ORIGINAL ARTICLE

Serum Ammonia in Associated With Transplant-free Survival in Hospitalized Patients With Acutely Decompensated Cirrhosis Vilas R. Patwardhan, MD,* Zhengui G. Jiang, MD, PhD,* Yesenia Risech-Neiman, MD,w Gail Piatkowski, BCSC,z Nezam H. Afdhal, MD,* Kenneth Mukamal, MD,w Michael P. Curry, MD,* and Elliot B. Tapper, MD*w

Background: As ammonia metabolism is a complex multiorgan process, we sought to determine whether serum ammonia concentrations were associated with transplant-free survival in patients with acutely decompensated cirrhosis and acute-on-chronic liver failure (ACLF). Methods: We studied 494 consecutive patients hospitalized with cirrhosis between April 2007 and September 2012 with venous ammonia measured on hospital admission. The primary outcome was transplant-free survival. Results: Overall, rates of death or transplant within 30 and 90 days were 23.1% (n = 114) and 37.7% (n = 186), respectively. Forty-six patients (9.2%) underwent liver transplantation within 90 days. In a multivariate Cox proportional hazards model, ammonia concentration was independently associated with death or transplantation within 30 and 90 days after adjusting for model for endstage liver disease, sodium, white blood cells, and number of ACLF organ failures; every doubling of ammonia was associated with respective hazard ratios of 1.22 (95% confidence interval, 1.031.38) and 1.21 (95% confidence interval, 1.04-1.44) for 90- and 30day transplant or mortality. Notably, after adjusting for ammonia, organ failures were not predictive of outcomes. In a Kaplan-Meier analysis, patients with admission ammonia concentrations >60 mmol/L had significantly lower 90-day transplant-free survival (P = 0.0004). Patients with admission ammonia concentrations >60 mmol/L had higher 90- and 30-day risk of death or transplantation (45.2% vs. 31.2%, P = 0.001; and 31.6% vs. 15.7%, P < 0.0001, respectively). Conclusion: For patients with acutely decompensated cirrhosis, an elevated serum ammonia concentration on admission is associated with reduced 90-day transplant-free survival after adjusting for established predictors. Key Words: model for end-stage liver disease, hepatic encephalopathy, sarcopenia, acute-on-chronic liver failure, renal failure

(J Clin Gastroenterol 2016;50:345–350)

Received for publication June 8, 2015; accepted October 4, 2015. From the *Division of Gastroenterology; wDepartment of Medicine; and zDecision Support, Beth Israel Deaconess Medical Center, Boston, MA. Author contributions: Concept: E.B.T. Analysis: V.R.P., Z.G.J., K.M., E.B.T. Data acquisistion: V.R.P., Y.R.-N., G.P., E.B.T. Writing: V.R.P., E.B.T. Critical revision: K.M., G.P., M.P.C., N.H.A. Elliot Tapper is the guarantor of this article. The remaining authors declare that they have nothing to disclose. Reprints: Elliot B. Tapper, MD, Beth Israel Deaconess Medical Center, Deaconess 309, 330 Brookline Avenue, Boston, MA 02215 (e-mail: [email protected]). Copyright r 2015 Wolters Kluwer Health, Inc. All rights reserved.

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T

he complications of cirrhosis progression are systemic and profound. Beyond hepatic insufficiency and portal hypertension, these include cognitive dysfunction, renal insufficiency, sarcopenia, and systemic inflammation.1–6 While the model for end-stage liver disease (MELD) score captures hepatic insufficiency and renal injury, it does not account for other important factors. Indeed, the mortality rate for patients with acutely decompensated cirrhosis exceeds that predicted by their MELD score, particularly for those with frailty, hepatic encephalopathy (HE), and acute-on-chronic liver failure (ACLF).4,5,7–9 The excess mortality associated with progressive cirrhosis is likely attributable to decreased physiological reserves associated with processes that are not directly measured by MELD.8 The ACLF paradigm is a step forward for risk discrimination in patients with decompensated cirrhosis in part because it accounts for organ failures that are not captured by the MELD.4,5,7 However, like other scoring systems that have been adopted for critically ill patients, the definition of ACLF has varied among studies, is evolving, and can be difficult for clinicians to determine at the bedside.10 There is a critical need for a biomarker that could risk stratify patients with acute decompensations and ACLF.10 Serum ammonia is a candidate biomarker for the risk of adverse outcomes in cirrhosis that is potentially capable of reflecting the cirrhotic patient’s physiological reserves.11 Although it is traditionally considered a gut-derived nitrogenous toxin, ammonia metabolism is actually a complex multiorgan process involving the liver, kidney, muscle, and brain.1,2,12 Intestinal epithelial glutaminase metabolizes luminal glutamine and releases ammonia into the portal circulation. However, cirrhosis results in diminished urea cycle capacity and portosystemic shunting, leading to systemic hyperammonemia. Renal contributions to ammonia homeostasis are particularly significant and more prominent in the setting of acidemia, bleeding, and hypokalemia.2,13 Renal mechanisms for the conservation of potassium ions and handling of academia or excess glutamine depend on tubular glutaminase, which produces ammonium from which protons may be used for potassium exchange or urinary acidification with some ammonia diffusing into the circulation.11 Sarcopenia, which predicts mortality in advanced cirrhosis, also increases serum ammonia because muscle-bound glutamine synthetase is an essential auxiliary system for the handling of hyperammonemia.1,6,14 Taken together, an elevated ammonia concentration in a patient with acutely decompensated cirrhosis appears to represent a state of altered homeostasis. www.jcge.com |

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For most clinicians, ammonia likely plays a confusing role in the management of patients with cirrhosis. Although ammonia levels do not correlate with HE symptoms,15–17 HE therapy includes agents that demonstrably reduce ammonia concentrations.18–21 Often despite discouragement of its use by many hepatologists, clinicians frequently check ammonia levels when patients with decompensated cirrhosis present to the emergency ward.22 As such, many patients with cirrhosis have been assessed for hyperammonemia on presentation to our hospital. Herein, we evaluate the ability of venous ammonia to perform as a prognostic biomarker in a cohort of patients with cirrhosis.

METHODS Study Design and Data Collection We conducted a retrospective cohort study, reviewing the medical records of all patients admitted to the Beth Israel Deaconess Medical Center (Boston, MA) who had venous ammonia concentrations evaluated upon admission to the hospital from April 25, 2007 to September 24, 2012. All included patients had venous ammonia concentrations measured upon arrival to the emergency department using our institution’s standard protocol. The decision to order an ammonia level was made by the treating emergency clinician for reasons than cannot be directly inferred. The protocol states that phlebotomy should be performed without use of a tourniquet; blood should be drawn into a vacuum container and immediately placed on ice; and plasma should be separated within 15 minutes for analysis. Venous ammonia levels, when obtained under these conditions, are roughly equivalent to arterial ammonia levels with respect to clinical associations.19 Venous ammonia concentration was assessed in a total of 1836 patients during the study period. Patients without cirrhosis were excluded, leaving 494 subjects that were studied. Charts were examined for documentation of a clinical diagnosis of cirrhosis based on the presence of portal hypertension (ascites and varices), HE, jaundice, and/or consistent histology. Histologic diagnoses were available for a minority of patients (30%), the vast majority of whom presented with a hepatic decompensation. Laboratory and demographic data were obtained from the electronic medical record. Model for end-stage liver disease (MELD) scores with United Network for Organ Sharing (UNOS) modification were calculated according to previously described algorithms.23 All patients included in the study had complete MELD labs drawn on admission. In this study, we make a distinction between acutely decompensated cirrhosis and ACLF. All patients with ACLF have an acute decompensation; but patients with ACLF also present with an organ failure. Rather than dividing our cohort, we recorded whether each patient demonstrated the organ failures, which typify ACLF for use in statistical analyses.4 Organ failures were defined based on the validated definitions described by the CLIF Acute-oNChrONic LIver Failure in Cirrhosis (CANONIC) study investigators including liver failure (total bilirubin >12.0 mg/dL), coagulopathy (INR > 2.5), renal failure (creatinine >2.0 mg/dL or initiation of hemodialysis), circulatory failure (use of vasopressors), and cerebral failure (West Haven grade 3 or 4 encephalopathy). There are varying opinions regarding how to define ACLF.4,10,24 In the absence of an operational definition,10 we report the number of CANONIC-defined organ failures in our cohort. Patient



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death was confirmed using a validated search of the social security death index.25 Follow-up was therefore complete and performed until the time of liver transplantation and/or death. Note was made of patients who had previously received a transjugular intrahepatic portosystemic shunt (TIPS). This study was conducted in accordance with the Declaration of Helsinki approved by our Institutional Review Board (protocol number 2013P-000373).

Statistical Analysis For statistical comparisons, we used the w2 test for binary and categorical variables, the Student t test for normally distributed continuous variables, and the Kruskal-Wallis test for continuous variables with nonparametric distributions. Descriptive statistics are displayed as mean ± SD, median [interquartile range], or as indicated otherwise. All statistical analyses were performed using JMP Pro 11 (Cary, NC). Predictive models were created as follows. First, we constructed restrictive cubic spline models using 90-day mortality as the outcome and 5 knots evenly distributed at ammonia concentrations from 0 to 300 mmol/L to explore the relationship of ammonia and mortality without imposing a predefined model. In addition, we performed linear regression using ammonia concentration, square, logarithmic, and inverse transformations of ammonia concentration to compare the strength of association. A logarithmic relationship was suggested by both methods and was adopted for further analysis. We used 60 mmol/L as the cutoff for high ammonia concentration because of its proximity to the plateau transition point on the ammonia-mortality association curve. The relationship between ammonia concentration and survival was examined by Cox proportional hazard model. Univariate Cox proportional hazard ratios were calculated to identify factors that may be associated with reduced survival including history of a prior TIPS procedure, markers liver inflammation including aspartate aminotransferase and alanine aminotransferase concentrations, and platelet count, as well as previously validated predictors of liver-related mortality including MELD score, serum sodium concentration, white blood cell (WBC) count, and number of CANONICdefined organ failures.5,23,26 We also included outpatient HE therapy (lactulose and/or rifaximin) as a variable, given their possible effect on admission ammonia levels. Multivariate analyses were performed using covariates that were significant on univariate analyses as well as the established correlates of liver-related morbidity and mortality (age, sex, ethnicity, the presence of a TIPS, MELD, sodium, WBC count, and number of organ failures). As liver transplantation and death are competing risks, we chose the composite of 90-day mortality or transplantation to be the primary outcome. Our secondary outcome was the composite of 30-day mortality or transplantation. Kaplan-Meier curves for transplant-free survival were generated to compare the outcomes of patients with admission venous ammonia concentrations above and below 60 mmol/L. Significance was assessed using a logrank test. The threshold for significance on all assessments was a 2-tailed P-value 3 organ failures 34 (6.9) *Includes autoimmune hepatitis, primary biliary cirrhosis, primary sclerosing cholangitis, and sarcoid. IQR indicates Interquartile range.

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Ammonia and Transplant-free Survival

30-day outcomes with ammonia concentration, MELD, and WBC count. Notably, the univariate association with organ failures did not persist in multivariate analysis. Whereas MELD is the most significant predictor of outcomes, ammonia concentration demonstrates an independent association after adjustment for MELD.

Ammonia as a Dichotomous Variable (Low and High) After establishing the independent association between ammonia and transplant-free survival (Table 2), we further characterize the relationship of ammonia with transplantfree survival in 3 ways. First, we constructed an ammoniamortality association curve to depict the rising adjusted 90-day risk of death or transplant with increasing ammonia levels (Fig. 1). Owing to its proximity to the plateau transition point on the curve, we used 60 mmol/L as the cutoff for high ammonia concentration in this relationship. Second, using a 60 mmol/L cutoff, we constructed a KaplanMeier curve that demonstrated a clear and significant separation of patient outcomes (P = 0.0004) (Fig. 2). Third, the clinical characteristics and outcomes associated with an admission ammonia concentration >60 mmol/L were compared with those with lower ammonia, as shown in Table 3. Compared with patients with low serum ammonia, those with high serum ammonia concentration had more organ failures and reduced transplant-free survival out of proportion to the difference in the MELD score.

DISCUSSION In this study of hospitalized patients with acutely decompensated cirrhosis, many with ACLF, we found a significant association between increased admission venous ammonia concentration and reduced transplant-free survival. In the context of a tertiary referral center with a liver transplant program, our data suggest that ammonia concentration may prove useful as a biomarker to identify patients at higher risk for death or need for liver transplantation. Ammonia is felt to have a limited role in the evaluation of patients with cirrhosis. Our study shows that when its use is restricted to the appropriate population, namely hospitalized patients with acutely decompensated cirrhosis, ammonia emerges as a biomarker for transplant-free survival. These data add to and extend the literature on outcomes in cirrhosis with 2 novel findings. First, elevated venous ammonia drawn at the time of hospital admission is associated with the reduced transplant-free survival, an effect that is statistically independent of established predictors in patients with decompensated cirrhosis as well as those with ACLF.5,23,26 In our cohort, each doubling of the admission ammonia concentration conferred a 22% increase in the risk of mortality or transplantation. Viewed another way, patients with a serum ammonia >60 mmol/L experienced a substantial increase in 30- and 90-day risk for transplant or mortality out of proportion to differences in the MELD score. This finding is contrary to 2 previous studies that have examined the prognostic value of ammonia in small cohorts of patients admitted to an intensive care unit.18,20 In contrast to these studies, our cohort is 5- to 7-fold larger and includes patients more reflective of the tertiary referral experience, namely those

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TABLE 2. Univariate and Multivariate Analyses of the Relationship Between Clinical Characteristics and Outcomes

Univariate Analysis 90 d risk of death or transplantation Log2 ammonia Age (y) MELD Sodium (meq/L) Platelet count (109/L) ALT (IU/L) AST (IU/L) Male sex Outpatient HE therapy TIPS 1 organ failure* 2 organ failures* Z3 organ failures* WBC (109/L) 30 d risk of death or transplantation Log2 ammonia Age (y) MELD Sodium (meq/L) Platelet (109/L) ALT (IU/L) AST (IU/L) Male sex Outpatient HE therapy TIPS 1 organ failure* 2 organ failures* Z3 organ failures* WBC (109/L)

Multivariate Analysis

95% CI

P

Hazard Ratio

95% CI

P

1.21 1.01 1.08 0.97 1.00 1.00 1.00 0.98 1.41 1.55 1.43 2.57 2.94 1.05

1.04-1.46 1.00-1.02 1.06-1.10 0.95-0.99 1.00-1.00 1.00-1.00 1.00-1.00 0.72-1.32 1.03-1.96 0.88-3.03 1.06-1.96 1.85-3.52 1.83-4.49 1.03-1.07

0.01 0.2 < 0.0001 0.002 0.8 0.6 1.0 0.9 0.03 0.1 0.02 < .0001 < 0.0001 0.0001

1.22

1.03-1.38

0.02

1.07 1.00

1.05-1.10 0.98-1.02

< 0.0001 0.8

1.49

1.07-2.10

0.02

1.22 1.26 1.11 1.03

0.82-1.79 0.76-2.06 0.57-2.20 1.01-1.06

0.3 0.4 0.5 0.01

1.37 1.01 1.08 0.97 1.00 1.00 1.00 1.09 1.05 1.77 1.84 2.80 4.98 1.07

1.06-1.79 0.99-1.03 1.06-1.10 0.95-0.99 1.00 1.00 1.00 0.73-1.69 0.72-1.57 0.80-5.03 1.19-2.93 1.82-4.22 2.97-7.98 1.04-1.10

0.02 0.3 < 0.0001 0.02 0.2 0.8 0.9 0.7 0.8 0.2 0.005 < 0.0001 < 0.0001 < 0.0001

1.21

1.04-1.44

0.02

1.06 0.99

1.03-1.09 0.97-1.02

1.04 1.88 1.89 1.04

0.57-1.89 1.00-3.52 0.81-4.07 1.01-1.07

Hazard Ratio

< 0.001 0.6

0.9 0.05 0.1 0.03

The hazard ratios provided reflect the risk of the outcome for every unit change in the exposure variable. Variables that were significant (P < 0.05) were included in the multivariate analysis. Regardless of significance, the following variables were also included: age, sex, ethnicity, the presence of a TIPS, MELD, and sodium. Please note that grade 3-4 hepatic encephalopathy is included as an organ failure. *Organ failures are defined in the methods, defined by CANONIC-ACLF criteria. ALT indicates alanine aminotransferase; AST, aspartate aminotransferase; HE, hepatic encephalopathy; MELD, model for end-stage liver disease; TIPS, transjugular intrahepatic portosystemic shunt; WBC, white blood cell count.

who were admitted to both the intensive care unit and medical ward, with and without ACLF. Second, our findings suggest that ammonia adds clinically relevant prognostic information to biomarkers previously established in patients with cirrhosis at high risk of death including MELD, sodium, WBC count, and number

FIGURE 1. Predicted adjusted mortality risk by admission ammonia concentration. Adjusted risk of death or transplant within 90 days by ammonia concentration.

of organ failures.5,23,26 Scoring systems to predict mortality in high-risk patients like APACHE and CLIF-C ACLF are powerful and validated predictors of patient outcome. However, these scores require expert evaluation and multiple tests.4,5,27 Ammonia, in contrast, may serve as a readily available, easily interpretable and simple biomarker of short-term mortality early in a patient’s presentation, when other data are still unknown. There are many reasons why ammonia may be a sign of reduced functional reserves and organ dysfunction in acutely decompensated patients with cirrhosis.11 An elevated ammonia may reflect early renal dysfunction not otherwise captured by creatinine clearance as well as gastrointestinal bleeding and infection—all of which carry an increased risk of mortality.2,5,12,20,28–32 Renal ammoniagenesis is critical in buffering dietary amino acids and may be increased during hypokalemia and acidemia, which frequently accompanies sepsis and other forms of shock.1 In addition, gastrointestinal hemorrhage leads to markedly increased renal ammonia production owing to increased renal delivery of glutamine from metabolized hemoglobin.2,4 Sarcopenia and cachexia also contribute to liverrelated mortality independent of the MELD score and may not be captured in traditional evaluations of organ failure.6

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Ammonia and Transplant-free Survival

TABLE 3. Patient Characteristics and Outcomes in Relation to Serum Ammonia (mmol/L)

Ammonia Concentration (lmol/L) N Patient characteristics Age (y) Sex (% male) TIPS (%) Mean MELD ICU admission (%) 1 organ failure* 2 organ failures* > 3 organ failures* Outcomes Death or transplant (%) 30 d 90 d

< 60

> 60

266

228

58.1 ± 10.2 56.5 ± 10.5 64.7 67.5 5.7 11.0 19.7 ± 8.5 21.3 ± 8.9 47.7 51.8 33.1 42.5 13.5 21.1 4.1 10.1 15.7 31.2

31.6 45.2

P

0.05 0.3 0.02 0.02 0.04 0.03 0.03 0.009 < 0.0001 0.001

*Organ failures are defined in the methods, defined by CANONICACLF criteria. ICU indicates intensive care unit; MELD, model for end-stage liver disease; TIPS, transjugular intrahepatic portosystemic shunt.

Skeletal muscle, importantly, is a major site of ammonia metabolism. Elevated ammonia concentrations in patients with cirrhosis, in turn, may reflect clinically significant sarcopenia. Accordingly, the reduced transplant-free mortality observed in association with ammonia concentrations after adjustment for organ failures and MELD may highlight clinically important sarcopenia. Prior studies have examined sarcopenia both directly, using cross-sectional imaging,6,14 and indirectly, measuring frailty, which is also associated with mortality.8,9 Future studies should examine whether venous ammonia concentration may provide a more readily available surrogate for sarcopenia in the setting of cirrhosis. In addition, elevated ammonia may reflect more severe portal hypertension and portosystemic shunting. Portal hypertension and shunting, like reduced renal and skeletal muscle reserves, are associated with both decompensated cirrhosis and increased mortality.33,34 Although the correlation between serum ammonia and symptomatic HE is imperfect,19 hyperammonemia does reflect portosystemic shunting.35 Therefore, in the setting of a liver transplant center, such as in our cohort where 61% of patients were

FIGURE 2. Transplant-free mortality by ammonia concentration. Kaplan-Meier curve of 90-day transplant-free mortality by admission ammonia concentration >60 mmol/L versus r60 mmol/ L censored at 90 days.

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receiving ammonia-lowering therapies at the time of laboratory evaluation, elevated ammonia concentrations may reflect more severe portosystemic shunting. These data must be interpreted within the context of the study design. First, clinicians order ammonia for a variety of reasons. Indeed, our cohort of 494 patients represented only 26.9% of all ammonia levels ordered in the emergency department during the study period. As such, our results, although robust, are applicable only in the context of the inclusion criteria (hospitalized patients with established cirrhosis and an acute decompensation). Second, as our study is retrospective we cannot confirm whether our patients were fasting or how often a tourniquet-free sampling protocol was followed. Given that this was a retrospective review, the reasons for ammonia testing cannot be known. While it is possible that sicker patients were tested, 3 factors should be noted. First, selection for ammonia testing should not diminish the implications of the finding that ammonia in the emergency department was able to discriminate those at increased risk of death within 90 days. Second, our emergency physicians tested 1836 patients implying that the threshold for ammonia assessment was low. Third, we cannot describe the cause of death in all cases as deaths were confirmed using administrative data. However, our data do suggest that ammonia is a biomarker of all-cause mortality in decompensated cirrhosis and ACLF. In summary, our data suggest that ammonia predicts transplant-free survival in hospitalized cirrhotic patients. Although the exact mechanisms by which increased venous ammonia is associated with reduced transplant-free survival are still unclear, ammonia shows promise as a prognostic biomarker of all-cause mortality in decompensated cirrhosis.

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Serum Ammonia in Associated With Transplant-free Survival in Hospitalized Patients With Acutely Decompensated Cirrhosis.

As ammonia metabolism is a complex multiorgan process, we sought to determine whether serum ammonia concentrations were associated with transplant-fre...
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