Authors: David Bostick, MD MPH; Megan Donohue, MD; Robert Brown, MD; and Nicholas Santavicca, MD
Edited by: Michael C. Bond, MD FAAEM and Kelly Maurelus, MD
Originally Published: Common Sense July/August 2017
Patients with chronic liver disease and acute liver failure have disease specific needs for which Eps must be cognizant. Below we review topics related to acetaminophen hepatotoxicity, use of rifaximin and lactulose in hepatic encephalopathy, and thromboelastography (TEG) directed transfusion in patients with liver disease requiring procedures.
Unrecognized Acetaminophen Toxicity as a Cause of Indeterminate Acute Liver Failure. Hepatology 2011; 53:567-576.
Approximately half of all cases of acute liver failure are due to acetaminophen (APAP) toxicity1, while in another 14%, no cause is found2. Given the prevalence of APAP liver toxicity and the often-unreliable histories obtained from patients, the authors of this study examined patients with an unknown etiology of liver failure for toxic metabolites of APAP (APAP-CYS adducts).
The patients presented to one of 23 tertiary care centers involved with the US Acute Liver Failure Study Group. Inclusion criteria was the presence of coagulopathy and any degree of hepatic encephalopathy within 26 weeks of onset of symptoms without previous history of liver disease. Overall, 118 patients were found to have an indeterminate case of acute liver failure and their blood samples from day one or two were tested for APAP-CYS. The group was divided into assay negative or assay positive. Another group of patients with known APAP toxicity were also tested and this group was also divided into APAP-CYS assay positive or negative.
Among the indeterminate cases, 18% (20 patients) had levels of APAP-CYS consistent with APAP toxicity. These patients may have benefited from the use of N-acetylcysteine (NAC); however, they were not prescribed NAC as the history provided by the patient or family was inconsistent, the patient had hepatic encephalopathy, or possible deception by the patient. While patients in the APAP overdose and clinically unrecognized APAP overdose group had similar demographic, laboratory findings, and other clinical characteristics, this paper was not developed to investigate the validity of using these characteristics in the early detection of these at-risk patients.
The use of NAC was lowest (18%) in patients with unrecognized APAP hepatotoxicity as determined by APAP-CYS. Conversely, 94% of patients with known APAP toxicity and elevated toxic metabolite levels received NAC. The indeterminate group without toxic metabolites suggestive of APAP hepatotoxicity had the highest rate of liver transplant (42% vs. 17%, 8%, and 22%, p<0.05) and the lowest rate of survival (21% vs. 63%, 55%, and 45%, p<0.05).
Major limitations of this study include its small sample size and the experimental nature and general unavailability of the APAP-CYS assay. Despite these limitations, this paper reinforces that a significant number of APAP toxicities are missed and that we should suspect APAP toxicity in instances of acute liver injury (a high ALT, low bilirubin pattern).
Take home point: APAP toxicity should be considered for all patients with an indeterminate cause of rapid onset acute liver failure and treatment with NAC should be considered.
WM Lee, LS Hynan, et al. Intravenous N-Acetylcysteine Improves Transplant-Free Survival in Early Stage Non-Acetaminophen Acute Liver Failure. Gastroenterology 2009; 137:856-864.
Acute liver failure is a syndrome that carries high mortality and frequently necessitates liver transplantation. Though NAC has been shown to minimize liver damage in acute liver failure secondary to APAP toxicity, its efficacy in non-APAP associated acute liver failure has yet to be established. As a result, the focus of this study was to determine the benefit of NAC in non-APAP induced acute liver failure.
This prospective, double-double blinded trial enrolled patients 18-70 years of age with non-APAP associated acute liver failure (as determined by encephalopathy and coagulopathy) across 22 sites over 8 years. Patients were stratified by site and coma grade, and then randomized to receive a 72-hour dosing regimen of placebo or NAC. Patients were excluded if they had a known APAP ingestion, had received NAC previously in the disease process, had hypotension or shock, or if their liver failure was due to hypotension, pregnancy, or cancer. The primary outcome was overall survival at 3 weeks after randomization. Secondary outcomes included transplant-free survival, transplant rate, hospital length of stay (LOS), and number of organ systems failing.
Of the 820 eligible patients, only 173 were not excluded and composed the final study group. Ninety-two patients received placebo and 81 patients received NAC. The placebo group had a higher number of females and longer duration of illness, but otherwise had similar characteristics than the NAC group. Only 58 patients in the placebo group and 48 patients in the NAC group completed the full 72 hours of therapy. 138 of the 173 total patients received at least 24 hours of therapy. The main reasons for early discontinuation included death, withdrawal of support, or transplantation.
Overall, three-week survival was noted to be similar (70% NAC v. 66% placebo). Of the secondary outcomes, only transplant-free survival was shown to be different. Transplant-free survival was significantly higher (40% NAC v. 27% placebo, OR 2.46) in the NAC group for patients with early stage hepatic encephalopathy (coma grades 1-2). There was a trend toward shorter hospital length of stay with NAC (9d NAC v. 13d placebo). Main adverse events with NAC were nausea and vomiting (14% NAC v. 4% placebo).
No difference was found in patients with advanced coma grades. Incidentally this group was quite small mainly due to early expedited liver transplantation. As a result, their mortality was driven mainly by early transplantation and post-transplant care. Overall, survival in the placebo group was higher than predicted, possibly due disproportionate number of early coma grades enrolled in the study (66% early v. 33% late). Quality of intensive care could also have impacted survival rates.
Take home point: NAC may be beneficial for patients with early stage non-APAP acute liver failure.
A Randomized, Double-Blind, Controlled Trial Comparing Rifaximin Plus Lactulose with Lactulose Alone in Treatment of Overt Hepatic Encephalopathy. Am J Gastroentero 2013; 108:1458-1463.
Hepatic encephalopathy (HE) is a serious and deadly complication of advanced liver disease. Most drugs used to treat HE reduce and eliminate ammonia. The two mainstay treatments are lactulose, a non-absorbable disaccharide and rifaximin, a minimally absorbed semi-synthetic antibiotic. Rifaximin was more effective than lactulose in randomized studies, but no study has yet evaluated the efficacy and safety of using rifaximin and lactulose in combination. In this paper, Sharma et al., evaluate the efficacy and safety of rifaximin plus lactulose vs. lactulose alone in treatment of HE.
This prospective, double-blind, randomized controlled trial preformed at a tertiary care center enrolled patients ages 18-80 years with liver cirrhosis and HE over a two-year period (October 2010-September 2012). Cirrhosis was diagnosed clinically by lab test, sonography, or biopsy. Patients were excluded if other causes of encephalopathy were identified. These included creatinine >1.5, active alcohol use within the past four weeks, hepatocellular carcinoma, degenerative central nervous system disease, major psychiatric illness, or other metabolic encephalopathy.
Enrolled patients were randomly assigned to receive rifaximin + lactulose or lactulose only. The combination group received 400mg rifaximin three times daily plus lactulose 30-60mL three times daily or until the patient passed two to three semi-soft stools daily. The lactulose only group received lactulose, as dosed above and a placebo sugar capsule given three times daily. Blinding was done with respect to rifaximin. Treatment was continued until HE resolved, as assessed twice daily by two expert hepatologists, or for 10 days. The primary endpoint was complete recovery of HE, with mortality and length of hospitalization measured as secondary outcomes.
A total of 120 patients were included in final analysis. Of these, 63 were in the combination group and 57 in the lactulose only group. Baseline characteristics including etiology of cirrhosis, ammonia levels, and grade of HE did not significantly differ between the two groups. Primary end-point analysis showed that 76% of patients in the combination group had complete reversal of HE within 10 days, compared to 44% in the lactulose only group. Combination patients had shorter hospital stays (5.8 days vs. 8.2 days, p=0.001) and decreased mortality (24% vs. 49.1%, p<0.05). There were significantly more deaths due to sepsis in the lactulose only group. Further subgroup analysis of non-responders identified higher baseline leukocyte count and higher baseline HE grades as independent predictors of non-responsiveness.
This was the first double-blind, randomized, controlled trial comparing rifaximin plus lactulose to lactulose only in the treatment of hepatic encephalopathy. Results showed superiority of rifaximin plus lactulose therapy. Prior studies have shown equal efficacy between rifaximin and lactulose as monotherapies, but most have studied patients with lower grades of hepatic encephalopathy than included in this study. Sharma, et al., cite the exclusive mechanisms of action of rifaximin and lactulose as the likely explanation for the synergistic effect and better efficacy of combination therapy. Lactulose lowers the colonic pH favoring the formation of insoluble ammonia from soluble ammonia to reduce systemic absorption. Lactulose also increases fecal nitrogen excretion. Rifaximin, on the other hand, restores gut microflora to decrease endotoxemia and inflammatory response. Combination therapy with rifaximin and lactulose showed no significant adverse effects and was concluded to be more effective than lactulose alone for treatment of HE in patients with cirrhosis.
Take home point: Rifaximin in combination with lactulose may increase the rate of resolution of HE, shorten hospital stay, and decrease mortality.
Thrombelastography-Guided Blood Product Use Before Invasive Procedures in Cirrhosis with Severe Coagulopathy: A Randomized, Controlled Trial. Hepatology 2016; 63:566-573.
Bleeding during or after procedures is a feared complication in patients with cirrhosis. Current guidelines recommend use of the INR and platelet count to guide therapy in cirrhotic patients with an elevated risk of bleeding who require invasive procedures. However, cirrhosis is characterized by decreased synthesis of both procoagulants and anticoagulants. In these patients, a thrombelastography (TEG) could help to guide management of these patients pre and post procedure as well as those that come into the ED with bleeding. TEG is a point-of-care test that can provide real time assessment of the hemostatic process and can help guide product use in the bleeding patient with cirrhosis. This study aimed to define safety and efficacy of TEG to guide the use of fresh frozen plasma (FFP) and platelet transfusion before invasive procedures in patients with cirrhosis and abnormal coagulation tests.
In this randomized, controlled, open-label, intention-to-treat trial patients with cirrhosis and abnormal INR and platelet counts were randomized to TEG or standard-of-care (SOC). A total of 60 patients were included in the study and their demographics and clinical characteristics were similar. The primary endpoint was the amount of blood products transfused and the secondary outcomes were related to bleeding complications, transfusion related complications, and 90-day survival. Procedures performed ranged from central line placement to abdominal surgery. Overall the use of blood products was significantly lower in the TEG group as compared to SOC (P<0.0001). None of the TEG patients needed FFP alone whereas 53% of the SOC received platelets alone (p<0.0001). In regard to platelets, 6.7% of the TEG group received platelets which was significantly less than the 33% of patients in the SOC group (p=0.021). A similar percentage of patients required both FFP and platelets (p>0.9999). These results were similar in low risk bleeding procedures and high risk bleeding procedures. The whole blood requirement in both groups was the same but again the TEG group received less products overall than those in the SOC group (p<0.0001).
Regarding secondary outcomes, survival for both groups was the same with the cause of death in both groups being unrelated to the procedures they received. One patient had a transfusion reaction and one patient had a bleeding complication related to a paracentesis. Both patients were randomized to the SOC group and neither patient died.
Take home point: TEG is a safe effective method to guide replacement of blood products for patients with liver disease who require procedures. This study suggests that using the TEG instead of traditional coagulation tests can be safe in this patient group and can reduce the use of blood products prior to procedures.
1. Larson AM, Polson J, Fontana RJ, Davern TJ, Lalani E, Hynan LS, et al. Acetaminophen-induced acute liver failure: results of a United States multicenter, prospective study. HEPATOLOGY 2005;42:1364-1372
2. Ostapowicz G, Fontana RJ, Schiodt FV, Larson AM, Davern TJ, Han SH, et al. Results of a prospective study of acute liver failure at 17 tertiary care centers in the United States. Ann Intern Med 2002;137:947-954