EASL Clinical Practice Guidelines

Hyponatremia

Hyponatremia is common in patients with decompensated cirrhosis and is related to impaired solute-free water excretion secondary to non-osmotic hypersecretion of vasopressin (the antidiuretic hormone), which results in a disproportionate retention of water relative to sodium retention [[163], [164], [165], [166]]. Hyponatremia in cirrhosis is arbitrarily defined when serum sodium concentration decreases below 130 mmol/L [163], but reductions below 135 mmol/L should also be considered as hyponatremia, according to recent guidelines on hyponatremia in the general patient population [167].

Patients with cirrhosis may develop two types of hyponatremia: hypovolemic and hypervolemic. Hypervolemic hyponatremia is the most common and is characterized by low serum sodium levels with expansion of the extracellular fluid volume, with ascites and edema. It may occur spontaneously or as a consequence of excessive hypotonic fluids (i.e., 5% dextrose) or secondary to complications of cirrhosis, particularly bacterial infections. By contrast, hypovolemic hyponatremia is less common and is characterized by low serum sodium levels and absence of ascites and edema, and is most frequently secondary to excessive diuretic therapy.

Serum sodium concentration is an important marker of prognosis in cirrhosis and the presence of hyponatremia is associated with an impaired survival [[64], [65], [168], [169], [170], [171], [172], [173], [174]]. Moreover, hyponatremia may also be associated with an increased morbidity, particularly neurological complications, and reduced survival after transplantation [[175], [176], [177]], although results of studies show discrepant findings with respect to survival.

Management of hyponatremia

It is generally considered that hyponatremia should be treated when serum sodium is lower than 130 mmol/L, although there is no good evidence as to what is the level of serum sodium in which treatment should be started.

The treatment of hypovolemic hyponatremia consists of administration of sodium together with identification of the causative factor (usually excessive diuretic administration) and will not be considered further in these guidelines.

The key of the management of hypervolemic hyponatremia is to induce a negative water balance with the aim of normalizing the increased total body water, which would result in an improvement of serum sodium concentration. Fluid restriction has been the standard of care but is seldom effective. It is the clinical experience that fluid restriction is helpful in preventing a further decrease in serum sodium levels, although it is rarely effective in improving serum sodium concentration. The lack of efficacy is probably due to the fact that in practice total daily fluid intake cannot be restricted to less than 1 L/day.

Although hypertonic sodium chloride administration has been used commonly in severe hypervolemic hyponatremia, its efficacy is partial, usually short-lived, and increases the amount of ascites and edema. The administration of albumin appears to improve serum sodium concentration, but more information is needed [[178], [179]].

The pathophysiologically-oriented treatment of hyponatremia consists of improving solute-free water excretion which is markedly impaired in these patients. Early attempts using agents such as demeclocycline or κ-opioid agonists were unsuccessful because of side effects [[180], [181], [182], [183]]. In recent years, the pharmacological approach to treatment of hypervolemic hyponatremia has made a step forward with the discovery of vaptans, drugs that are active orally and cause a selective blockade of the V2-receptors of AVP in the principal cells of the collecting ducts [[184], [185], [186]]. These drugs are effective in improving serum sodium concentration in conditions associated with high vasopressin levels, such as the syndrome of inappropriate antidiuretic hormone secretion (SIADH), heart failure, or cirrhosis [[101], [184], [187], [188], [189], [190], [191]]. The results of these studies consistently demonstrate that the administration of vaptans for a short period of time (1 week to 1 month in most of the studies) is associated with an increased urine volume and solute-free water excretion and improvement of the low serum sodium levels in 45–82% of patients. No significant changes have been observed in renal function, urine sodium, circulatory function, and activity of the renin–angiotensin–aldosterone system. The most frequent side effect is thirst. Potential theoretical concerns of the administration of vaptans in patients with cirrhosis include hypernatremia, dehydration, renal impairment, and osmotic demyelination syndrome owing to a too rapid increase in serum sodium concentration. However, in the studies reported, the frequency of hypernatremia, dehydration, and renal impairment has been very low and no case of osmotic demyelination syndrome has been reported. Nevertheless, these complications should be taken into account and treatment should always be started in the hospital with close clinical monitoring and assessment of serum sodium levels, to avoid increases of serum sodium of more than 8–10 mmol/L/day. Vaptans should not be given to patients in an altered mental state (i.e., encephalopathy) who cannot drink appropriate amounts of fluid because of the risk of dehydration and hypernatremia. Vaptans are metabolized by CYP3A enzymes in the liver; therefore, drugs that are strong inhibitors of CYP3A such as ketoconazole, grapefruit juice, and clarithromycin among others, increase the exposure to vaptans and may be associated with large increases in serum sodium concentration. Conversely, drugs that are inducers of the CYP3A system, such as rifampin, barbiturates, and phenytoin, may decrease the effectiveness of vaptans.

Tolvaptan has been recently approved in the USA for the management of severe hypervolemic hyponatremia (<125 mmol/L) associated with cirrhosis, ascites, heart failure, and the SIADH. In Europe the drug is currently only licensed for the treatment of SIADH. Conivaptan is also approved in the USA for the short-term (5 day) intravenous treatment of hypervolemic hyponatremia associated with different conditions. Treatment of tolvaptan is started with 15 mg/day and titrated progressively to 30 and 60 mg/day, if needed, according to changes in serum sodium concentration. In randomized studies, a slightly increased frequency of gastrointestinal bleeding was reported in patients receiving tolvaptan compared to that in patients treated with placebo. No differences in the incidence of other side effects were observed. Nevertheless, it should be pointed out that tolvaptan was given for a period of 1 month and only limited long-term safety data exists with the use of this drug. Long-term, placebo-controlled studies in patients with cirrhosis treated with tolvaptan are clearly needed. No prospective evaluation on the efficacy and safety of conivaptan has been performed in patients with cirrhosis and hyponatremia.

As discussed previously, a phase-3 randomized double-blind placebo-controlled study comparing the efficacy of long-term treatment with satavaptan in combination with diuretics aimed at preventing ascites recurrence in patients with cirrhosis following LVP showed an increased frequency of complications and reduced survival in patients receiving satavaptan compared to those receiving placebo [104].

Recommendations It is important to differentiate hypovolemic from hypervolemic hyponatremia. Hypovolemic hyponatremia is characterized by low serum sodium concentrations in the absence of ascites and edema, and usually occurs after a prolonged negative sodium balance with marked loss of extracellular fluid. Management consists of administration of normal saline and treatment of the cause (usually diuretic withdrawal) (Level A1).

Fluid restriction to 1000 ml/day is effective in increasing serum sodium concentration in only a minority of patients with hypervolemic hyponatremia, but may be effective in preventing a further reduction in serum sodium levels (Level A1). There are no data to support the use of either normal or hypertonic saline in the management of hypervolemic hyponatremia (Level A1). Albumin administration might be effective but data are very limited to support its use currently (Level B2).

Treatment with vaptans may be considered in patients with severe hypervolemic hyponatremia (<125 mmol/L). Tolvaptan is licensed in some countries for oral treatment. Conivaptan is only licensed in some countries for short-term intravenous treatment. Treatment with tolvaptan should be started in the hospital and the dose titrated to achieve a slow increase in serum sodium. Serum sodium should be monitored closely particularly during the first days of treatment and whenever the dose of the drug is increased. Rapid increases in serum sodium concentration (>8–10 mmol/day) should be avoided to prevent the occurrence of osmotic demyelination syndrome. Neither fluid restriction nor administration of saline should be used in combination with vaptans to avoid a too rapid increase in serum sodium concentration. Patients may be discharged after serum sodium levels are stable and no further increase in the dose of the drug is required. Concomitant treatment with drugs that are either potent inhibitors or inducers of the CYP3A should be avoided. The duration of treatment with vaptans is not known. Safety has only been established for short-term treatment (1 month) (Level B1).