Pregnant patients with acute liver failure (ALF) are believed to have a worse outcome than nonpregnant women and men with ALF. However objective data supporting this supposition are scant. Therefore, ...the current study compared the outcome, complications, and causes of ALF among pregnant women and girls with age‐matched nonpregnant women and girls and men and boys with ALF. One thousand fifteen consecutive ALF patients in the reproductive age group, admitted at the All India Institute of Medical Sciences, New Delhi, from January 1986 to December 2006, were included in the study. A total of 249 (38.5%) women were pregnant. They were compared with 341 nonpregnant women and girls and 425 men and boys, aged 15 to 45 years. The mortality rate of pregnant women and girls (53.8%) was similar to age‐matched nonpregnant women and girls (57.2%), and men and boys (57.9%); P = 0.572.The clinical and biochemical features, disease severity, and complications were also similar in the three groups. A significantly higher proportion of ALF was attributable to hepatitis E virus (HEV) among women and girls who were pregnant (59.4%), as compared with both nonpregnant women and girls (30.4%), and men and boys (23.1%); P < 0.001. However, the outcome of HEV‐related ALF was independent of the sex and pregnancy status of the patients (P = 0.103). Mortality in HEV‐ALF and non–HEV‐ALF patients in pregnant women and girls was 51% (74/145) and 54.7% (52/95)(P > 0.1), respectively. The outcome of pregnant ALF patients was also unrelated to the trimester of pregnancy. The mortality of non–HEV‐related ALF among the pregnant women and girls (54.7%), age‐matched nonpregnant women and girls (61.7%), and men and boys (62.8%) were also similar (P > 0.1). Conclusion: The mortality of pregnant patients with ALF is similar to that of nonpregnant women and girls and men and boys and is independent of the cause or trimester. Pregnancy per se should not be regarded as a poor prognostic factor for a patient with ALF. (HEPATOLOGY 2008.)
Background/Aims India is hyper-endemic for hepatitis E virus (HEV). HEV infection in cirrhosis may cause high mortality. Prospective study evaluating HEV infection in cirrhotics is scarce. Methods ...Consecutive patients with cirrhosis and healthy controls were included. Cirrhotics were categorized to 3 groups, (Group I – rapid decompensation, Group II – chronically decompensated, Group III – cirrhotics without decompensation). Sera from cirrhotics and controls were tested for HEV-RNA (RT-PCR). HEV-RNA positivity among cirrhotics and controls was compared. Natural course and mortality rate between HEV infected and non-infected cirrhotics were assessed during a 12-month follow-up. Results 107 cirrhotics and 200 controls were included. 30 (28%) cirrhotics and 9 (4.5%) controls had detectable HEV-RNA ( p < 0.001). HEV- RNA positivity among Group I ( n = 42), II ( n = 32) and III ( n = 33) cirrhotics was 21 (50%), 6 (19%) and 3 (10%), respectively ( p = 0.002). 70% (21/30) with HEV infection and 27% (21/77) without it had rapid decompensation ( p = 0.001). Mortality between HEV infected and non-infected cirrhotics at 4 weeks (43% vs. 22%, p = 0.001) and 12 month (70% vs. 30%, p = 0.001) was different. Multivariate analysis identified HEV infection, Child-Pugh’s score, renal failure, and sepsis as independent factors for mortality. Conclusions In India, cirrhotics were prone to HEV infection, which was associated with rapid decompensation and death.
Background & Aims In acute liver failure (ALF), high blood ammonia levels have been documented that correlate with mortality and complications. L-ornithine L-aspartate (LOLA) reduces ammonia levels ...by increasing hepatic ammonia disposal and its peripheral metabolism. Present study evaluated efficacy and ammonia lowering effect of LOLA in ALF. Methods This study was placebo-controlled and blinded. We randomized 201 patients with ALF between January 2005 and October 2007 to either placebo or LOLA infusions (30 g daily) for 3 days. Arterial ammonia was measured at baseline and daily for 6 days. The primary end point was improvement in survival. The study followed CONSORT guidelines and was registered at the ClinicalTrials.gov (Identifier: NCT00470314 ). Results There was no reduction in mortality with LOLA treatment (mortality: 33.3% in placebo and 42.4% in LOLA; relative risk of death 1.27; 95% CI: 0.88–1.85; P = .204). By multivariate analysis, ammonia levels were an independent predictor of survival. There was significant decrease in ammonia levels in both groups with time ( P < .001), but the levels of ammonia between the randomized groups at any time point, either during the 72 hours of LOLA infusion or during the follow-up were similar ( P = .492). There was no difference between the 2 groups in the improvement in encephalopathy grade ( P = .418), consciousness recovery time ( P = .347), survival time ( P = .612), or complications like seizures ( P = .058) and renal failure ( P = .615). The fetal outcome was also similar ( P = .172). No adverse drug effect was noted. Conclusions LOLA infusion did not lower the ammonia or improved survival in ALF.
It is difficult to predict the outcome in patients with acute liver failure (ALF) using existing prognostic models. This study investigated whether early changes in the levels of dynamic variables ...can predict outcome better than models based on static baseline variables.
380 patients with ALF (derivation cohort n=244, validation cohort n=136) participated in a prospective observational study. The derivation cohort was used to identify predictors of mortality. The ALF early dynamic (ALFED) model was constructed based on whether the levels of predictive variables remained persistently high or increased over 3 days above the discriminatory cut-off values identified in this study. The model had four variables: arterial ammonia, serum bilirubin, international normalised ratio and hepatic encephalopathy >grade II. The model was validated in a cohort of 136 patients with ALF.
The ALFED model demonstrated excellent discrimination with an area under the receiver operator characteristic curve of 0.91 in the derivation cohort and of 0.92 in the validation cohort. The model was well calibrated in both cohorts and showed a similar increase in mortality with increasing risk scores from 0 to 6. The performance of the ALFED model was superior to the King's College Hospital criteria and the Model for End stage Liver Disease score, even when their 3-day serial values were taken into consideration. An ALFED score of ≥4 had a high positive predictive value (85%) and negative predictive value (87%) in the validation cohort.
The ALFED model accurately predicted outcome in patients with ALF, which may be useful in clinical decision-making.
Acute on chronic liver failure (ACLF) because of precipitating factors (variceal bleed/infections) identifies cirrhotics at risk for high short-term mortality. Information on ACLF because of acute ...hepatic insults is lacking. The aim of the study was to evaluate acute hepatic insults in ACLF and their effect on the course and outcome.
In a prospective study, 213 consecutive patients of ACLF because of acute hepatic insults were included. Etiology of acute hepatic insult, frequency of silent, and overt chronic liver disease (CLD), organ failure (OF), and outcomes were assessed. Prognostic models such as model for endstage liver disease (MELD), acute physiology and chronic health evaluation (APACHE II), and chronic liver failure-sequential organ failure (CLIF-SOFA) were evaluated.
Etiologies of acute hepatic insult were hepatitis virus(es)- 81 (38%; HBV-42, HEV-39), continuous alcohol consumption-77 (33.3%), antituberculosis drugs-11 (5.2%), autoimmune hepatitis flare-5(2.3%), cryptogenic-44 (20.7%). The common causes of CLD were alcohol (n = 85/40%), HBV(n = 52/24%), and cryptogenic(n = 50/20%). The MELD, APACHE II, and CLIF-SOFA scores were similar among silent and overt CLD and did not influence outcome. Predominant etiologies of ACLF were hepatitis virus(es) reactivation or superinfection in silent CLD(52/112, 46.4%) and alcohol among overt CLD(43/101, 43%). Independent predictors of mortality included hepatic-encephalopathy (early, HR: 4.01; advanced, HR: 6.10), serum creatinine ≥1.5 mg/dl (HR: 4.53), CLIF-SOFA ≥8(HR: 1.69), and etiology of acute hepatic insult (alcohol, HR: 4.08; cryptogenic, HR: 3.18). HEV-ACLF had lower mortality (12.8% vs. 33-54% in other etiologies;P < 0.001). OF was major determinant of mortality. With increasing number of OF, mortality increased linearly(P = 0.001).
Hepatitis virus(es) and continuous alcohol consumption are important causes of ACLF caused by acute hepatic insults. HEV-ACLF has lower mortality. OF is an important prognostic predictor.
Viral infections are among the major causes of acute liver failure (ALF) worldwide. While the role of agents such as hepatitis A, B, C, D and E viruses in precipitating ALF are well known, ...improvements in serological assays have led to the detection of viral agents such as Epstein Barr virus, cytomegalovirus etc. as atypical causes of ALF. Despite the plethora of literature available on viral hepatitis and ALF, there is very limited large-scale epidemiologic data on the prevalence, risk factors of progression and outcomes in ALF of viral causes. This is important as viral infections remain the leading cause of ALF in the East and in developing countries, while the impact of viral ALF in the West has largely been ameliorated by effective vaccination and sanitization programs. This review focuses specifically on the available prognostic scores that aid in the management of ALF of viral etiologies while also briefly reviewing the current literature on newer viral agents known to cause ALF, risk factors of progression, outcomes and how management algorithms can be developed by incorporation of prognostic scoring systems for referral and transplant listing.
Background & Aims:
Genome sequence of hepatitis B virus (HBV) from occult chronic infection is scarce. Fifty-six (9.4%) of 591 patients seronegative for hepatitis B surface antigen (HBsAg) with ...chronic liver disease were positive for HBV DNA. The complete HBV genome from 9 of these patients (S1-S9) and 5 controls positive for HBsAg (SWT.1-SWT.5) were analyzed.
Methods:
Overlapping genome fragment amplification, cloning, and sequencing was performed on these cases. Functional analysis of surface promoter was conducted using fusion construct.
Results:
All patients with occult infection except one (S8) had a low viral titer. Eight patients had infection with genotype A (S1-S5, SWT.1–2, SWT.5) and 6 had infection with genotype D (S6-S9, SWT.3–4). S4 and S5.1 of genotype A had the characteristic nucleotide deletions in core and pre-S1 region seen in genotype D. The major observations in patients with occult HBV infection were as follows: frequent quasispecies variation, deletions in pre-S2/S region affecting the surface promoters (nt 3025-54) and pre-S protein (S3, S5, S6, S8), truncated precore (S6, S8, S7.1) and core (S9) owing to stop signal, alternate start codon for the
Polymerase gene (S3, S9), and YMDD mutation (S1, S4, S9) in patients not on antiviral therapy. HBsAg and core proteins could be shown immunohistochemically in 3 of 5 liver biopsy specimens available. The mutant surface promoters (pre-S2 and S) on functional analysis showed alterations in HBsAg expression.
Conclusions:
These changes in the regulatory region with possible alterations in the ratio of large and small surface proteins along with other mutations in the genome may decrease the circulating HBsAg level synergistically, making the immunodetection in serum negative.
Patients admitted to the hospital with acute liver failure (ALF) and high arterial levels of ammonia are more likely to have complications and poor outcomes than patients with lower levels of ...ammonia. ALF is a dynamic process; ammonia levels can change over time. We investigated whether early changes (first 3 days after admission) in arterial levels of ammonia were associated with complications and outcomes and identified factors associated with persistent hyperammonemia.
We performed a prospective observational study that measured arterial ammonia levels each day for 5 days in 295 consecutive patients with ALF. We analyzed associations of changes in ammonia levels during the first 3 days with complications and outcomes.
Patients with persistent arterial hyperammonemia (≥122 μmol/L for 3 consecutive days), compared with those with decreasing levels, had lower rates of survival (23% vs 72%; P < .001) and higher percentages of cerebral edema (71% vs 37%; P < .001), infection (67% vs 28%; P = .003), and seizures (41% vs 7.7%; P < .001). Patients with persistent hyperammonemia had greater mortality, with an odds ratio (OR) of 10.7, compared with patients with baseline levels of ammonia ≥122 μmol/L (OR, 2.4). Patients with persistent hyperammonemia were more likely to progress to and maintain advanced hepatic encephalopathy than those with decreasing levels. Patients with persistent, mild hyperammonemia (≥85 μmol/L for 3 days) were also more likely to have complications or die (P < .001) than patients with serial ammonia levels <85 μmol/L. Infections (OR, 4.17), renal failure (OR, 2.20), and decreased arterial pH (OR, 0.003) were independent predictors of persistent hyperammonemia.
Patients with ALF and persistent arterial hyperammonemia for 3 days after admission are more likely to develop complications and have greater mortality than patients with decreasing levels or high baseline levels. Infection, renal failure, and decreased arterial pH are independent predictors of persistent hyperammonemia.
Hepatitis E virus (HEV) is the major cause of epidemic hepatitis and many outbreaks of sporadic hepatitis. The virus responsible has a single-stranded, positive-sense RNA. Its replication and the ...regulatory process involved therein are poorly understood. Much of the HEV biology studied has been done by using full-length capped RNA transcripts (replicons) and transient transfections in cell cultures. We investigated replicon replication using negative-sense strand-specific molecular beacons in live cell imaging, and quantifying intracellular viral RNA using strand-specific real-time PCR every 2 h until 24 h post-transfection. A graph of the copy numbers of both positive- and negative-sense RNA at the different time points was plotted. This showed a temporal separation and alternating cycles of negative- and positive-sense RNA formation. As a control, a dysfunctional replicase mutant (GDD→GAA) was used, which showed no increase in copy number. The live cell imaging corroborated the quantitative data, in that the maximal amount of negative-sense RNA was observed at 8 h post-transfection. The real-time-PCR copy-number analysis of the subgenome showed the presence of a single subgenomic RNA. Using fluorescent protein genes mCherry and EGFP fused in-frame to ORF2 and ORF3 in separate constructs and immunofluorescence, we showed the formation of both proteins pORF2 and pORF3 from a single subgenomic RNA. Our study demonstrated cyclical bursts of virus replication and the role of subgenomic RNA in the HEV life cycle.
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