Current management of acute liver failure.

PURPOSE OF REVIEW: Acute liver failure (ALF) is a rare but life-threatening systemic disorder. Survival rates with or without emergency liver transplantation (ELT) are increasing. The benefit of ELT in some cases has been questioned and the potential for survival with medical management alone is changing our approach to the management of this disease. RECENT FINDINGS: Survival rates for all causes of ALF are increasing because of improvements in the care of the critically ill patient. A multifactorial approach involving support of respiratory, circulatory and renal function together with measures to avoid intracranial hypertension, metabolic disequilibrium and sepsis are required. For those who do not respond to these measures or specific antidotes, the selection methods for those likely to benefit from transplantation remain imperfect and novel methods based on the prediction of hepatic regeneration are required. For patients with ALF secondary to acetaminophen overdose, some experts believe a randomized controlled trial is required to find those most likely to benefit from ELT. SUMMARY: ALF remains a life-threatening condition with a high mortality rate requiring prompt support of multiorgan failure. Historical listing criteria for ELT are being questioned and improvement in medical management offers the option of continued improvements in transplant-free survival.

The association of pretransplant ferritin level with waiting list and post-transplant survival. Does ferritin actually predict outcome?

Recent data suggest an association of serum ferritin (SF) with waiting list (WL) and postliver transplant (LT) outcomes. To assess the predictive capacity of SF on pre- and post-LT outcomes, and to identify whether recipient or donor liver siderosis is associated with post-LT survival; a retrospective analysis of 1079 patients assessed for first LT, 2000-2007 was performed. Iron deposition in the liver tissue was assessed using a semi-quantitative grading system. Median age was 54 (18-82) years and 67% were male. Seventeen per cent had hepatocellular carcinoma (HCC). Median Model for End-stage Liver Disease MELD score was 14 (6-40), ferritin was 174 µg/l (4-4597) with 36.5% had a SF ≥ µg/l. Age (OR = 1.028) and MELD score (OR = 1.158) were independently associated with WL mortality (P < 0.001), whilst SF was not (P = NS). Age (OR = 1.018), HCC (OR = 1.542) and cold ischemia time (CIT) ≥ 10 h (OR = 1.418) were independently associated with post-LT survival (P < 0.05). Explant siderosis grade <2 was seen in 376 (71.7%) patients. Patients with explant siderosis grade ≥ 2 had inferior 12-month post-LT survival (P = 0.030). Presence of graft siderosis (15.8% of patients) was not associated with survival. In conclusion, we found a limited role for SF as a prognostic indicator for pre- or post-transplant survival.

Outcomes of pregnancy in women with autoimmune hepatitis.

INTRODUCTION: Optimal management during pregnancy of patients with autoimmune hepatitis (AIH) remains undefined. We therefore reviewed all patients with AIH who reported pregnancy at our centre to identify any pre-conception factors that might predict adverse outcomes. RESULTS: There were 81 pregnancies in 53 women. Median age at conception was 26 years (range 16-42); with 41% of pregnancies occurring in the context of cirrhosis. At conception, 61 patients (75%) were on therapy for AIH. The live birth rate (LBR) was 73% (59/81). Prematurity, occurred in 12/59 (20%) and 6 (11%) required admission to special care baby unit (SCBU). In mothers who were cirrhotic at the time of conception the LBR was lower (p = 0.02) and need for admission to SCBU was higher. The overall maternal complication rate was 31/81 (38%) conceptions. A flare in disease activity occurred in 26/81 (33%) pregnancies. A serious maternal adverse event (death or need for liver transplant) during or within 12-months of delivery, or hepatic decompensation during or within 3-months of delivery, occurred with 9 pregnancies (11%) and was more common in women with cirrhosis (p = 0.028). Maternal therapy had no significant impact on the LBR (p = 0.24), termination rate (p = 0.72), miscarriage rate (p = 0.19) or gestational period (p = 0.8). Flares in AIH were more likely in patients who were not on therapy (p = 0.048) or who had a disease flare in the year prior to conception (p = 0.03). Patients who had a flare in association with pregnancy were more likely to decompensate from a liver standpoint (p = 0.01). CONCLUSIONS: This study demonstrates that poor disease control in the year prior to pregnancy and the absence of drug therapy are associated with poor outcomes whist pregnant. These data should facilitate appropriate pre-conception counselling and appropriate pregnancy management in this cohort.

Current concepts in the diagnosis and management of autoimmune hepatitis.

Autoimmune hepatitis (AIH) is a progressive necroinflammatory liver disease associated with significant morbidity and mortality. Mainly affecting females, AIH has a varied clinical presentation from minor symptomatology to acute liver failure. The diagnosis should be considered in anyone with abnormal liver function tests. Diagnostic features include biochemical evidence of transaminitis, elevated IgG and positive autoantibodies. Liver biopsy may show interface hepatitis with portal-based plasma cell infiltrates. A clinical and pathological spectrum of disease exists with other autoimmune liver disease in rare cases. AIH responds promptly to immunosuppression therapy, including corticosteroids (prednis(ol)one or budesonide) with azathioprine. Treatment failure can be addressed with several second-line immunosuppressive agents. Liver transplantation remains a successful salvage therapy for acute autoimmune liver failure or treatment failure in chronic AIH complicated by synthetic dysfunction, portal hypertension or hepatocellular carcinoma.

Popular and unpopular infectious agents linked to primary biliary cirrhosis.

Primary biliary cirrhosis (PBC) is a progressive cholestatic liver disease characterized by the autoimmune destruction of the biliary epithelial cells of the small and medium-size bile ducts. The disease affects middle aged women and usually affects more than one member within a family. The pathognomonic serological hallmark of the disease is the presence of circulating anti-mitochondrial antibodies, and disease-specific anti-nuclear antibodies. Susceptibility genes and environmental risk factors such as infections and smoking have been reported as important for the development of the disease. Among the environmental agents, infectious triggers are the best studied. Most of the work published so far has investigated the role of infections caused by Novosphingobium aromaticivorans and Escherichia coli. This review will discuss the popular and unpopular infectious agents causatively linked to PBC. It will also examine reports investigating the epidemiological aspects of the disease and their direct or indirect implications to bacterial-induced PBC.

Autoantibodies in autoimmune pancreatitis.

Autoimmune pancreatitis (AIP) was first used to describe cases of pancreatitis with narrowing of the pancreatic duct, enlargement of the pancreas, hyper-γ-globulinaemia, and antinuclear antibody (ANA) positivity serologically. The main differential diagnosis, is pancreatic cancer, which can be ruled out through radiological, serological, and histological investigations. The targets of ANA in patients with autoimmune pancreatitis do not appear to be similar to those found in other rheumatological diseases, as dsDNA, SS-A, and SS-B are not frequently recognized by AIP-related ANA. Other disease-specific autoantibodies, such as, antimitochondrial, antineutrophil cytoplasmic antibodies or diabetes-specific autoantibodies are virtually absent. Further studies have focused on the identification of pancreas-specific autoantigens and reported significant reactivity to lactoferrin, carbonic anhydrase, pancreas secretory trypsin inhibitor, amylase-alpha, heat-shock protein, and plasminogen-binding protein. This paper discusses the findings of these investigations and their relevance to the diagnosis, management, and pathogenesis of autoimmune pancreatitis.

Urinary tract infection as a risk factor for autoimmune liver disease: from bench to bedside.

Autoimmune liver diseases include autoimmune hepatitis (AIH), primary biliary cirrhosis (PBC), and primary sclerosing cholangitis. A variety of environmental and genetic risk factors have been associated with these conditions. Recurrent urinary tract infections (rUTI) have been strongly associated with PBC, and to a lesser extent with AIH. These observations were initially based on the observation of significant bacteriuria in female patients with PBC. Larger epidemiological studies demonstrated that there was indeed a strong correlation between recurrent UTI and PBC. AIH has not been linked to recurrent UTI in epidemiological studies; however treatment of UTI with nitrofurantoin can induce AIH. As Escherichia coli is the most prevalent organism isolated in women with UTI, it has been suggested that molecular mimicry between microbial and human PDC-E2 (the main autoantigenic target in PBC) epitopes may explain the link between UTI and PBC. Multiple studies have demonstrated molecular mimicry and immunological cross-reactivity involving microbial and self-antigen mimics. This review will examine the literature surrounding UTI and autoimmune liver disease. This will include case reports and epidemiological studies, as well as experimental data.

Primary biliary cirrhosis: family stories.

Primary biliary cirrhosis (PBC) is a chronic immune-mediated cholestatic liver disease of unknown aetiology which affects mostly women in middle age. Familial PBC is when PBC affects more than one member of the same family, and data suggest that first-degree relatives of PBC patients have an increased risk of developing the disease. Most often, these familial clusters involve mother-daughter pairs, which is consistent with the female preponderance of the disease. These clusters provide evidence towards a genetic basis underlying PBC. However, clusters of nonrelated individuals have also been reported, giving strength to an environmental component. Twin studies have demonstrated a high concordance for PBC in monozygotic twins and a low concordance among dizygotic twins. In conclusion, studies of PBC in families clearly demonstrate that genetic, epigenetic, and environmental factors play a role in the development of the disease.