Buck Rogers (9) | Opera Mini | Indro. L’uomo che scriveva sull’acqua (2016)

Factors related to quality of life in patients with cirrhosis and ascites: Relevance of serum sodium concentration and leg edema

Factors related to quality of life in patients with cirrhosis and ascites: Relevance of serum sodium concentration and leg edema

Research Article Factors related to quality of life in patients with cirrhosis and ascites: Relevance of serum sodium concentration and leg edema Els...

845KB Sizes 0 Downloads 0 Views

Research Article

Factors related to quality of life in patients with cirrhosis and ascites: Relevance of serum sodium concentration and leg edema Elsa Solà1,2,3,4, Hugh Watson5, Isabel Graupera1,2,3,4, Fanny Turón1,2,3,4, Rogelio Barreto1,2,3,4, Ezequiel Rodríguez1,2,3,4, Marco Pavesi1,2,3, Vicente Arroyo1,2,3,4, Mónica Guevara1,2,3,4, Pere Ginès1,2,3,4,⇑ 1

Liver Unit, Hospital Clínic, University of Barcelona, Barcelona, Catalunya, Spain; 2Institut d’Investigacions Biomèdiques August-Pi-Sunyer (IDIBAPS), Spain; 3Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Spain; 4 Instituto Reina Sofía de Investigación Nefrológica, Spain; 5Sanofi-Aventis Recherche, France

Background & Aims: Hyponatremia is common in patients with cirrhosis and ascites and is associated with significant neurological disturbances. However, its potential effect on health-related quality of life (HRQL) in cirrhosis has not been investigated. We aimed at assessing the relationship between serum sodium concentration and other clinical and analytical parameters on HRQL in cirrhosis with ascites. Methods: A total of 523 patients with cirrhosis and ascites were prospectively investigated. Assessment of HRQL was done with the Medical Outcomes Study Short-Form 36 (SF-36) questionnaire, which is divided into 8 domains, summarized in two components: physical component score (PCS) and mental component score (MCS). Demographic, clinical, and analytical data at baseline were analyzed for their relationship with HRQL. Results: In multivariate analysis, independent predictive factors associated with an impaired PCS were non-alcoholic etiology of cirrhosis, severe ascites, history of previous episodes of hepatic encephalopathy and falls, presence of leg edema, and low serum sodium concentration. With respect to MCS, only two factors were associated with the independent predictive value: low serum sodium concentration and treatment with lactulose or lactitol. In both components, the scores decreased in parallel with the reduction in serum sodium concentration. Variables more commonly associated with the independent predictive value in the individual 8 domains of PCS and MCS were presence of leg edema and serum sodium concentration, 7 and 6 domains, respectively. Conclusions: Serum sodium concentration and presence of leg edema are major factors of the impaired HRQL in patients with cirrhosis and ascites. Ó 2012 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

Keywords: Quality of life; Cirrhosis; Ascites; Hyponatremia; Edema. Received 6 February 2012; received in revised form 26 June 2012; accepted 11 July 2012; available online 20 July 2012 ⇑ Corresponding author. Address: Liver Unit, Hospital Clínic, Villarroel 170, 08036 Barcelona, Spain. E-mail address: [email protected] (P. Ginès).

Introduction Hyponatremia is common in patients with cirrhosis and ascites and its frequency increases with disease progression [1–3]. A large body of information indicates that hyponatremia in cirrhosis is not a simple laboratory abnormality without clinical significance. In fact, several lines of evidence indicate that hyponatremia, by inducing changes in the central nervous system, is an important factor of increased morbidity in cirrhosis [3–5]. Hyponatremia with the concomitant hypo-osmolality is associated with an adaptive response of the central nervous system aimed at preventing the passage of fluid from the extracellular to the intracellular space and the development of cerebral edema. This adaptive response is characterized by a marked decrease in the brain concentration of several organic osmolytes, particularly myo-inositol [5–9]. In patients with marked hyponatremia, a low-grade cerebral edema exists despite this adaptive response of the brain and increased ammonia levels also play a role in low-grade cerebral edema [8–11]. Serum sodium concentration, together with serum ammonia levels, correlates with electroencephalographic abnormalities in cirrhosis [12]. Moreover, in patients treated with TIPS, a situation that increases serum ammonia levels, hyponatremia is a major risk factor of hepatic encephalopathy [13,14]. Along the same lines, clinical studies have demonstrated that hyponatremia is a major risk factor of hepatic encephalopathy and there is an inverse relationship between brain myo-inositol levels and occurrence of hepatic encephalopathy [14–16]. Besides, hyponatremia is also a risk factor for neurological complications and increased mortality before and after transplantation [17–20]. Considering this relationship between serum sodium levels and neurological disturbances in cirrhosis, it is tempting to speculate that serum sodium concentration could be related to quality of life in cirrhosis. Several studies assessing factors related to quality of life in patients with cirrhosis have been reported in the last decade [21–25]. However, none of these studies have specifically investigated serum sodium concentration as a potential factor related to quality of life in a large series of patients. Moreover, although the presence of ascites was found to be associated with an impaired HRQL in cirrhosis, no studies have been reported so far, assessing variables influencing HRQL in patients

Journal of Hepatology 2012 vol. 57 j 1199–1206

Research Article with ascites. On this background, the current study was designed to assess factors related to an impaired HRQL in a large population of patients with cirrhosis and ascites and evaluate whether serum sodium concentration has an impact on HRQL in cirrhosis.

Table 1. Baseline characteristics of the 523 patients included in the study.

Age (yr)

58 ± 9 (34-82)

Gender - M/F

390/133

Alcoholic cirrhosis - n (%)

391 (75%)

Ascites: mild/moderate/severe - n (%)

109 (21%)/354 (68%)/60 (11%) 295 (56%)

Patients and methods

Leg edema - n (%) Study population Baseline data from 523 patients with cirrhosis and ascites included in five randomized, double-blind or single-blind, international placebo-controlled clinical trials evaluating the effects of the vasopressin V2-receptor antagonist satavaptan, were analyzed [26–29]. Eighty-five patients were originally excluded from these trials because they did not meet the inclusion criteria or had exclusion criteria (Supplementary material). The studies were approved by the institutional review board of participating hospitals and patients gave written informed consent. Methods Demographical, clinical, and laboratory data were obtained from all patients at baseline. Clinical data included information about current and previous complications of cirrhosis, while laboratory data included standard liver and renal tests and serum sodium and potassium levels. Health-related quality of life (HRQL) was evaluated using the Medical Outcomes Study Short-Form 36 (SF-36) self-administered questionnaire at baseline [30–32]. SF-36 is a generic, standardized instrument including 36 items divided into eight domains. It measures 4 domains in the area of physical health (role physical, physical functioning, bodily pain, and general health) and 4 domains in the area of mental health (role emotional, social functioning, vitality, and mental health). Two summary scores can be obtained, a physical component score (PCS) and a mental component score (MCS). Domain scores range from 0 to 100. Summary scores for the PCS range from 8 to 73 and scores for the MCS range from 10 to 74. A higher score indicates a better quality of life [30–32]. Statistical analysis Descriptive analyses were carried out by estimating means and SD for continuous variables and frequencies and percentage for categorical characteristics. A univariate analysis of the association between the individual and summary scores and patient demographics, clinical characteristics and laboratory values was carried out by means of Student’s t tests and one-way ANOVA or by estimating Pearson’s correlation coefficients, depending on the nature of each specific factor. Those patient characteristics showing a clinical and statistical association to each of the two summary scores were selected to fit a multiple linear regression model in order to assess the most important predictive factors of mental and physical components. A forward stepwise regression method was used to select the best predictors (statistical criteria: p-in = 0.05; p-out = 0.01).

Results Baseline characteristics of patients The baseline characteristics of patients included in the study are shown in Table 1. As expected, most patients had advanced cirrhosis, as indicated by clinical characteristics and impairment of liver tests. Mean serum sodium concentration was low, averaging 132 mEq/L, and 27% of patients had hyponatremia [1,33]. Only 44% of patients had serum sodium levels above the normal value of 135 mEq/L. There were no significant differences in baseline factors between patients with alcoholic and non-alcoholic cirrhosis. Factors associated with health-related quality of life in patients with cirrhosis and ascites The relationship between demographic characteristics and clinical and analytical variables with components of the SF-36 is 1200

Previous hepatic encephalopathy - n (%)

132 (25%)

Previous spontaneous bacterial peritonitis - n (%) Falls within the previous month - n (%)

100 (19%) 39 (7%)

Baseline treatment Diuretics

489 (94%)

Lactulose/lactitol

189 (36%)

Beta-blockers

180 (35%)

Norfloxacin

61 (12%)

Serum bilirubin (mg/dl)

2.7 ± 2.1 (0.3-14.6)

Serum albumin (g/L)

31 ± 6 (14-49)

INR

1.5 ± 0.3 (0.9-3.3)

Serum creatinine (mg/dl) ≤1.5 - n (%)

467 (90%)

>1.5 - n (%)

54 (10%)

Mean

1.0 ± 0.3 (0.4-2.7)

Serum sodium (mEq/L) ≥135 - n (%)

229 (44%)

130-134 - n (%)

151 (29%)

<130 - n (%)

143 (27%)

Mean

132 ± 6 (112-146)

MELD score

15 ± 4 (6-31)

Child-Pugh score

9 ± 1.6 (6-15)

Values are means ± SD and ranges or frequencies and percentages. MELD, Model for End-stage Liver Disease.

shown in Tables 2 and 3. The values of the PCS were related to a number of variables including gender, etiology of cirrhosis, ascites severity, presence of leg edema, previous history of hepatic encephalopathy, spontaneous bacterial peritonitis and falls, serum bilirubin, serum albumin, serum sodium concentration, and Child–Pugh and MELD scores (Table 2). The majority of variables that correlated with the total PCS also correlated with 3 out of the 4 domains included in the PCS: role physical, physical functioning, and general health. By contrast, bodily pain was only related to severity of ascites, leg edema, previous encephalopathy, and previous falls (Table 2). The relationship between PCS and treatment with drugs commonly used in patients with cirrhosis is shown in Supplementary Table 1. In multivariate analysis, independent predictive factors associated with an impaired PCS were non-alcoholic etiology of cirrhosis, severe ascites, positive history of previous episodes of hepatic encephalopathy and falls, presence of leg edema, and low serum sodium concentration (Table 4). Multivariate analyses for each domain of the PCS are shown in Supplementary Table 2. In sharp contrast with the large number of variables related to values of the PCS, only few variables correlated with the MCS in univariate analysis (Table 3). These factors were presence of leg

Journal of Hepatology 2012 vol. 57 j 1199–1206

JOURNAL OF HEPATOLOGY Table 2. Values of SF-36 physical component score and its domains, according to demographic, clinical, and analytical variables in patients with cirrhosis and ascites.

Variable Age <65 yr ≥65 yr Gender Male Female Etiology Alcoholic Non-alcoholic Ascites Mild Moderate Tense Leg edema No Yes Previous encephalopathy No Yes Previous SBP No Yes Falls within the last month No Yes Serum bilirubin (mg/dl) ≤2.2 >2.2 Serum albumin (g/L) ≤30.5 >30.5 INR ≤1.4 <1.4 Serum creatinine (mg/dl) ≤1.5 >1.5 Serum sodium (mEq/L) ≥135 130-134 <130 MELD score ≤14 >14 Child-Pugh score A/B C

Role physical

Physical functioning

Bodily pain

General health

Physical component score

25 ± 36 25 ± 37

49 ± 27 43 ± 28

59 ± 30 61 ± 29

41 ± 19 43 ± 28

35 ± 10 34 ± 9

26 ± 37 22 ± 34

50 ± 27 42 ± 28

*

61 ± 29 56 ± 33

42 ± 19 41 ± 21

35 ± 10 33 ± 10

**

43 ± 19 37 ± 19

36 ± 10 32 ± 9

**

36 ± 8 35 ± 10 29 ± 8

**

28 ± 37 12 ± 33

**

51 ± 28 38 ± 26

**

60 ± 29 58 ± 32

27 ± 37 26 ± 37 13 ± 26

*

55 ± 26 48 ± 27 33 ± 27

**

60 ± 26 62 ± 31 48 ± 29

**

43 ± 20 42 ± 19 39 ± 18

28 ± 39 19 ± 32

**

54 ± 26 40 ± 27

**

61 ± 29 56 ± 30

**

45 ± 18 39 ± 18

**

38 ± 9 32 ± 9

**

28 ± 37 17 ± 31

**

51 ± 28 39 ± 27

**

61 ± 29 51 ± 29

**

43 ± 19 37 ± 19

**

36 ± 9 32 ± 9

**

27 ± 37 19 ± 30

*

40 ± 28 31 ± 24

**

61 ± 29 56 ± 31

42 ± 19 38 ± 17

**

35 ± 9 32 ± 9

**

26 ± 37 10 ± 23

**

49 ± 27 34 ± 28

**

61 ± 29 43 ± 30

42 ± 19 32 ± 19

*

35 ± 9 29 ± 8

**

29 ± 38 21 ± 33

**

51 ± 27 45 ± 28

**

61 ± 29 58 ± 30

43 ± 19 40 ± 19

**

36 ± 9 33 ± 10

**

21 ± 35 29 ± 37

**

44 ± 28 52 ± 27

**

58 ± 30 61 ± 29

39 ± 19 44 ± 19

**

34 ± 10 36 ± 9

**

29 ± 37 21 ± 34

*

49 ± 26 46 ± 28

59 ± 29 59 ± 30

42 ± 19 41 ± 18

48 ± 28 44 ± 26

59 ± 29 57 ± 31

42 ± 19 36 ± 19

*

35 ± 10 33 ± 8

61 ± 28 60 ± 31 56 ± 32

45 ± 19 40 ± 19 38 ± 18

**

37 ± 9 35 ± 10 31 ± 9

**

61 ± 29 58 ± 30

43 ± 19 40 ± 19

36 ± 10 34 ± 7

*

60 ± 30 59 ± 31

43 ± 19 40 ± 19

36 ± 10 33 ± 9

**

26 ± 36 19 ± 34 33 ± 39 24 ± 36 14 ± 28

**

56 ± 25 47 ± 27 35 ± 27

29 ± 37 21 ± 34

*

49 ± 26 46 ± 29

29 ± 37 18 ± 32

**

52 ± 27 41 ± 29

**

**

**

**

35 ± 10 34 ± 9

SBP, spontaneous bacterial peritonitis; MELD, Model for End-stage Liver Disease. ⁄ p <0.05. ⁄⁄ p <0.01.

edema, previous falls, serum albumin, and serum sodium concentration. The relationship between MCS and treatment with drugs commonly used in patients with cirrhosis is shown in Supple-

mentary Table 3. In multivariate analysis, only two factors were associated with an independent predictive value of impaired MCS: low serum sodium concentration and treatment with

Journal of Hepatology 2012 vol. 57 j 1199–1206

1201

Research Article Table 3. Values of SF-36 mental component score and its domains, according to demographic, clinical, and analytical variables in patients with cirrhosis and ascites.

Variable Age <65 yr ≥65 yr Gender Male Female Etiology Alcoholic Non-alcoholic Ascites Mild Moderate Tense Led edema No Yes Previous encephalopathy No Yes Previous SBP No Yes Falls within the last month No Yes Serum bilirubin (mg/dl) ≤2.2 >2.2 Serum albumin (g/L) ≤30.5 >30.5 INR ≤1.4 <1.4 Serum creatinine (mg/dl) ≤1.5 >1.5 Serum sodium (mEq/L) ≥135 130-134 <130 MELD score ≤14 >14 Child-Pugh score A/B C

Role emotional

Social functioning

Vitality

Mental health

Mental component score

53 ± 43 47 ± 45

58 ± 30 62 ± 29

42 ± 23 42 ± 21

62 ± 21 63 ± 23

44 ± 11 45 ± 12

52 ± 44 50 ± 43

59 ± 29 59 ± 32

43 ± 23 41 ± 24

63 ± 21 60 ± 23

44 ± 11 44 ± 13

53 ± 43 47 ± 44

61 ± 28 46 ± 32

63 ± 21 60 ± 23

45 ± 11 43 ± 13

54 ± 41 53 ± 43 40 ± 45

63 ± 28 60 ± 30 ** 48 ± 30

44 ± 22 43 ± 24 * 35 ± 21

64 ± 21 62 ± 22 61 ± 20

45 ± 12 44 ± 12 43 ± 11

59 ± 28 56 ± 30

**

49 ± 23 38 ± 22

**

62 ± 21 60 ± 22

52 ± 43 49 ± 44

62 ± 28 51 ± 30

**

44 ± 23 38 ± 22

**

63 ± 22 61 ± 20

45 ± 12 43 ± 11

53 ± 43 47 ± 44

60 ± 29 53 ± 30

*

43 ± 23 40 ± 23

63 ± 22 60 ± 22

44 ± 11 43 ± 12

60 ± 29 43 ± 33

**

44 ± 23 29 ± 23

**

62 ± 22 57 ± 23

45 ± 11 41 ± 13

60 ± 29 58 ± 30

45 ± 24 40 ± 22

**

62 ± 22 62 ± 21

44 ± 12 44 ± 11

57 ± 29 61 ± 30

38 ± 22 46 ± 23

**

60 ± 21 64 ± 22

53 ± 42 50 ± 45

60 ± 29 57 ± 31

44 ± 24 41 ± 22

62 ± 22 62 ± 21

45 ± 11 44 ± 12

52 ± 43 46 ± 47

59 ± 29 55 ± 30

43 ± 23 40 ± 23

62 ± 21 59 ± 23

44 ± 11 43 ± 12

57 ± 42 47 ± 44

53 ± 43 35 ± 44

**

*

52 ± 42 51 ± 44 46 ± 44 57 ± 42

56 ± 41 50 ± 43 45 ± 46

**

*

64 ± 28 57 ± 30 52 ± 30

**

*

43 ± 24 35 ± 21

**

**

45 ± 12 43 ± 11

43 ± 11 46 ± 12

49 ± 23 40 ± 23 34 ± 21

**

65 ± 22 60 ± 22 59 ± 21

*

63 ± 22 61 ± 22

45 ± 12 44 ± 11

63 ± 21 60 ± 22

45 ± 11 44 ± 12

52 ± 42 51 ± 45

60 ± 29 57 ± 30

44 ± 23 40 ± 23

53 ± 42 47 ± 45

60 ± 29 57 ± 31

45 ± 23 37 ± 22

**

SBP, spontaneous bacterial peritonitis; MELD, Model for End-stage Liver Disease. ⁄ p <0.05. ⁄⁄ p <0.01.

1202

**

Journal of Hepatology 2012 vol. 57 j 1199–1206

*

46 ± 11 43 ± 12 43 ± 11

*

*

*

**

JOURNAL OF HEPATOLOGY Table 4. Multivariate analysis of factors associated with the physical and mental component scores of SF-36 questionnaire in patients with cirrhosis and ascites.

Physical component score

Mental component score

Variable

Coefficient

p value

95% CI

Alcoholic cirrhosis Ascites Previous hepatic encephalopathy Falls within the last month Serum sodium Leg edema

2.7 -1.3 -2.7 -3.6 0.3 -3.6

0.031 0.06 0.002 0.01 <0.0001 <0.0001

0.9-4.5 -2.8-0.06 -4.5- -0.9 -6.6- -0.6 0.19-0.46 -5.3- -2.07

Coefficient Serum sodium 0.21 Lactulose/lactitol treatment* -3.0 Variable

p value

95% CI

0.01 0.004

0.04-0.38 -5.09- -0.9

⁄ If lactulose/lactitol treatment was not included into the multivariate analysis, the independent predictive factors associated with the mental component score were serum sodium and serum albumin concentration.

Na ≥135 mEq/L Na 130-134 mEq/L Na <130 mEq/L

60 50

60 50

Score

70 *

* *

*

30 20 10

*

*

40

40

0

120

125

30 *

20

Without leg edema and hepatic encephalopathy With leg edema or previous hepatic encephalopathy

alcoholic cirrhosis

0 RP

145

Patients with:

10 PF

130 135 140 Serum [Na] (mEq/L)

BP

GH

Physical component

SF

RE

VT

MH

non-alcoholic cirrhosis

Mental component

With leg edema or previous hepatic encephalopathy With leg edema and previous hepatic encephalopathy

*p <0.05

lactulose or lactitol (Table 4). Multivariate analyses for each domain of the MCS are shown in Supplementary Table 4. The variables that were more common as independent predictive factors in the 8 domains of PCS or MCS were presence of leg edema and serum sodium concentration, which were independent predictive factors in 7 and 6 domains, respectively. Other factors common to several domains were etiology of cirrhosis and history of previous falls (5 and 4, respectively). The effect of serum sodium concentration on the 8 domains is shown in Fig. 1. When all patients were categorized into three groups according to normal serum sodium concentration (equal to or greater than 135 mEq/L; 44% of patients), moderately impaired serum sodium concentration (130–134 mEq/L); 29% of patients, and markedly impaired serum sodium concentration (hyponatremia: lower than 130 mEq/L; 27% of patients), a progressive decrease in the scores of all domains was observed, except bodily pain. Figs. 2–4 show a graphical representation of the effect of serum sodium concentration in 3 of the 8 domains, role physical, general health, and vitality, adjusted according to independent predictive factors found in multivariate analyses. In all cases,

Fig. 2. Effect of serum sodium concentration on role physical domain scores, adjusted for presence of leg edema, previous hepatic encephalopathy, and etiology of cirrhosis.

30 Score

Fig. 1. Values of SF-36 individual domains, according to serum sodium concentration (normal: >135 mEq/L, mild decrease 130–134 mEq/L; and hyponatremia <130 mEq/L). PF, physical functioning; RP, role physical; BP, bodily pain; GH, general health; SF, social functioning; RE, role emotional; VT, vitality; MH, mental health. ⁄p <0.05.

20 10 0

120

125

Patients with: non-alcoholic cirrhosis

alcoholic cirrhosis

130 135 140 Serum [Na] (mEq/L)

145

With leg edema and without previous falls Without leg edema and with history of previous falls With leg edema and previous falls With leg edema and history of previous falls

Fig. 3. Effect of serum sodium concentration on general health domain scores, adjusted for presence of leg edema, previous falls, and etiology of cirrhosis.

Journal of Hepatology 2012 vol. 57 j 1199–1206

1203

Research Article 60

Score

50 40 30 20 10 0

Patients with non-alcoholic cirrhosis

120

125

130 135 140 Serum [Na] (mEq/L)

145

With leg edema and without previous falls within the last month Without leg edema and with history of previous falls With leg edema and with history of previous falls

Fig. 4. Effect of serum sodium concentration on vitality domain scores, adjusted for presence of leg edema, previous falls, and etiology of cirrhosis.

quality of life scores decreased in parallel with the reduction in serum sodium concentration. A multivariate analysis of factors associated with HRQL performed only in patients with alcoholic cirrhosis, yielded results similar to those of the whole population (Supplementary Table 5).

Discussion The current study performed in a large series of patients with cirrhosis and ascites confirms the working hypothesis that serum sodium concentration is an important factor of health-related quality of life (HRQL) in cirrhosis, in such a way that patients with hyponatremia have marked impairment of HRQL compared to patients with normal serum sodium concentration. Moreover, patients with mild reductions in serum sodium concentration below the lower limit of normal values, but who do not reach the threshold value of 130 mEq/L required for the definition of hyponatremia [1,33], also have a significant impairment of HRQL compared to patients with normal serum sodium concentration, indicating that serum sodium is a sensitive factor predicting HRQL in cirrhosis. The value of serum sodium concentration in the prediction of HRQL persisted after adjustment for possible confounding factors related to the severity of liver failure. Furthermore, serum sodium levels were an independent predictive factor of both physical and mental summary scores of HRQL and of 6 out of the 8 domains of the SF-36: role physical, physical functioning, general health, social functioning, vitality, and mental health. This indicates that reductions in serum sodium levels affect most areas of daily life. The only two domains that were not associated with serum sodium levels were bodily pain and role emotional. Bodily pain is the only domain of the SF-36 that is not altered in cirrhosis compared to the general population [21,24]. A number of studies reported in the last 10 years have convincingly demonstrated that HRQL is significantly impaired in patients with cirrhosis compared to the general population and identified several factors associated with an impaired HRQL in cirrhosis [21–25]. These studies included patients with compensated cirrhosis and decompensated cirrhosis. The identified factors relating to HRQL included a history of previous or current

1204

complications of the disease (specifically, ascites, hepatic encephalopathy), non-alcoholic etiology of cirrhosis, Child–Pugh score as an indicator of disease severity, and a few other factors, including anemia, pruritus, and muscle cramps [21–25]. The current study focused on patients with cirrhosis and ascites, which is the population of patients with cirrhosis most frequently seen in hospital practice. To our knowledge, no specific studies have been reported to date analyzing factors related to HRQL in patients with ascites. The strengths of our study are that it was conducted on a large population of patients that covers the whole spectrum of patients with ascites and that we analyzed variables that had not been included in previous studies, assessing HRQL in cirrhosis. Variables that were independent predictive factors of HRQL were serum sodium concentration, as discussed above, presence of leg edema, history of previous falls, non-alcoholic etiology of cirrhosis, severity of ascites, history of previous hepatic encephalopathy, and treatment with lactulose/lactitol. Interestingly, neither the Child–Pugh score nor variables directly measuring the intensity of liver dysfunction, such as serum bilirubin, serum albumin or prothrombin time, were identified as independent predictive factors of HRQL in this patient population. In keeping with the results of previous studies, the MELD score was also not predictive of HRQL [23]. As mentioned above, serum sodium concentration was found to be a powerful independent factor associated with HRQL in cirrhosis. Similarly, hyponatremia has been identified as an important factor of HRQL in another condition, such as cardiac failure [34] that shares with cirrhosis a common pathogenic mechanism for the development of hyponatremia. The possible mechanisms explaining the relationship between hyponatremia and impaired HRQL are difficult to ascertain and were not the objective of the current study. Considering the important effects of hyponatremia on the central nervous system, it is tempting to speculate that hyponatremia impairs HRQL by altering the functioning of parts of the SNC related to the sense of well-being [35–37]. Studies in experimental animals indicate that chronic hyponatremia has marked effects on the central nervous system and exacerbates multiple manifestations of senescence [9,38,39]. The presence of edema in the legs had a very powerful relationship with HRQL as it was an independent predictive factor of all domains of the SF-36 except the domain of bodily pain, which has been consistently reported as not being altered in cirrhosis [21]. The relevance of leg edema as independent predictive factor of HRQL in cirrhosis had not been previously reported but it fits nicely with the clinical observation that presence of leg edema is one of the most frequent and important complains of patients with decompensated cirrhosis seen at a liver clinic. We are not aware of any study specifically estimating the amount of fluid in the legs in patients with cirrhosis. Nevertheless, the amount of fluid that may be present in both legs of a patient with decompensated cirrhosis may be very important and, by markedly increasing the weight of the legs, produce a negative impact on daily activities. The implementation of therapeutic measures to decrease leg edema may have a beneficial effect on well being in patients with cirrhosis. Interestingly, a history of falls within the previous month was an independent predictive factor of HRQL in 4 out of the 8 domains analyzed. Whether previous falls represent a cause or a consequence of the impaired HRQL is not possible to unravel. Falls are common in patients without liver disease and hyponatremia of different etiologies [40].

Journal of Hepatology 2012 vol. 57 j 1199–1206

JOURNAL OF HEPATOLOGY Interestingly, recent studies have also reported an increased incidence of falls in patients with advanced cirrhosis and suggest that falls may be related to the presence of minimal hepatic encephalopathy [41,42]. In the current series, falls were more common in hyponatremic than in normonatremic patients (10% vs. 4.8%; p = 0.045). Although the number of patients who had fallen within the previous month in the current series was relatively low (7.5%), its occurrence was associated with markedly reduced values in all domains of the PCS compared to patients without falls. Interestingly, patients with previous history of falls had the lowest value of the role physical domain among all parameters analyzed (Table 2). Taken together, these results suggest that more attention should be paid to this problem and preventive measures should be implemented to decrease the frequency of falls in these patients. Lastly, we identified other factors related to an impaired HRQL including non-alcoholic etiology of cirrhosis, severity of ascites, previous history of hepatic encephalopathy, and treatment with lactulose/lactitol. This is in keeping with the results of other studies and emphasizes the role of HCV infection and previous history of decompensation, particularly hepatic encephalopathy, as important factors causing an impaired HRQL in cirrhosis [21–25,43–46]. In contrast with previous results [21], in our study we found a negative effect of lactulose/lactitol treatment on HRQL. We do not have a convincing explanation for these findings. The possibility exists that the predictive value of lactulose/lactitol on HRQL is related to the underlying hepatic encephalopathy and not to the treatment itself. Alternatively, the treatment itself (or perhaps excessive treatment) might impair HRQL by causing gastrointestinal side effects. This latter possibility is supported by the results of previous studies [47,48]. This study has some limitations that should be acknowledged. First, the study was not primarily designed to evaluate HRQL in cirrhosis. However, data on SF-36 questionnaires together with all other variables analyzed were collected prospectively in patients included in several randomized studies to assess the efficacy of satavaptan, a v2 receptor antagonist, on ascites in cirrhosis. Patients with severe renal failure (serum creatinine greater than 2 mg/dl) were not included in these studies and therefore this may represent a small bias in the interpretation of the results as most of these patients have ascites in addition to renal failure. Unfortunately, some variables known or likely to correlate with HRQL in cirrhosis, such as pruritus, muscle cramps, and abstinence [21–25], were not assessed in the current study. Finally, because this was a cross-sectional study, data on the evolution of parameters of HRQL during the course of the disease are not available. Abstinence from alcohol probably improves HRQL in patients with alcoholic cirrhosis. However, the demonstration of the possible beneficial effect of abstinence on HRQL would require a longitudinal study. In conclusion, the results of the current study identified serum sodium concentration and presence of leg edema as major factors related to the impaired health-related quality of life in patients with cirrhosis and ascites. This information may help improve quality of life in patients with advanced cirrhosis.

Financial support This work was supported by a grant from Fondo de Investigación Sanitaria (FIS PI080126; to PG). Elsa Solà was supported by a

grant from the Instituto de Salud Carlos III (FI10/00438). CIBEREHD is funded by the Instituto de Salud Carlos III.

Conflict of interest The authors who have taken part in this study declared that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript. Supplementary data Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.jhep.2012. 07.020. References [1] Ginès P, Berl T, Bernardi M, et al. Hyponatremia in cirrhosis: from pathogenesis to treatment. Hepatology 1998;28:851. [2] Angeli P, Wong F, Watson H. CAPPS Investigators. Hyponatremia in cirrhosis: results of a patient population survey. Hepatology 2006;44:1535–1542. [3] Ginès P, Guevara M. Hyponatremia in cirrhosis: pathogenesis, clinical significance, and management. Hepatology 2008;48:1002–1010. [4] Córdoba J, García-Martinez R, Simón-Talero M. Hyponatremic and hepatic encephalopathies: similarities, differences and coexistence. Metab Brain Dis 2010;25:73–80. [5] Häussinger D, Kircheis G, Fischer R, Schliess F, Vom Dahl S. Hepatic encephalopathy in chronic liver disease: a clinical manifestation of astrocyte swelling and low-grade cerebral edema? J Hepatol 2000;32:1035–1038. [6] Restuccia T, Gómez-Ansón B, Guevara M, Alessandria C, Torre A, Alayrach ME, et al. Effects of dilutional hyponatremia on brain organic osmolytes and water content in patients with cirrhosis. Hepatology 2004;39:1613–1622. [7] Häussinger D, Laubenberger J, Vom Dahl S, Ernst T, Bayer S, Langer M, et al. Proton magnetic resonance spectroscopy studies on human brain myoinositol in hypo-osmolarity and hepatic encephalopathy. Gastroenterology 1994;107:1475–1480. [8] Córdoba J, Alonso J, Rovira A, Jacas C, Sanpedro F, Castells L, et al. The development of low-grade cerebral edema in cirrhosis is supported by the evolution of (1)H-magnetic resonance abnormalities after liver transplantation. J Hepatol 2001;35:598–604. [9] Córdoba J, Gottstein J, Blei AT. Chronic hyponatremia exacerbates ammoniainduced brain edema in rats after portacaval anastomosis. J Hepatol 1998;29:589–594. [10] Haussinger D. Low grade cerebral edema and the pathogenesis of hepatic encephalopathy in cirrhosis. Hepatology 2006;43:1187–1190. [11] Shawcross DL, Balata S, Olde Damink SW, Hayes PC, Wardlaw J, Marshall I, et al. Low myo-inositol and high glutamine levels in brain are associated with neuropsychological deterioration after induced hyperammonemia. Am J Physiol Gastrointest Liver Physiol 2004;287:G503–G509. [12] Amodio P, Del Piccolo F, Petteno E, Mapelli D, Angeli P, Iemmolo R, et al. Prevalence and prognostic value of quantified electroencephalogram (EEG) alterations in cirrhotic patients. J Hepatol 2001;35:37–45. [13] Jalan R, Elton RA, Redhead DN, Simpson KJ, Finlayson NDC, Hayes PC, et al. Analysis of prognostic variables in the prediction of shunt failure, variceal rebleeding, early mortality and encephalopathy following the transjugular intrahepatic portosystemic stent-shunt (TIPSS). J Hepatol 1995;23:123–128. [14] Guevara M, Baccaro ME, Ríos J, Martín-Llahí M, Uriz J, Ruiz del Arbol L, et al. Risk factors for hepatic encephalopathy in patients with cirrhosis and refractory ascites: relevance of serum sodium concentration. Liver Int 2010;30:1137–1142. [15] Guevara M, Baccaro ME, Torre A, Gómez-Ansón B, Ríos J, Torres F, et al. Hyponatremia is a risk factor of hepatic encephalopathy in patients with cirrhosis: a prospective study with time-dependent analysis. Am J Gastroenterol 2009;104:1382–1389. [16] Riggio O, Angeloni S, Salvatori FM, De Santis A, Cerini F, Farcomeni A, et al. Incidence, natural history, and risk factors of hepatic encephalopathy after transjugular intrahepatic portosystemic shunt with polytetrafluoroethylenecovered stent grafts. Am J Gastrol 2008;103:2738–2746. [17] Londoño MC, Guevara M, Rimola A, Navasa M, Taurà P, Mas A, et al. Hyponatremia impairs early posttransplantation outcome in patients with

Journal of Hepatology 2012 vol. 57 j 1199–1206

1205

Research Article [18]

[19]

[20]

[21]

[22]

[23]

[24]

[25]

[26]

[27]

[28]

[29]

[30] [31]

[32]

cirrhosis undergoing liver transplantation. Gastroenterology 2006;130:1135–1143. Dawwas MF, Lewsey JD, Neuberger JM, Gimson AE. The impact of serum sodium concentration on mortality after liver transplantation: a cohort multicenter study. Liver Transpl 2007;13:1115–1124. Biggins SW, Rodriguez HJ, Bacchetti P, Bass NM, Roberts JP, Terrault NA. Serum sodium predicts mortality in patients listed for liver transplantation. Hepatology 2005;41:32–39. Kim WR, Biggins SW, Kremers WK, Wiesner RH, Kamath PS, Benson JT, et al. Hyponatremia and mortality among patients on the liver-transplant waiting list. N Engl J Med 2008;359:1018–1026. Marchesini G, Bianchi G, Amodio P, Salerno F, Merli M, Panella C, et al. Factors associated with poor health-related quality of life of patients with cirrhosis. Gastroenterology 2001;120:170–178. Les I, Doval E, Flavià M, Jacas C, Cárdenas G, Esteban R, et al. Quality of life in cirrhosis is related to potentially treatable factors. Eur J Gastroenterol Hepatol 2010;22:221–227. Saab S, Ibrahim AB, Shpaner A, Younossi ZM, Lee C, Durazo F, et al. MELD fails to measure quality of life in liver transplant candidates. Liver Transpl 2005;11:218–233. Younossi ZM, Boparai N, Price LL, Kiwi ML, McCormick M, Guyatt G. Healthrelated quality of life in chronic liver disease: the impact of the type and severity of disease. Am J Gastroenterol 2001;96:2199–2205. Afendy A, Kallman JB, Stepanova M, Younpszai Z, Aquino RD, Bianchi G, et al. Predictors of health-related quality of life in patients with chronic liver disease. Aliment Pharmacol Ther 2009;30:469–476. Ginès P, Wong F, Watson H, Milutinovic S, del Arbol LR. HypoCAT Study Investigators. Effects of satavaptan, a selective vasopressin V(2) receptor antagonist, on ascites and serum sodium in cirrhosis with hyponatremia: a randomized trial. Hepatology 2008;48:204–213. Ginès P, Wong F, Watson H, Terg R, Bruha R, Zarski JP. NormoCAT Study Investigators. Clinical trial: short-term effects of combination of satavaptan, a selective vasopressin V2 receptor antagonist, and diuretics on ascites in patients with cirrhosis without hyponatraemia–a randomized, double-blind, placebo-controlled study. Aliment Pharmacol Ther 2010;31:834–845. Wong F, Gines P, Watson H, Horsmans Y, Angeli P, Gow P, et al. Effects of a selective vasopressin V2 receptor antagonist, satavaptan, on ascites recurrence after paracentesis in patients with cirrhosis. J Hepatol 2010;53:283–290. Wong F, Watson H, Gerbes A, Vilstrup H, Badalamenti S, Bernardi M, et al. Satavaptan for the management of ascites in cirrhosis: efficacy and safety across the spectrum of ascites severity. Gut 2012;61:108–116. Ware J, Sherbourne C. 36-item short form health survey (SF-36). I. Conceptual framework and item selection. Med Care 1992;30:473–482. Warw JE, Snow KK, Kosinski M, Gandek B. The SF-36 health survey. Manual and interpretation guide. Boston, MA: The Health Institute, New England Medical Center; 1993. Warw JE, Kosinski M, Dewey JE. How to score version 2 of the SF-36 health survey. Lincoln, RI: Quality Incorporated; 2000.

1206

[33] Gines P, Angeli P, Lenz K, Moller S, Moore K, Moreu R, et al. European Association for the Study of the Liver. EASL clinical practice guidelines on the management of ascites, spontaneous bacterial peritonitis, and hepatorenal syndrome in cirrhosis. J Hepatol 2010;53:397–417. [34] Allen LA, Gheorghiade M, Reid KJ, Dunlay SM, Chan PS, Hauptman PJ, et al. Identifying patients hospitalized with heart failure at risk for unfavourable future quality of life. Circ Cardiovasc Qual Outcomes 2011;4:389–398. [35] Adrogué HJ, Madias NE. Hyponatremia. N Engl J Med 2000;342:1581–1589. [36] Sterns RH, Silver SM. Brain volume regulation in response to hypoosmolality and its correction. Am J Med 2006;119 (Suppl. 1):S12–S16. [37] Videen JS, Michaelis T, Pinto P, Ross BD. Human cerebral osmolytes during chronic hyponatremia. A proton magnetic resonance spectroscopy study. J Clin Invest 1995;95:788–793. [38] Barsony J, Manigrasso MB, Xu Q, Tam H, Verbalis JG. Chronic hyponatremia exacerbates multiple manifestations of senescence in male rats. Age 2012; Jan 5 [Epub ahead of print]. [39] Miyazaki T, Ohmoto K, Hirose T, Fujiki H. Chronic hyponatremia impairs memory in rats: effects of vasopressin antagonist tolvaptan. J Endocrinol 2010;206:105–111. [40] Renneboog B, Musch W, Vandemergel X, Manto MU, Decaux G. Mild chronic hyponatremia is associated with falls, unsteadiness, and attention deficits. Am J Med 2006;119, 71.e1-8. [41] Soriano G, Román E, Córdoba J, Torrens M, Poca M, Torras X, et al. Cognitive dysfunction in cirrhosis is associated with falls. A prospective study. Hepatology 2012;55:1922–1930. [42] Román E, Córdoba J, Torrens M, Torras X, Villanueva C, Vargas V, et al. Minimal hepatic encephalopathy is associated with falls. Am J Gastroenterol 2011;106:476–482. [43] Teuber G, Schafer A, Rimpel J, Paul K, Keicher C, Scheurlen M, et al. Deterioration of health-related quality of life and fatigue in patients with chronic hepatitis C: association with demographic factors, inflammatory activity and degree of fibrosis. J Hepatol 2008;49:923–929. [44] John-Baptiste A, Tomlinson G, Hsu PC, Krajden M, Heathcote EJ, Laporte A, et al. Sustained responders have better quality of life and productivity compared with treatment failures long after antiviral therapy for hepatitis C. Am J Gastroenterol 2009;104:2439–2448. [45] Arguedas A, DeLawrence TG, McGUIRE BM. Influence of hepatic encephalopathy on health-related quality of life in patients with cirrhosis. Dig Dis Sci 2003;48:1622–1626. [46] Sidhu SS, Goyal O, Mishra BP, Sood A, Chhina RS, Soni RK. Rifaximin improves psychometric and health-related quality of life in patients with cirrhosis with minimal hepatic encephalopathy (the RIME Trial). Am J Gastroenterol 2011;106:307–316. [47] Kalaitzakis E, Simrén M, Olsson R, Henfridsson P, Hugosson I, Bengtsson M, et al. Gastrointestinal symptoms in patients with liver cirrhosis: associations with nutritional status and health-related quality of life. Scand J Gastroenterol 2006;41:1464–1472. [48] Bajaj JS, Sanyal A, Bell D, Gilles H, Heuman M. Predictors of the recurrence of hepatic encephalopathy in lactulose-treated patients. Aliment Pharmacol Ther 2010;31:1012–1017.

Journal of Hepatology 2012 vol. 57 j 1199–1206