Diagnosis

Psychometric tests

Hepatic encephalopathy (HE) represents a continuum of neuropsychiatric changes and altered consciousness. Progression of covert HE (CHE) to overt HE (OHE) and its impact of quality of life make its early diagnosis imperative. Despite the availability of several diagnostic techniques ranging from simple clinical scales to sophisticated computerised tests, diagnosis remains a challenge due to the time, cost and personnel involved. Psychometric tests therefore appear promising due to their high sensitivity and low cost, but results are variable depending on age and education.1

Well-validated and easily quantifiable psychometric test procedures, which determine deficits in psychomotor performance speed and visual constructive ability, are the number connection test (NCT), versions A and B, the digit symbol test, the serial dotting test, and the line tracing test. These tests are simple to explain to the patient, quick to perform, and easy to evaluate.1

The portosystemic encephalopathy (PSE) syndrome test is a standardised assessment tool especially useful for the diagnosis of minimal hepatic encephalopathy (MHE) that collects the number connection test, the digit symbol test, and the line tracing test, and adds the pointing in the circle test.1

The recently developed EncephalApp-Stroop is a high-sensitivity test to screen for covert HE and meets the need for a brief screening tool for covert HE that does do not require psychological expertise in administration and interpretation.1

Number connection test, versions A (NCT-A) and B (NCT-B)

In NCT-A the numbers have to be joined consecutively in ascending numerical order (1, 2, 3…) as quickly as possible. In the more complicated NCT-B, the numbers and letters must be connected alternately numerically and alphabetically (1, A, 2, B…). Evaluation of both tests is based on the time required to complete the test.2

Digit-symbol test and the tracking test, examples of psychometric tests which can be used as a diagnostic tool in patients with suspected HE

Psychometric tests are simple to administer and appropriate for the diagnosis of minimal HE and HE.1

Disadvantages: learning effects, strong emphasis on fine motor skills

Using EncephalApp-Stroop

EncephalApp-Stroop is a high-sensitivity test to screen for covert HE and meets the need for a brief screening tool for covert HE that does do not require psychological expertise in administration and interpretation. Stroop tasks have been used for a long time to evaluate psychomotor speed and cognitive flexibility. They are now available as a new Smartphone app that is available on iTunes. The most recent of these, the EncephalApp-Stroop app, is free to download. The age-based cut-offs for EncephalApp-Stroop are highly sensitive for covert HE screening and could be used to guide future dedicated testing in cirrhosis. The app has good discriminative validity and good test-retest reliability. It is easy to perform and administer (being patient-controlled) and within 5 min is able to give >88% sensitivity for the diagnosis of MHE and cognitive dysfunction in cirrhosis.1

EncephalApp-Stroop

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EncephalApp-Stroop

EncephalApp-Stroop features and functionality1

EncephalApp is a series of applications designed to evaluate patients with liver disease; the first of which is a Stroop task.
It has neutral and incongruent stimuli only.

Stroop “Off” state No words, just symbols

The task is to correctly and rapidly press the colour corresponding to the colour of the symbols presented.

Stroop “On” state Words in discordant colours

The task is to correctly and rapidly press the colour corresponding to the colour of the word presented, not the colour it means.

Stroop outputs

  • Each run has 10 stimuli
  • One mistake stops it
  • 5 complete runs in off and on state are needed
  • Outputs in “on” and “off” state:
  1. Number of runs needed to achieve 5 correct runs
  2. Time needed to complete those 5 correct runs

1. Nabi E, Bajaj JS. Useful tests for hepatic encephalopathy in clinical practice. Curr Gastroenterol Rep. 2014;16(1):362.
2. Weissenborn K et al. Neuropsychological characterization of hepatic encephalopathy. J Hepatol. 2001;34:768-773.

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.