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Liver stiffness predicts variceal bleeding in HIV/HCV-coinfected patients with compensated cirrhosis

Merchante, Nicolás; Rivero-Juárez, Antonio; Téllez, Francisco; Merino, Dolores; Ríos-Villegas, Maria José; Ojeda-Burgos, Guillermo; Omar, Mohamed; Macías, Juan; Rivero, Antonio; Pérez-Pérez, Monserrat; Raffo, Miguel; López-Montesinos, Inmaculada; Márquez-Solero, Manuel; Gómez-Vidal, Maria Amparo; Pineda, Juan A. on behalf of the Grupo Andaluz para el Estudio de las Hepatitis Víricas (HEPAVIR) de la Sociedad Andaluza de Enfermedades Infecciosas (SAEI)

Author Information
doi: 10.1097/QAD.0000000000001358

Abstract

Introduction

Acute bleeding due to variceal hemorrhage is one of the most lethal complications of cirrhosis [1]. As for the main complications in cirrhosis, portal hypertension is the underlying cause of esophageal varices formation and rupture [1–3]. Namely, clinically significant portal hypertension, defined as a hepatic-vein pressure gradient above 10 mmHg, is the threshold above which the development of esophageal varices can occur. In patients with cirrhosis, it has been estimated that the risk of development and growth of esophageal varices is 7% per year [4,5] and that of the first variceal bleeding is 12% per year [1]. Apart from this, the presence of esophageal varices has been associated with a higher rate of liver decompensation and death in patients with cirrhosis [6]. Consequently, current recommendations of experts are that all patients with cirrhosis should be screened for esophageal varices [1–3].

Upper gastrointestinal endoscopy (UGE) is the method of choice to determine the presence and size of esophageal varices [1,2]. Apart from this, it allows evaluating the presence of red wale marks, which indicates a higher risk of further esophageal varices bleeding [1]. Drawbacks of endoscopy are the invasive nature of the procedure, which leads to poor acceptance by patients and costs. For these reasons, less invasive methods are being investigated [7–10].

Liver stiffness, assessed by transient elastography, is being increasingly used in clinical practice as a surrogate marker of portal hypertension in patients with end-stage liver disease. It has been demonstrated that liver stiffness correlates with hepatic-vein pressure gradient [11–13] and predicts clinical outcome in patients with compensated cirrhosis [14]. Apart from this, the performance of liver stiffness as a noninvasive tool for esophageal varices surveillance has also been explored in several studies with good results [15–19]. Namely, our group demonstrated that a liver stiffness below 21 kiloPascals (kPa) had a 100% negative predictive value (NPV) to exclude the presence of high-risk esophageal varices in a previous study conducted in 102 HIV/hepatitis C virus (HCV)-coinfected patients with cirrhosis [19]. Consequently, UGE for the screening of esophageal varices could be spared in these patients. In fact, it has been our routine clinical practice since November 2009 not to perform UGE for esophageal varices detection in patients harboring liver stiffness below 21 kPa [14]. However, the use of liver stiffness-based strategies for esophageal varices surveillance has not been widely used in other centers and settings because of concerns of safety and lack of long-term data.

The objective of our study was to assess the ability of liver stiffness to predict the risk of portal hypertensive gastrointestinal bleeding (PHGB) in HIV/HCV-coinfected patients with compensated cirrhosis.

Methods

Study design and patients

The HEPAVIR cirrhosis cohort (ClinicalTrials.gov ID: NCT02693847) is a prospective cohort recruiting HIV/HCV-coinfected patients with a new diagnosis of cirrhosis from seven hospitals from Andalusia in Southern Spain. From February 2006, all consecutive patients with a new diagnosis of cirrhosis, as indicated by a first determination of liver stiffness at least 14 kPa, are included in the cohort, provided that they show detectable HCV RNA at inclusion and no evidence of autoimmune or metabolic liver disease. Patients with a previous or concomitant liver decompensation at diagnosis of cirrhosis are not included.

Esophageal varices screening and prevention of variceal bleeding

From February 2006 to November 2009, all patients had to undergo an UGE at cohort entry for the screening of esophageal varices. In November 2009, the investigator team decided to modify the initial protocol, allowing patients with liver stiffness below 21 kPa to be spared from endoscopy, provided that liver stiffness maintained below this threshold level. In patients with a baseline liver stiffness at least 21 kPa, and also those with baseline liver stiffness below 21 kPa, but with subsequent progression to liver stiffness at least 21 kPa, an endoscopic examination was indicated. In those individuals with a liver stiffness at least 21 kPa and no esophageal varices in the initial UGE, a follow-up examination had to be performed after 2–3 years or if worsening or new signs of portal hypertension appeared.

Esophageal varices were staged following the Japanese Research Society for Portal Hypertension staging system [20]. Thus, according to their size, esophageal varices were classified in the following way: F0, no varices; F1, small and nontortuous; F2, tortuous but less than 50% radius of esophagus; and F3, very large and tortuous. Likewise, the presence of red signs (red wale markings, cherry red spots, or hematocystic spots) was also considered. According to Baveno criteria [3], we considered that patients with high-risk esophageal varices were those harboring large esophageal varices (F2 and F3) or small esophageal varices (F1), but with red wale signs or Child–Turcotte–Pugh (CTP) class C. Primary and secondary prophylaxis for variceal bleeding was done according to the recommendations of experts in force during the study period [21,22]. Regarding to primary prophylaxis, patients with small esophageal varices with red wale marks or CTP class C were treated with nonselective beta-blockers (NSBBs), whereas patients with medium-large esophageal varices were treated with either NSBB or endoscopic band ligation (EBL), depending on the center preference. Patients who developed a variceal bleeding during follow-up received secondary prophylaxis with NSBB and EBL.

Follow-up

The management of cirrhosis in the cohort was done according to a specific protocol of care created by the investigator team at the design of the study and modified during the entire study period according to new evidence and updating of international clinical guidelines. Patients were evaluated at least every 6 months, including clinical visits focusing on the early detection of liver decompensation and the performance of routine laboratory examinations. The prevention, diagnosis, and management of liver decompensation other than PHGB were performed as previously described [14]. Periodic transient elastography examinations were performed after inclusion, usually every 12 months, according to the caring physician criteria and the availability in each center. Treatment of HCV was prescribed according to the physician criteria in accordance to guidelines in force during the follow-up.

Patients were prospectively seen until death, liver transplant, or the censoring date (31 January 2015). Episodes of liver decompensation, vital status, and causes of death were obtained from clinical records. Patients lost to the follow-up or their next of kin were contacted via telephone whenever possible. In patients lost to the follow-up, the electronic clinical record from each patient, which all public hospitals and emergency departments in Andalusia share, was also accessed to find out if bleeding episodes occurred.

Statistical analysis

The primary end-point of the study was the emergence of a first episode of PHGB. The relationship between the time to the emergence of the primary end-point and variables that potentially could be associated, which included baseline liver stiffness, was analyzed. For survival analyses, the date of the first transient elastography examination that established the diagnosis of cirrhosis was considered as the baseline time-point. The time-to-event was computed as the time elapsed from baseline to the emergence of the primary end-point. Kaplan–Meier estimates of the cumulative probability of survival were compared using the log-tank test. For these analyses, continuous variables were categorized according to the median value or cut-off points considered to be clinically relevant. Baseline liver stiffness was categorized by clinically relevant cut-off points based on previous studies [14,19]. Those variables with a P value 0.1 or less on univariate analyses were entered in competing risk regression models, which also included age, sex, and the achievement of sustained virological response (SVR) during follow-up. Associations with a P value less than 0.05 were considered significant. The sub-hazard ratio (SHR) and the respective 95% confidence interval (CI) were calculated. The statistical analysis was carried out carried out by means of the SPSS Statistical Software Package release 22.0 (IBM Corporation, Somers, New York, USA) and STATA version 9 (StataCorp LP, College Station, Texas, USA).

Ethical aspects

The study was designed and conducted following the Helsinki declaration. The Ethics committee of the Hospital Universitario de Valme approved the study.

Results

Features of the study population

Four hundred and forty-six patients were included in the study. The main characteristics of the study population are summarized in Table 1. One hundred and ninety-seven (44%) patients had a liver stiffness below 21 kPa at cohort entry. Liver stiffness remained below this threshold in 136 of them (30.5% of the study population) during the entire follow-up. One hundred and three (23%) patients had been previously treated against HCV without achieving SVR. During follow-up, 196 (43%) patients were treated against HCV. In 32 and three patients, a second and a third course of treatment, respectively, were initiated after failing to achieve SVR with the previous therapy. At the end of the study, 18 out of the 196 patients who started therapy during follow-up were still on treatment or had not reached 12 weeks after the end of therapy. Thus, SVR was not evaluable in these patients. Among the 178 evaluable patients, 67 (38%) achieved SVR.

T1-8
Table 1:
Features of the study population (N = 446).

The median [quartile 1 (Q1) to quartile 3 (Q3)] follow-up was 49 (25–68) months. Forty-four (10%) individuals, 19 of them with baseline liver stiffness below 21 kPa, were lost to the follow-up. Sixty-one (13.6%, 95% CI 10.3–16.9) patients died during follow-up. The mortality rate was 3.5 per 100 person-years (95% CI 2.8–4.5). In 37 (8.3%, 95% CI 5.7–10.9) patients, death was liver-related. Three patients underwent a liver transplant.

Upper gastrointestinal endoscopy examinations and prophylaxis measures

Figure 1 summarizes UGE examinations performed in the study population. In 305 (68%) patients, an UGE was performed to screen for the presence of esophageal varices. These included 17 out of 131 patients with baseline liver stiffness below 21 kPa who enrolled after protocol modification in November 2009 and underwent a UGE for other clinical reasons. In 223 (73%) of 305 UGEs, esophageal varices were not found. Fifty-seven (19%) patients harbored esophageal varices F1, one of them with red wale signs, 19 (6%) individuals had esophageal varices F2, and six (2%) showed esophageal varices F3. Thus, 26 (8.5%) out of 305 patients showed high-risk esophageal varices according to Baveno criteria.

F1-8
Fig. 1:
Upper gastrointestinal endoscopies performed during follow-up.kPa, kiloPascals; LS, liver stiffness;, UGE, upper gastrointestinal endoscopy.

During follow-up, a second and a third UGE was done in 147 and 53 patients, respectively. Twenty-one patients underwent four or more examinations. Twelve (5.4%) out of the 223 patients without esophageal varices at baseline developed high-risk esophageal varices during follow-up. Sixty-two (14%) patients received treatment with NSBB during follow-up, combined with endoscopic band ligation of esophageal varices in seven of them.

Association between liver stiffness and esophageal varices

During follow-up, a total of 533 endoscopies were performed in 305 patients. The presence of esophageal varices according to the values of liver stiffness was analyzed. For this purpose, we selected all baseline UGE examinations and follow-up endoscopies performed in patients with a previous examination without esophageal varices, provided that a liver stiffness assessment was done in the previous 12 months. Four hundred and eleven (77%) out of 533 examinations fulfilled criteria for this analysis. The median elapsed time between endoscopy and liver stiffness assessment was 21 (−12, 78) days. Two (2.6%) patients harboring a liver stiffness below 21 kPa at UGE showed high-risk esophageal varices, whereas this occurred in 43 (12.9%) of those with a liver stiffness at least 21 kPa (P = 0.008). These two patients had a liver stiffness value of 20.2 and 20.9 kPa, respectively. Figure 2 shows liver stiffness values according to the presence of high-risk esophageal varices.

F2-8
Fig. 2:
Liver stiffness values according to the presence of high-risk esophagueal varices.EV, esophagueal varices; kPa, kiloPascals.

Liver stiffness and risk of portal hypertensive gastrointestinal bleeding

Fifteen (3.4%; 95% CI 1.7–5) patients developed a first PHGB episode during follow-up. In eight of them, PHGB was the first hepatic decompensation of cirrhosis. Recurrence of PHGB occurred in three out of the 15 patients after the initial episode. The density of incidence of PHGB was 0.8 per 100 person-years (95% CI 0.5–1.4). The probability of presenting a bleeding episode at 1, 3, 5, and 6 years was 1, 2, 4, and 8%, respectively.

Table 2 summarizes the main features of the 15 patients who developed a PHGB during follow-up. Two (patient 1 and patient 6) out of the 15 cases occurred in patients harboring CTP stage B cirrhosis at baseline, whereas the remaining 13 cases occurred in patients with baseline CTP A stage. In nine out of 15 patients, PHGB was the first liver decompensation of cirrhosis. Two patients (patient 2 and patient 13) developed simultaneously ascites and PHGB, whereas four patients (patients 1, 3, 9, and 14) had decompensated cirrhosis before bleeding. Two patients (patient 1 and patient 8) had received therapy against HCV with pegylated interferon with ribavirin before the emergence of the PHGB. Patient 1 started but was stopped after 1 month of therapy due to adverse effects, whereas patient 8 had achieved SVR 1 year prior to the bleeding episode.

T2-8
Table 2:
Main features of the patients who developed a first portal hypertensive gastrointestinal bleeding during follow-up (n = 15).

Baseline liver stiffness was at least 21 kPa in all cases (Table 2 and supplementary Fig. 1, https://links.lww.com/QAD/B24). Thus, the NPV of this cut-off value of liver stiffness to predict a PHGB episode during follow-up was 100%. Apart from this, liver stiffness was at least 21 kPa at the time of PHGB in all cases (Table 2 and Supplementary Fig. 1, https://links.lww.com/QAD/B24). Figure 3 shows the probability of remaining free of developing a first PHGB during follow-up according to baseline liver stiffness.

F3-8
Fig. 3:
Probability of developing a first portal hypertensive gastrointestinal bleeding episode during follow-up according to baseline liver stiffness.kPa, kilopascals; LS, liver stiffness.

After competing risk regression models adjusted by age, sex, and SVR during follow-up, the independent predictors of the emergence of PHGB were a baseline platelet count below 50.000/μl (SHR 4.2, 95% CI 1.3–13.5, P = 0.015) and a baseline liver stiffness at least 21 kPa (SHR 1.9, 95% CI 1.04–3.64, P < 0.0001).

Discussion

The study demonstrates that baseline liver stiffness identifies patients with compensated cirrhosis with a very low risk of presenting a PHGB episode. Apart from this, we provide prospective long-term data that confirm the NPV of a specific cut-off value of liver stiffness (21 kPa) for the development of PHGB. Thus, no individual with baseline liver stiffness below 21 kPa developed this outcome in our cohort. These results confirm that patients with liver stiffness below 21 kPa can be safely spared from UGE, provided that they maintain liver stiffness below this threshold.

Surveillance of esophageal varices by UGE has been a standard of care in patients with cirrhosis. In the past years, several studies have reported a high sensitivity of liver stiffness to exclude the presence of esophageal varices in patients with cirrhosis of various causes [15–19]. We have previously reported that liver stiffness has a very high NPV to exclude esophageal varices at risk of bleeding in the setting of HCV-related cirrhosis in HIV-coinfected patients [19]. Consequently, it has been our daily practice not to perform UGE for the screening of esophageal varices in patients with below 21 kPa since 2009. However, some experts have considered that there were insufficient data to avoid UGE on the basis of liver stiffness [10]. Limitations of previous studies that have been claimed by experts were small sample size, mixed causes of cirrhosis with variability of liver disease severity across studies, and a nonuniform classification of esophageal varices [10]. As a consequence of this, concerns on the safety of this strategy have limited its use in routine clinical practice.

The present study validates a novel liver stiffness-based strategy in a real clinical practice setting, and, in our opinion, solves the above-mentioned issues. First, we provide data that confirm the role of liver stiffness in excluding the presence of high-risk esophageal varices in a large population of HIV/HCV-coinfected patients with previously compensated cirrhosis and with preserved liver function. As we previously reported in a smaller population [19], a liver stiffness below 21 kPa is a cut-off value that discriminates very reliably the absence of high-risk esophageal varices. Second, a baseline liver stiffness below 21 kPa had also a very high NPV for the subsequent development of PHGB during follow-up. In fact, no individual with baseline liver stiffness below 21 kPa developed a PHGB episode in our cohort, and all PHGB episodes occurred in individuals harboring a liver stiffness at least 21 kPa at the moment of bleeding. Consequently, UGE-sparing management in the cohort was well tolerated and did not have a negative impact on outcome. Finally, our study confirms that a liver stiffness below 21 kPa identifies a subgroup of patients with a low risk of clinically significant portal hypertension.

The paradigm of cirrhosis has evolved in the past decade. At present, liver cirrhosis is seen as a dynamic process with a variable prognosis, which has led to subclassify patients in different stages categories depending on its risk of complications and death [2]. Apart from this, transient elastography has allowed performing a reliable and early diagnosis of patients with chronic liver disease at risk of developing clinically significant portal hypertension. In agreement with this concept, the panel of experts of the Baveno VI consensus workshop have proposed the alternative term ‘compensated advanced chronic liver disease’ for the classical term ‘compensated cirrhosis.’ Additionally, transient elastography appears to be a proper instrument for further prognostication in this early asymptomatic phase. We have previously reported that liver stiffness predicts clinical outcome in patients with compensated liver cirrhosis, being patients with a liver stiffness value at least 40 kPa at a high risk of liver decompensation in the short term [14]. The results presented herein confirm that a liver stiffness below 21 kPa has a high NPV to exclude the presence of high-risk esophageal varices and demonstrate for the first time that avoiding UGE in patients with liver stiffness below this threshold is well tolerated, because the risk of bleeding is very low.

Sequential liver stiffness assessment is becoming part of routine clinical care of patients with liver disease in settings where this technique is available. Liver stiffness-based decision-making is an attractive challenge for the management of patients with cirrhosis. The new Baveno VI Consensus Workshop recommendations consider for the first time the possibility of avoiding screening UGE in patients with a liver stiffness below 20 kPa and with a platelet count above 150.000/μl [3]. On the contrary, other European guidelines that have been recently updated explicitly recommend surveillance with UGE in all cases [23]. The new Baveno VI proposal is similar to the liver stiffness-based approach that we have developed and followed in our cohort since 2009. Our experience provides clinical evidence coming from a hard clinical end-point, the emergence of PHGB, which adds strength to support the role of liver stiffness in UGE surveillance policies. Remarkably, liver stiffness-based esophageal varices surveillance spares UGE in a high proportion of patients, because 30% of patients in our cohort who harbored a liver stiffness below 21 kPa at baseline and showed no progression of liver stiffness above this threshold during follow-up would not need to undergo a UGE.

The study has some limitations. First, before the protocol modification, most of the patients underwent a surveillance UGE, which could theoretically have reduced the risk of bleeding during this period in patients with liver stiffness below 21 kPa. However, this is unlikely, as these patients did not receive any intervention because they did not harbor high-risk esophageal varices. Second, our study includes only HIV-infected patients with HCV-related cirrhosis. Consequently, the predictive value of liver stiffness and the cut-off values proposed herein should be applied with caution in cirrhosis of other causes. Third, in spite of a median follow-up longer than 4 years, the number of bleeding episodes was somewhat low. However, our population represents the current clinical picture of virus-related cirrhosis in settings where routine transient elastography examinations are available and an early detection of cirrhosis is made. Due to this, it is not surprising that the prevalence of esophageal varices in our cohort was 27%, with only 8.5% of patients harboring high-risk esophageal varices, and that the incidence of esophageal varices formation and variceal bleeding during follow-up were lower than that reported in other populations of cirrhotic patients [1,4,5]. In addition, we present data from a prospective cohort of patients with the same cause of liver disease, in which diagnosis of cirrhosis was made early on the basis on the same diagnostic method, transient elastography, and managed according to the same protocol of care, which included a novel approach of esophageal varices surveillance. These are the strengths of our study.

In summary, a liver stiffness below 21 kPa identifies patients with HCV-related compensated cirrhosis with a very low risk of presenting a PHGB episode. UGE for the surveillance of esophageal varices can be safely avoided in patients with a liver stiffness below 21 kPa, provided that liver stiffness maintains below this threshold. Consequently, liver stiffness must be periodically determined, at least every year. Our results add new evidence that reinforces that sequential liver stiffness assessment by transient elastography should be part of the routine daily clinical management of patients with cirrhosis.

Acknowledgements

Author contributions: Study concept and design: N.M. and J.A.P; acquisition, analysis, or interpretation of data: N.M., A.R.-J., F.T., D.M., M.J.R.-V., G.O.-B., M.O., J.M., M.P.-P., M.R., I.L.-M., M.M.-S., M.A.G.-V., and J.A.P.; statistical analysis: N.M., J.M., and J.A.P.; drafting of the manuscript: N.M. and J.A.P.; critical revision of the manuscript for important intellectual content: N.M., A.R.-J., F.T., D.M., M.J.R.-V., G.O.-B., M.O., J.M., M.P.-P., M.R., I.L.-M., M.M.-S., M.A.G.-V., J.A.P.; obtained funding: N.M., J.M., J.A.P.; study supervision: N.M. and J.A.P.

Grant support: This study was supported by grants from the Consejería de Salud de la Junta de Andalucía (grant numbers PI-0008/2007, PI-0014/2014), the Servicio Andaluz de Salud (grant number SAS/111239), and the Fondo de Investigaciones Sanitarias ISCIII (grant number PI13/01621). Apart from this, this work has been partially funded by the RD12/0017/0012 project as part of the Plan Nacional R + D + I and cofinanced by ISCIII-Subdirección General de Evaluación y el Fondo Europeo de Desarrollo Regional (FEDER).

Conflicts of interest

A.R.J. is the recipient of a postdoctoral perfection grant from the Consejería de Salud de la Junta de Andalucía (grant number RH-0024/2013). J.M. is the recipient of a grant from the Servicio Andaluz de Salud de la Junta de Andalucía (grant number B-0037). J.A.P. is the recipient of an intensification grant from the Instituto de Salud Carlos III (grant number Programa-I3SNS).

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Keywords:

esophagueal varices; hepatitis C virus; liver cirrhosis; portal hypertensive gastrointestinal bleeding; transient elastography

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