Management of Hyponatremia in Cirrhosis: Comparison
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Please note this is a comparison between Version 2 by Fanny Huang and Version 1 by Martin Janicko.

Hyponatremia is a strong predictor of mortality and is also associated with an increased probability of hepatorenal syndrome, disturbance of consciousness, infections, and unfavorable post-transplant outcomes. In the management of hyponatremia, it is crucial to distinguish between hypovolemic and hypervolemic hyponatremia. The treatment of hypervolemic hyponatremia should be started only in symptomatic patients. The cessation of the treatment with traditional diuretics and fluid restriction may prevent further decrease in natremia. Pharmacological treatment is directed towards cirrhosis itself, precipitating factor, or hyponatremia directly. Currently, only albumin infusions can be recommended routinely. Other possibilities, such as vaptans, splanchnic vasoconstrictors, niravoline, or osmotic diuretics, are restricted to specific use cases (e.g., imminent liver transplantation) or need more research to determine their efficacy.

  • hyponatremia
  • cirrhosis

1. Introduction

The choice of treatment method depends on two principal factors. The first is the pathophysiology of hyponatremia and the second is the rate of sodium decline. A different approach is needed for acute hypovolemic hyponatremia caused by excessive diuretic treatment and different for chronic hypervolemic (dilutional) hyponatremia in patients with sodium and fluid retention. In the first case the immediate rehydration with the replenishment of body sodium by normal saline infusion is required, along with the cessation of diuretics [7][1]. Hypervolemic hyponatremia in cirrhosis is more a result than a cause of hemodynamic changes in cirrhosis. Therefore, the treatment should be aimed at the cause of liver disease (e.g., hepatitis B treatment improves portal hypertension [50][2]). The secondary option is the symptomatic treatment, which should be focused at the amelioration of splanchnic vasodilation and the increase in the solute-free water excretion together with the preservation of body sodium [9][3]. 
The initiation of the treatment should follow the development of symptoms. Although hyponatremia significantly lowers the quality of life of cirrhotic patients [37][4], many of the patients are asymptomatic or present with very mild symptoms. No specific s-Na cut-off value for the start of the treatment has been defined and both major guidelines (AASLD and EASL) recommend treatment only after the development of symptoms [53,54][5][6]. The rate of chronic hyponatremia correction should never exceed 12 mmol/L in 24 h because of the risk of central pontine myelinolysis [55][7].

2. Diet and Lifestyle Changes

Fluid restriction to 1000 mL/day is currently the first-line treatment for hypervolemic hyponatremia. Despite relatively low efficacy, it is considered a standard of care in current EASL and AASLD guidelines [53,54][5][6]. Although no placebo-controlled studies are possible, some efficacy data come from the multiple Vaptans trials. In the study by Gines et al. 1.5 L/24 h fluid restriction regimen increased the s-Na by 1.3 ± 4.2 mmol/L at day 5 and the improvement of s-Na of more than 5 mmol/L occurred in 18% of patients [57][8]. Even more strict fluid restriction (1.0 L/24 h) did not result in an increase in s-Na in a control arm of the study for lixivaptan [58][9]. Fluid restriction prevented further decrease in s-Na in both studies. In the registry data reported by Sigal et al., fluid restriction led to an increase in s-Na ≥ 5 mmol/L in 39% of patients [56][10].
Expansion of effective blood volume by physical methods could also have some positive effects on hyponatremia. Patients who were treated by head-out water immersion showed a significant decrease in AVP levels after acute water load (20 mL/kg) compared to the control group without water immersion. These lower levels of AVP were also preserved after the water load had been excreted. 

3. Transjugular Intrahepatic Portosystemic Shunt (TIPS)

Hypervolemic hyponatremia in cirrhosis is usually accompanied by severe ascites. The ascites are refractory in about 10% from the onset and become diuretic-resistant in a further 20% of patients during the course of the disease [61][11]. The insertion of TIPS is a valid treatment option in these patients [62][12] and it could also improve hyponatremia. Multiple studies documented the increase in serum sodium approximately 30 days after the insertion of TIPS [63,64,65,66][13][14][15][16]; however, some studies did not [67,68][17][18], and no clear recommendation can be given.

4. Pharmacological Therapy

Symptomatic pharmacological therapy could either directly antagonize the effect of AVP or attempt to increase effective arterial blood volume by ameliorating vasodilation (inhibition of NO synthase), inducing vasoconstriction, or plasma expansion by albumin.
The first step should be the evaluation of medical treatment the patient is currently taking. Known medications that decrease s-Na concentration include traditional diuretics (furosemide, spironolactone, thiazides), vasopressin analogs, and potentially non-selective beta-blockers (NSBB). According to older EASL guidelines, traditional diuretics should be discontinued if there is severe hyponatremia (serum sodium concentration < 120 mmol/L) (Level B1) [54][6]; however, this recommendation is no longer present in the current guideline [6][19].
Several reports about non-selective beta-blockers and carvedilol leading to worsening of arterial hypovolemia and higher risk of kidney injury caused confusion about their use in patients with severely decompensated cirrhosis and infections [69][20]. However, current reports, reflected also in the most recent guidelines, show, that NSBB has the potential to reduce mortality in severely decompensated cirrhotic patients without worsening hyponatremia [53][5].
Hypertonic saline solution with loop diuretic has been used in clinical practice for the management of SIADH [70][21]. Its efficacy in cirrhosis is limited and, most of all, short-lived. Furthermore, it worsens ascites and edema, therefore this treatment cannot be recommended universally in the management of hypervolemic hyponatremia [9][3], but it should be restricted to symptomatic life-threatening hyponatremia (e.g., patients with cardiorespiratory distress or severely disturbed consciousness, or can be considered in severe hyponatremia immediately before liver transplantation [6][19].
There is mounting evidence about albumin in the treatment of hypervolemic hyponatremia in cirrhosis. Initial case reports were reported in 1990 by McCormic et al. [71][22], followed by RCT published by Jalan et al. One-week treatment with albumin not only significantly increased s-Na, but also reduced the risk for infections, renal failure, hepatic encephalopathy, and mortality during the treatment period [72][23]. These results were confirmed in two retrospective observations in rather large cohorts of cirrhotic patients [73,74][24][25]. A recent meta-analysis, that included 25 RCTs and five cohort studies confirmed the effect of human albumin on the resolution of hyponatremia (OR = 1.50, 95% CI = 1.17–1.92, p = 0.001) and the prevention of hyponatremia (OR = 0.55, 95% CI = 0.38–0.80, p = 0.001) [75][26]. The quality of evidence in the meta-analysis was unfortunately low. The largest randomized controlled study focused on the efficacy of long-term albumin administration in decompensated cirrhosis was the ANSWER study, which randomized 440 patients into the standard-of-care plus albumin versus standard-of-care only groups. Improvement of hyponatremia was one of the secondary outcomes. Hyponatremia normalization was observed in 45% of the albumin group patients versus 28% of the standard medical therapy-only group, p = 0.042, regular albumin infusions also prevented the development of hyponatremia in previously normonatremic patients (incidence risk ratio 0.539 [CI 0.338–0.859, p = 0.008]) during the 18-month duration of the study. No follow-up after treatment conclusion was reported [76][27]. The persistence of this effect after the discontinuation of the albumin seems unlikely. Therefore, this treatment should be considered in the short term for patients awaiting transplantation.
Another interesting notion is the induction of free water excretion by osmotic diuresis. One small study evaluated the effect of urea on ascites and hyponatremia and found that the administration of 30–90 g of urea daily significantly increased diuresis, s-Na level, and sodium output. The average diuresis increased from 1.05 ± 0.10 to 2.24 ± 0.24 L/day, the change being so big that one patient suffered from dehydration and subsequent prerenal kidney failure [77][28]. A similar effect on the diuresis has been described for mannitol infusion as well [78][29]. Treatment with osmotic diuretics is regarded as outdated and thus frequently overlooked; however, it can be of value in the management of patients with ascites and hyponatremia.

4.1. Vasoconstriction Therapy

Terlipressin is a vasoconstrictive drug used often in patients with bleeding esophageal varices. It is an analog of AVP that works predominantly on V1 receptors in blood vessels; however, it also retains some affinity for V2 receptors [79][30]. Therefore, it has a mixed effect on the s-Na level. As described by Sola et al. terlipressin, but not somatostatin, led to a significant decrease in s-Na in patients with bleeding esophageal varices [80][31]. This decrease is most apparent in patients with the highest baseline sodium (i.e., patients with low baseline SAS, RAAS, and AVP activation) and is not as evident in patients with baseline hyponatremia [80,81][31][32]. On the other hand, the treatment of hepatorenal syndrome with terlipressin in combination with albumin could increase the s-Na [81][32], although it is difficult to ascertain if it is predominantly the effect of vasoconstrictor or albumin.
Duvoux et al. reported a significant increase in s-Na (123.0 ± 6.0 vs. 131.2 ± 4.1, p = 0.01) after ten days of hepatorenal syndrome treatment with noradrenaline and albumin [82][33]. The tendency toward s-Na increase was also reported in the study by Tavakkoli et al., who examined the effect of solo noradrenaline compared to midodrine + octreotide on hepatorenal syndrome. Although the rise of s-Na was relatively steep (noradrenaline group 118.72 ± 34.82 to 131.63 ± 5.04 and midodrine + octreotide group 121.35 ± 34.4 to 128.58 ± 21.08), it did not reach statistical significance, probably because the study was not designed for this outcome [83][34]. Also, a small retrospective observation of 10 patients reported significant increase in s-Na after Midodrine and Octreotide treatment [84][35]
Midodrine was evaluated in multiple conditions associated with liver cirrhosis, because of its convenient oral formulation, no need for vital functions monitoring, and relatively few side effects. Singh et al. tried midodrine in the management of refractory ascites, but also reported the changes of s-Na. Sodium in the standard medical therapy group decreased significantly (after 1 month and after 3 months as well), however, no significant change was observed in the midodrine + standard medical therapy group [85][36]. Mid-sized randomized controlled trial explored the effect of midodrine with albumin vs. placebo on the incidence of complications of cirrhosis among patients on the liver transplant waiting list, where hyponatremia was one of them. Although no significant effects on the overall incidence of complications or mortality were found, patients in the active arm had less severe hyponatremia episodes with the lowest s-Na levels 134 ± 3 vs. 129 ± 5 mEq/L in the placebo group, p = 0.04 [86][37].
Nitric oxide is a major contributor to splanchnic vasodilation in cirrhosis. Therefore, the therapeutic possibilities of Nitric oxide synthase inhibitors have been explored in multiple trials. The results, however, are controversial. It seems that longer infusions (>3 h) administered repeatedly have a positive effect on sodium excretion and renal functions, compared to a single dose [87][38], but no data on the s-Na or AVP concentrations have been reported.

4.2. Antidiuretic Hormone Antagonists

Increased concentrations of AVP may well be the most important mechanism of hypervolemic hyponatremia in cirrhosis. It is not surprising that the antagonists of AVP have been tried in multiple clinical studies. Demeclocycline, a tetracycline derivate, reduces the sensitivity to AVP thus increasing the free water excretion. Clinical usefulness is limited due to frequent nephrotoxicity [88][39]. Centrally acting κ-opioid receptor agonist Niravoline has the ability to decrease the synthesis and release of AVP. Doses between 0.5–1 mg/day have been shown to significantly increase free water excretion and s-Na concentration in patients with cirrhosis. Higher doses also induced reversible confusion and personality changes [89][40]. Further development of this drug has been abandoned and it is not clinically available.
Vassopresin V2 receptor blockers (vaptans) have successfully passed clinical testing and have been approved for the treatment of hyponatremia in SIADH. Further testing evaluated their effectiveness in congestive heart failure and cirrhosis. Multiple studies have documented the increase in free water excretion and increase in s-Na following the administration of vaptans.
Based on the efficient increase in s-Na in SALT-1 and SALT-2 trials in predominantly cardiac patients [90][41], several subsequent studies evaluated the efficacy specifically in hypervolemic hyponatremia associated with liver cirrhosis. A subanalysis of SALT 1 and 2, which contained only cirrhotic patients, was published in 2012 by Cardenas et al. and revealed that tolvaptan caused a mean increase in the area under the curve of s-Na level over the study period by 4.2 ± 3.4 mmol/L compared to 1.2 ± 3.5 mmol/L in the placebo group. Furthermore, the treatment showed the improvement of symptoms measured by the mental component of the SF-36 questionnaire (47.7 vs. 43.3 points in the placebo group). However, after the cessation of the therapy hyponatremia recurred [91][42]. Okita et al. reported similar results, with additional improvement of the ascites and edema [92][43]. This finding has been confirmed in another study from Japan that evaluated tolvaptan with concomitant standard diuretic treatment [93][44]. Tolvaptan remained effective also when administered for more than 50 days [94][45]. Recent data question the efficacy of tolvaptan, particularly in patients with severe hyponatremia. Real-life observations showed response rate (increase in s-Na > 130 mEq/L) in only 20–22% of patients with baseline hyponatremia ≤ 125 or 130 mmol/L [95,96][46][47].
Conivaptan, currently the only FDA-approved short-term parenteral treatment for hypervolemic hyponatremia, unfortunately, does not have available robust clinical data in patients with liver cirrhosis. One RCT with conivaptan included 84 patients with hypervolemic and euvolemic hyponatremia (various causes); however, the proportion of cirrhotics was low (possibly from 1 to 8%) and not precisely reported. Conivaptan significantly increased the s-Na area under the curve over 4 days compared to the placebo. The treatment needed to be discontinued in 4 patients due to serious injection site reactions [97][48]. The only other available publication is a retrospective observation of 24 cirrhotic patients with hyponatremia evaluated for a liver transplant. Conivaptan raised serum sodium in patients on but also off diuretic treatment [98][49].
Lixivaptan was the first of the vaptans that was tried in patients with cirrhosis. Two small RCTs with a short treatment period (7 days) demonstrated dose-related free water excretion and an increase in the s-Na during the treatment period [58,99][9][50]. A larger BALANCE trial, that included 652 patients, was performed in hypervolemic hyponatremia with congestive heart failure. In the treatment group, the change of s-Na at day 7 was 2.5 mmol/L compared to 1.3 mmol/L in the placebo group [100][51]. Based on this modest efficacy, the FDA, in 2012, recommended the use of lixivaptan in hypervolemic hyponatremia [101][52].
Satavaptan has been also evaluated in the setting of cirrhotic hyponatremia in three large studies by Wong et al. Patients were followed for 52 weeks in all three studies. The first study involved patients with uncomplicated ascites that were managed with satavaptan or placebo, both with diuretic treatment. The second and third studies were focused on the refractory ascites that needed repeated large volume paracenteses and patients received satavaptan in combination with diuretics or as a solo treatment. Satavaptan was more effective in the correction of hyponatremia. However, at week 12, no significant difference was observed in the incidence of worsening ascites (study 1) or in the cumulative number of required large-volume paracenteses (studies 2 and 3) between the satavaptan and placebo groups [102][53].
The primary outcomes of most of the referenced studies were the changes in s-Na or symptoms. A meta-analysis published by Dahl et al. tried to summarize the effect of tolvaptan, satavaptan, and lixivaptan on mortality. Twelve studies that included 2266 patients were included. The meta-analysis confirmed the strong effect of vaptans on hyponatremia and partially also the effect on water retention. However, no effect of the vaptan treatment on mortality (RR = 1.06, 95% CI = 0.90–1.26), hepatic encephalopathy (RR = 0.87, 95% CI = 0.73–1.03), variceal bleeding (RR = 1.04, 95% CI = 0.56–1.92), spontaneous bacterial peritonitis (RR = 0.73, 95% CI = 0.53–1.01) or renal impairment (RR = 1.16, 95% CI = 0.88–1.53) was found [103][54].
Adverse effects of vaptans consistently reported in all trials are dry mouth and thirst sensations. More detrimental adverse effects also reported with higher frequency than placebo were dehydration, acute prerenal kidney injury, and hypotension [56][10]. Tolvaptan could also lead to liver injury on its own [104][55], which led the FDA to limit the duration of the treatment to 30 days and recommend the avoidance of this treatment in patients with liver disease, including cirrhosis [105,106][56][57].
Currently, FDA approves only short-term i.v. administration of conivaptan for the treatment of hypervolemic hyponatremia, with special precautions in patients with hepatic impairment. In Europe, only tolvaptan from the vaptan group has been approved by EMEA and only for the treatment of SIADH. The use of vaptans to treat hypervolemic hyponatremia in cirrhosis is limited to clinical trials in Europe (EASL), also there is no clear recommendation in the AASLD guidelines, only acknowledgment, that for short-term (≤30 days) treatment may raise serum sodium level [53,54][5][6].

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