Treatment

Treatment options

Treatment for HE aims to normalise neurophysiological functions by eliminating causative factors and reducing ammonia levels. If successful, treatment results in improvement of cerebral neurotransmission, astroglial function and ultimately in clinical improvement. As the underlying disease is not eliminated the patient remains at risk of a reoccurrence of HE, even after successful therapy.1

Treatment should be initiated in the early stages of HE as patients suffer from fatigue, show disturbances of their sleeping and waking cycle and are at particular risk when driving and performing manual work.

Treatment should be given to any patient experiencing any form of clinically manifest HE or in a situation which could lead to clinically manifest HE. In subclinical HE, treatment should be given in accordance with the everyday demands on the patient i.e. their job and fitness to drive.1

The therapeutic possibilities in treating HE:1

Eliminate precipitating factors

The first step should be the identification and elimination of precipitating factors, as these can play a role in 70-80% of HE patients:1

  • Stop gastrointestinal bleeding
  • Treatment of anaemia (aim: haematocrit = 30%)
  • Treatment of acidosis with bicarbonate
  • Correction of electrolytes to within normal range
  • Discontinue diuretics and sedatives
  • Treatment of infections with antibiotics
  • Abstinence from alcohol

Successfully eliminating the triggering factors can positively influence the progression of HE.

Decreasing ammonia production

Intestinal cleansing or inhibition of intestinal ammonia production would result in a decrease of ammoniagenic substrates. This can be accomplished by synthetic, non-absorbable disaccharides (lactulose) or non-absorbable antibiotics (e.g. rifaximin).1

  • Lactulose

Lactulose (along with lactilol) is a nonabsorbable disaccharide that has been in common clinical use since the early 1970s. Lactulose is degraded by intestinal bacteria to lactic acid and other organic acids. It appears to inhibit intestinal ammonia production by a number of mechanisms. The conversion of lactulose to lactic acid results in acidification of the gut lumen and this promotes conversion of NH4+ to NH3 and the subsequent passage of NH3 from tissues into the lumen. Gut acidification inhibits ammoniagenic coliform bacteria, leading to increased levels of nonammoniagenic lactobacilli. Lactulose also works as a cathartic, reducing the overall colonic bacterial load. A 2013 meta-analysis affirmed the clinical utility of lactulose in the management of HE.2

The mode of action of lactulose in the treatment of HE1

  • Antibiotics1

The use of poorly absorbed antibiotics such (e.g., rifaximin, paromomycin, neomycin, metronidazole) has been indicated. Recommended dose is up to 4-6 g/d for at most 7 days. Rifaximin is now available for long-term use. These antibiotics act to reduce the physiological flora in the large intestine, therefore reducing the production of ammonia. This treatment option is expensive and associated with considerable side effects (diarrhoea, malabsorption, urticaria, infection ) with the added risk of antibiotic resistance.

Increasing detoxification of ammonia in liver and muscle

  • L-ornithine L-aspartate (LOLA; Hepa-Merz®)1

Therapeutic administration of LOLA increases ammonia affects detoxification in two ways:

  1. Activation of the urea cycle in the residual hepatocytes of the liver, through provision of the metabolic substrates ornithine and aspartate, these promote glutamine formation, thereby stimulating ammonia detoxification via glutamine synthesis in the liver, in the brain and muscle;
  2. In the presence of hyperammonemia and collateral circulation or a hepatic detoxification deficit, ammonia detoxification via glutamine synthesis in the brain and muscle tissue makes an additional contribution to the ammonia-lowering effect of LOLA.
  • Benzodiazepine antagonists1

These work by inhibiting endogenous benzodiazepine excess thus counteracting the neurodepressive effects of GABAergic activation. Flumazenil (Anexate®) is a commonly used benzodiazepine antagonist.

The use of benzodiazepine antagonists in the treatment of HE has been supported by study data (> 90% improvement in HE III/IV)* and they are considered easy to use (0.5 mg i.v.). The principle disadvantages of this treatment option is that the efficacy is extremely short-lived (30-60 min, max in 1 study 5.5 h), also the effect is unpredictable in patients who have received prior treatment with exogenous benzodiazepines (e.g. for gastroscopy).

  • Silymarin1

Silymarin is a phytopharmaceutical agent (extract of milk thistle seeds). The extract contains an active compound called flavonoid silibinin. It acts to protect the liver by

  • Preventing entry of toxins into liver
  • Supporting protein synthesis
  • Stimulating regeneration of damaged hepatocytes

In clinical studies there is an improvement in laboratory parameters and histological findings (less fibrosis).

Summary of evidence-based effectiveness of drug therapy for treating HE

Therapeutic
principle
Active
substance
Results of
placebo controlled
trials
Reduction of
intestinal ammonia
production
Lactulose enema
Better than placebo1
Oral lactulose
Better than placebo
Neomycin
Not better than placebo
Increading
extra-intestinal
ammonia detoxification
L-ornithine-L-aspartate
Better than placebo
Correcting amino
acid imbalance
LBrnached-chain amino acids (BCAA)
Better than placebo
Benzodiacepine
Rezeptor antagonist
Flumazenil
Better than placebo

1. Merz Data on file.
2. Gluud LL et al. Lactulose, rifaximin or branched chain amino acids for hepatic encephalopathy: what is the evidence?. Metab Brain Dis. 2013;28(2):221-5.

Hepa-Merz® – Summary of prescribing information

Hepa-Merz® Granules. Composition: One sachet with 5 g of Granules contains: Active substance: 3 g L-ornithine- L-aspartate. Excipients: citric acid, aspartame (E951), povidone 25, fructose, flavorings, orange yellow S (E110). Note for diabetics: One sachet of Hepa-Merz® Granules contains 1.13 g of fructose (corresponds to approx. 0.11 BU). Therapeutic indications: Treatment of concomitant disease and sequelae due to impaired detoxification activity (e.g. in cirrhosis of the liver) with the symptoms of latent and manifest hepatic encephalopathy. Contraindications: Absolute: Hypersensitivity to L-ornithine-L-aspartate, orange yellow S or any of the other excipients. Severely impaired renal function (renal insufficiency). A serum creatinine value over 3 mg/100 ml can be used as a guideline value. Relative: Pregnancy and lactation: No clinical data are available relating to intake of Hepa-Merz® Granules in children and during pregnancy. No exhaustive animal studies have been performed for L-ornithine-L-aspartate, to investigate its toxicity in relation to reproduction. Administration of Hepa-Merz® Granules during pregnancy should therefore be avoided. If, however, treatment with Hepa-Merz® Granules is considered necessary, careful consideration should be given to the benefit versus risk ratio. It is not known whether L-ornithine-L-aspartate is excreted into the breast milk. Administration of Hepa-Merz® Granules should therefore be avoided during lactation. If, however, treatment with Hepa-Merz® Granules is considered necessary, careful consideration should be given to the benefit versus risk ratio. No data regarding fertility. Undesirable effects: Uncommon (³ 1/1,000 to < 1/100): Nausea, vomiting, stomach ache, flatulence, diarrhea. Very rare (< 1/10,000): Pain in the limbs. These undesirable effects are usually transient and do not require withdrawal of the medicine. Orange yellow S (E110) can trigger allergic reactions. Warnings: Hepa-Merz® Granules contain fructose. Patients with rare hereditary problems of fructose intolerance should not take this medicine. Aspartame (E951): Contains a source of phenylalanine. May be harmful for people with phenylketonuria. Further precautions: As a result of the disease, the ability to drive and operate machinery may be impaired during treatment with L-ornithine-L-aspartate.

Hepa-Merz® Granules. Composition: One sachet with 5 g of Granules contains: Active substance: 3 g L-ornithine- L-aspartate. Excipients: citric acid, saccharin sodium, sodium cyclamate, povidone 25, fructose, flavorings, orange yellow S (E110). Note for diabetics: One sachet of Hepa-Merz® Granules contains 1.13 g of fructose (corresponds to approx. 0.11 BU). Therapeutic indications: Treatment of concomitant disease and sequelae due to impaired detoxification activity (e.g. in cirrhosis of the liver) with the symptoms of latent and manifest hepatic encephalopathy. Contraindications: Absolute: Hypersensitivity to L-ornithine-L-aspartate, orange yellow S or any of the other excipients. Severely impaired renal function (renal insufficiency). A serum creatinine value over 3 mg/100 ml can be used as a guideline value. Relative: Pregnancy and lactation: No clinical data are available relating to intake of Hepa-Merz® Granules in children and during pregnancy. No exhaustive animal studies have been performed for L-ornithine-L-aspartate, to investigate its toxicity in relation to reproduction. Administration of Hepa-Merz® Granules during pregnancy should therefore be avoided. If, however, treatment with Hepa-Merz® Granules is considered necessary, careful consideration should be given to the benefit versus risk ratio. It is not known whether L-ornithine-L-aspartate is excreted into the breast milk. Administration of Hepa-Merz® Granules should therefore be avoided during lactation. If, however, treatment with Hepa-Merz® Granules is considered necessary, careful consideration should be given to the benefit versus risk ratio. No data regarding fertility. Undesirable effects: Uncommon (³ 1/1,000 to < 1/100): Nausea, vomiting, stomach ache, flatulence, diarrhea. Very rare (< 1/10,000): Pain in the limbs. These undesirable effects are usually transient and do not require withdrawal of the medicine. Orange yellow S (E110) can trigger allergic reactions. Warnings : Hepa-Merz® Granules contain fructose. Patients with rare hereditary problems of fructose intolerance should not take this medicine. Further precautions: As a result of the disease, the ability to drive and operate machinery may be impaired during treatment with L-ornithine-L-aspartate.

Hepa-Merz® Infusion concentrate. Composition: One ampoule of 10 ml contains: Active substance: 5 g L-ornithine-L-aspartate. Excipients: Water for injections. Therapeutic indications: Latent and manifest hepatic encephalopathy. Contraindications: Absolute: Hypersensitivity to L-ornithine-L-aspartate. Severe renal impairment (renal failure). A serum creatinine level in excess of 3 mg/100 ml can be taken as a guide. Relative: Pregnancy and lactation: There are no clinical data available on the use of Hepa-Merz® Infusion concentrate in children and during pregnancy. L-ornithine L-aspartate has been investigated for reproduction toxicity only to a limited extent in experimental animal studies. The administration of Hepa-Merz® Infusion concentrate in pregnancy should therefore be avoided. If treatment with Hepa-Merz® is nevertheless thought to be necessary, the benefits and risks should be carefully assessed. It is not known whether L-ornithine-L-aspartate passes into breast milk. Administration of Hepa-Merz® should therefore be avoided during lactation. If treatment with Hepa-Merz® is nevertheless thought to be necessary, the benefits and risks should be carefully assessed. No data regarding fertility. Undesirable effects: Uncommon (³ 1/1,000 to < 1/100): Nausea. Rare (³ 1/10,000 to < 1/1,000): vomiting. Frequency not known (frequency cannot be estimated from the available data): hypersensitivity, anaphylactic reaction. Generally however, the gastrointestinal symptoms are transient, and do not necessitate discontinuation of treatment. They disappear on reduction of the dose or the infusion rate. Further precautions: Hepa-Merz concentrate for solution for infusion can be mixed with the usual infusion solutions. So far, no peculiarities have been observed with regard to miscibility. However, the ampoules should be admixed to the infusion solution only immediately before application. At high doses of Hepa-Merz® Infusion concentrate, serum and urine urea levels should be monitored. If liver function is substantially impaired, the infusion rate must be adjusted to the individual patient in order to prevent nausea and vomiting. Depending on the underlying disease, the ability to drive and operate machines may also be impaired on treatment with L-ornithine L-aspartate. Hepa-Merz® Infusion concentrate must not be injected into an artery. Status: January 2016. Merz Pharmaceuticals GmbH, 60048 Frankfurt.