic steatosis, the impact hepatic steatosis has on the natural history of the disease and finally, explores if treatments leading to a reduction in the amount of steatosis might lead to improved treatment outcomes. The basic medical science of steatosis in CHC will be discussed including proposed models of steatogenesis and the influence of viral and metabolic factors at the molecular level and how these might impact on current and future therapies.

Non-invasive markers for the prediction of fibrosis in chronic hepatitis C infection

Liver fibrosis occurs as a result of chronic liver injury and is the hallmark of chronic liver disease. The final stage of progressive liver fibrosis is cirrhosis, which is implicated in portal hypertension, end‐stage liver disease and hepatocellular carcinoma. Liver biopsy has historically been the gold standard test for the assessment of liver fibrosis for liver diseases such as viral hepatitis, autoimmune hepatitis and primary biliary cirrhosis. Improved serological tests have enhanced the diagnosis of these conditions and reduced the need for liver biopsy. Liver biopsy is unpopular among patients and clinicians. It is associated with morbidity and mortality, and in addition is subject to sampling error, inter‐ and intra‐observer variability. There is therefore a need for non‐invasive markers of liver fibrosis that are accurate, reliable, cheap and easy to use. The aim of this review is to examine the different non‐invasive methods that can be used to estimate the severity of fibrosis. The methods evaluated include clinical examination, routine laboratory investigations, imaging tests, specialized tests of liver function and finally serum extra‐cellular matrix markers of fibrosis. The review mainly focuses on fibrogenesis in the context of chronic hepatitis C infection.

Chronic hepatitis C

Antiviral therapy is approved by NICE but too few patients receive it