Rachel H. Westbrook

Natural history of hepatitis C

There has long been evidence that hepatitis C can lead to persistent infection in a high proportion of infected individuals, and can progress to chronic liver disease, cirrhosis and hepatocellular carcinoma (HCC). The transition from acute to chronic hepatitis C is usually sub-clinical. Accurate studies of the time course for clearance of acute hepatitis C are difficult to carry out because of the silent onset of the acute disease. The likelihood of spontaneous HCV resolution is associated with several genetic factors, including IL28B inheritance and the DQB1*0301 allele of the major histocompatibility complex class II. Most data suggest that resolution in the acute phase without progression to chronic disease is not accompanied by significant disease, but minor histological lesions have been observed in anti-HCV positive, HCV RNA negative individuals. The risk of reinfection remains a possibility after clearance of acute hepatitis C. High rates of sexually-transmitted infection are being reported in HIV positive men who have sex with men (MSM). Chronic infection with HCV is the leading cause of end-stage liver disease, hepatocellular carcinoma (HCC) and liver related death in the Western world. The natural history of the chronic disease remains incompletely defined. It is generally a slowly progressive disease characterized by persistent hepatic inflammation, leading to the development of cirrhosis in approximately 10-20% of patients over 20-30 years of HCV infection. However, the published data indicate varying progression rates to cirrhosis. Overall, once cirrhosis has developed there is a 1-5% annual risk of HCC and a 3-6% annual risk of hepatic decompensation. Following an episode of decompensation the risk of death in the following year is between 15% and 20%. The high number of chronically infected individuals, the burden of disease, and the absence of a vaccine indicates that treatment will form part of the disease control but the impact, effectiveness and outcomes of treatment in various groups remain uncertain. Several studies and meta-analysis have concluded that eradication of HCV with antiviral therapy reduces the risk of HCC in patients with chronic hepatitis C, independent of fibrosis stage, but the risk is not eliminated.

Liver disease in pregnancy

Severe liver disease in pregnancy is rare. Pregnancy-related liver disease is the most frequent cause of liver dysfunction in pregnancy and provides a real threat to fetal and maternal survival. A rapid diagnosis differentiating between liver disease related and unrelated to pregnancy is required in women who present with liver dysfunction during pregnancy. Research has improved our understanding of the pathogenesis of pregnancy-related liver disease, which has translated into improved maternal and fetal outcomes. Here, we provide an overview of liver diseases that occur in pregnancy, an update on the key mechanisms involved in their pathogenesis, and assessment of available treatment options.

Diagnostic value and utility of the simplified International Autoimmune Hepatitis Group (IAIHG) criteria in acute and chronic liver disease

Diagnostic criteria for autoimmune hepatitis (AIH) have been created and revised by the International Autoimmune Hepatitis Group (IAIHG). Simplified criteria have been created, but remain independently unvalidated. We report on the diagnostic accuracy of the simplified criteria in patients across a range of diagnoses, including a subset of patients presenting with fulminant liver failure who required liver transplant. Patients with AIH and non‐AIH etiologies of liver disease were identified from dedicated patient databases. Parameters relevant to the simplified and 1999 IAIHG criteria were recorded, and sensitivity, specificity, and positive and negative predictive values for scores of ≥6 (probable AIH) and ≥7 (definite AIH) were calculated. A total of 549 patients with chronic liver disease were evaluated, (221 with AIH, 26 with variant syndromes, and 302 with non‐AIH). For scores ≥6, sensitivity was 90%, and specificity was 98% with positive and negative predictive values of 97% and 92%, respectively. For scores ≥7; sensitivity was 70%, and specificity was 100% with positive and negative predictive values of 100% and 74%, respectively. Seven false positive diagnoses of AIH occurred, all with simplified scores of 6. Concordance with 1999 criteria was 90% for probable and 61% for definite AIH. The frequency of an overall diagnosis of AIH (probable or definite AIH) among the 70 patients with fulminant liver failure was 24% for simplified criteria and 40% for 1999 criteria, respectively. Conclusion: The simplified criteria retain high specificity but exhibit lower sensitivity for scores of ≥7. The explanations for this are unclear but may relate to loss of such discriminating information as response to corticosteroids. Prospective evaluation of these criteria is required to corroborate these observations. (HEPATOLOGY 2009.)

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.

Early predictors of corticosteroid treatment failure in icteric presentations of autoimmune hepatitis

Autoimmune hepatitis (AIH) typically responds to treatment in 90% of patients. Early prediction of treatment outcome would be advantageous in clinical practice. We evaluated whether parameters at initiation of therapy or changes in these parameters at day 3 and day 7 following corticosteroid initiation predicted treatment failure. Treatment‐naive, jaundiced patients presenting to our tertiary unit between 1999‐2009 were identified and mathematical models of prognosis in liver disease scores calculated at day 0, day 3, and day 7. Overall, 72 patients were identified (48 women, 24 men). Treatment failure occurred in 18% (13/72) of patients. At diagnosis, higher median bilirubin (451 μmol/L versus 262 μmol/L, P = 0.02), INR (1.62 versus 1.33, P = 0.005), model for endstage liver (MELD) score (26 versus 20, P = 0.02), MELD‐sodium (Na) score (27 versus 22, P = 0.03) and United Kingdom endstage liver disease score (UKELD) score (59 versus 57, P = 0.01) significantly correlated with treatment failure. Analysis of area under the receiver operator characteristic curve (AUROC) values at day 7 identified change (Δ) bilirubin (AUROC 0.68), Δ creatinine (0.69), Δ MELD (0.79), Δ MELD‐Na (0.83) and Δ UKELD (0.83) best predicted treatment failure. Specifically, a fall in UKELD of less than 2 points predicted treatment failure with a sensitivity of 85% and specificity of 68%. Of 13 treatment failures, nine required second‐line immunosuppression, three required emergency transplant, and one died of sepsis. In total, four patients died in the treatment failure group compared with one in the responder group (4/13 = 31% versus 1/59 = 1.7%, P = 0.003). Conclusion: Approximately 20% of icteric AIH presentations fail corticosteroid therapy. This is associated with significant mortality and the need for emergency transplantation. Treatment failure is best predicted by change in MELD‐Na and UKELD at day 7. Early identification of nonresponders may allow timely escalation of immunosuppression to prevent clinical deterioration. (HEPATOLOGY 2011;)

Prognosis of acute severe autoimmune hepatitis (AS-AIH): The role of corticosteroids in modifying outcome

BACKGROUND & AIMS No standardised definition exists for acute, severe AIH (AS-AIH). However, rapid identification of AS-AIH and early corticosteroid therapy may prevent the need for liver transplantation (LT). We set out to determine the clinical outcomes of patients with AS-AIH presenting to our institution with particular focus on the role of corticosteroids. METHODS Retrospective analysis of a prospectively collated database identified patients presenting with AS-AIH from 1999 to 2009. We defined AS-AIH as an acute presentation with an INR of ⩾1.5 at any time without histological evidence of cirrhosis. RESULTS 32 patients were identified with AS-AIH. Among the 32 AS-AIH patients 23 were treated with corticosteroids of whom 10 (48%) required LT, whilst all 9 untreated patients required LT (p = 0.01). Untreated patients demonstrated higher MELD scores at presentation (34 vs. 28 p = 0.01) and a non-significant decrease in episodes of sepsis but no difference in sepsis or mortality was observed between untreated or treated patients (11% vs. 26% p = 0.6 and 22% vs. 17% p = 0.99 respectively). Among treated patients, no difference in MELD scores was observed between responders or failures. Despite 59% undergoing LT, six deaths (19%) occurred. CONCLUSION In a well characterised cohort of patients with AS-AIH, almost 60% required LT and 20% died. There was no difference in prognostic scores between steroid responders and failures and steroid exposure did not appear to jeopardise survival. Patients with AS-AIH should be considered for a trial of corticosteroids expediently whilst a thorough search for sepsis and assessment for LT should occur if clinical deterioration or encephalopathy develops.

Model for End-Stage Liver Disease Score Predicts Outcome in Cirrhotic Patients During Pregnancy

BACKGROUND & AIMS Pregnancy is rare among patients with cirrhosis, and data about complications and outcomes are sparse. We evaluated the utility of prognostic models of severity of cirrhosis in determining outcomes in pregnant women with cirrhosis. METHODS We evaluated all cirrhotic patients who self-reported pregnancy at our center and correlated prognostic scores at the time of conception with outcomes. RESULTS Sixty-two pregnancies occurred in 29 women. The median model for end-stage liver disease (MELD) score at conception was 7 (range, 6-17), the median MELD sodium score was 9 (range, 6-17), the median United Kingdom end-stage liver disease (UKELD) score was 44 (range, 36-53), and the median Child-Pugh score was 5 (range, 5-8). The live birth rate was 58%; the median gestational age was 36 weeks. Higher MELD (P = .01), MELD sodium (P = .01), UKELD (P = .01), and Child-Pugh (P = .03) scores were associated with gestation <37 weeks. Maternal complications (ascites, encephalopathy, or variceal hemorrhage) occurred in 10% of patients and were associated with higher MELD (P = .01) and UKELD (P = .02) scores. Receiver operator curve analysis demonstrated that a MELD score ≥10 predicted, with 83% sensitivity and 83% specificity, which patients were likely to have significant, liver-related complications (area under curve, 0.8); a UKELD score ≥47 had 83% sensitivity and 79% specificity (area under curve, 0.8). No patient who had a MELD score ≤6 or a UKELD score ≤42 developed any significant hepatologic complications. CONCLUSIONS MELD and UKELD scores at the time of conception can be used to predict specific clinical outcomes in pregnant women with cirrhosis.

Validation of the Baveno VI criteria to identify low risk cirrhotic patients not requiring endoscopic surveillance for varices

BACKGROUND & AIMS The Baveno VI guidelines propose that cirrhotic patients with a liver stiffness measurement (LSM) <20kPa and a platelet count >150,000/μl can avoid screening endoscopy as their combination is highly specific for excluding clinically significant varices. The aim of the study was to validate these criteria. METHODS Transient elastography data was collected from two institutions from 2006-2015. Inclusion criteria were a LSM ⩾10kPa and an upper gastrointestinal endoscopy within 12months, with a diagnosis of compensated chronic liver disease. Exclusion criteria were porto-mesenteric-splenic vein thrombosis and non-cirrhotic portal hypertension. Varices were graded as low risk (grade <2) or high risk (grade ⩾2). RESULTS The study included 310 patients (169 (55%) hepatitis C, and 275 (89%) Child-Pugh A). Varices were present in 23% cases, with 5% prevalence of high risk varices. Overall 102/310 (33%) met the Baveno VI criteria. Within this group 11% had varices and 2% had high risk varices, representing 2/15 (13%) of all high risk varices. The Baveno VI criteria gave a sensitivity 0.87, specificity 0.34, positive predictive value 0.06, negative predictive value 0.98, positive likelihood ratio 1.31 and negative likelihood ratio 0.39. The AUROC for LSM and platelet count combined was 0.746. CONCLUSIONS The Baveno VI criteria performed well correctly identifying 98% of patients who could safely avoid endoscopy. LAY SUMMARY This study examines the effectives of a recent set of guidelines published by the Baveno VI conference, which states that patients with chronic liver disease and a low liver stiffness (<20kPa) and high platelet count (>150) are at low risk of having varices and do not need a screening endoscopy. Varices are a complication of cirrhosis, confer a risk of serious bleeding, and can be diagnosed and treated by endoscopy. Our study reviewed the clinical records of patients who have had liver stiffness scans and endoscopy over a 9-year period at two hospitals. The results show that only about 2% of patients who meet the Baveno VI criteria will be miss-classified as not having varices.

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 Kings 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.

The prevalence of the activating JAK2 tyrosine kinase mutation in chronic porto‐splenomesenteric venous thrombosis

Aliment Pharmacol Ther 31, 1330–1336