Diagnosis

Blood data

Every single insult of the liver leads to molecular changes in hepatic cells with concomitant changes in corresponding biochemical parameters. A biochemical pattern, which deviates from the norm, allows conclusions to be drawn about the nature and location of the liver damage.1

There are a range of basic blood tests that should be conducted in the initial diagnosis of HE, these include:2

  • Liver function tests
  • Blood glucose
  • Electrolytes (with calcium and phosphate)
  • Creatinine, urea
  • Drug screening
  • Alcohol level
  • Blood gas analysis
  • Fasting ammonia concentration
  • Cultures (blood, urine, sputum, faeces)
  • Hepatitis and HIV
  • Ascites (cells and culture)
  • Blood picture, c-reactive protein, erythrocyte sedimentation rate

An overview of liver enzymes which should be investigated1

Liver cell
damage
Cholestasis
Liver
function
Mesenchymal
activity
Immunology/
Serology
  ALT
Alkaline phosphatase
Indirect bilirubin
γ-Globulin
AH-antibody (ab) HBs-antigen (ag)
  AST
LAP
Cholinestersase
IgA
HBs-ab HBc-ab
GLDH
  γ- GT
Quick`s test
IgG
HBe-ag HBe-ab
  γ-GT
  GLDH
Albumin
IgM
HBV-DNA HCV-ab
  LDH
Direct bilirubin
Bile acid
Copper
HDV ANA
Iron/Ferritin
Bile acid
Fibrinogen
Procollagen-III-peptide
AMA SMA
Zinc
Cholesterol
Ammonia
LMA LKM
Copper
Indocyanine green
LE
5´-nucleotidase
Galactose
α1-Fetoprotein

Enzymatic activity Synthesis capability Excretory capability

Liver synthesis function

Albumin is the most important binding and transport protein, synthesised only in the liver. Daily synthesis rate: 15-17 g (12-20% of total protein synthesised in the liver), which can be doubled when necessary. Average daily loss is 1 g via the intestine, 15 mg via the kidneys. Albumin is an important parameter for hepatic albumin synthesis capacity. Low serum albumin levels indicate poor liver function however in chronic liver diseases albumin levels are usually normal until significant liver damage and cirrhosis is present.1

Quick test (TPT)

Prothrombin is synthesised in the liver, the thromboplastin time (TPT) is a parameter for detecting disturbances in the exogenous blood coagulation system (factors II, V, VII, and X). TPT is determined by measurement of the coagulation time after incubation of citrated plasma with tissue thromboplastin and calcium ions (“Quick test”). Pathological altered prothrombin times indicate an impaired synthesis function of the liver.1

Liver metabolic function

Ammonia

Ammonia arises from endogenous protein metabolism and it can be formed in all organs of the body. The majority of the ammonia is synthesised by the intestinal flora and is then absorbed into the blood. At physiological pH (~7), about 98% of the ammonia is protonated (NH4+) and 2% is gas (NH3). Ammonia is 70% eliminated via the urea cycle (periportal) and 30% via glutamine synthesis (perivenous). Plasma ammonia levels are elevated in severe liver disease.1

Enzymes

The range of enzymes which can be tested to aid in the diagnosis of HE.1

Enzyme Type
Name
Excretion enzymes
AP (alkaline phosphatase) LAP (leucine aminopeptidase) γ-GT (γ-glutamyl transferase) 5´-Nucleotidase
Secretion enzyme
ChE (Cholinesterase)
Indicator enzymes
cytoplasmatic
ALT (alanine aminotransferase) LDH (lactate dehydrogenase )
mitochondrial
GLDH (glutamate dehydrogenase)
endoplasmatic
γ-GT, ChE
mitochondrial/ cytoplasmatic
AST (aspartate aminotransferase)

Liver Function Tests (or Liver Enzymes)

Includes blood tests that assess the general health of the liver. When elevated above normal values, the ALT (alanine aminotransferase) and AST (aspartate aminotransferase) tests indicate liver damage. They are enzymes located in liver cells that can leak out into the bloodstream when liver cells are injured.

Alanine Transaminase (ALT):

  • Produced in hepatocytes
  • Very specific marker of hepatocellular injury
  • Relatively low concentrations in other tissues so more specific than AST
  • Levels fluctuate during the day
  • Rise may occur with the use of certain drugs or during periods of strenuous exercise.

Aspartate Transaminase (AST):

  • Occurs in two isoenzymes, indistinguishable on standard AST assays.
  • The mitochondrial isoenzyme is produced in hepatocytes and reacts to membrane stresses in a similar way to ALT.
  • The cytosolic isoenzyme is present in skeletal muscle, heart muscle and kidney tissue.
  • Caution must be exercised in its use to evaluate hepatocellular damage.
  • Usually rises in conjunction with ALT to indicate hepatocellular injury: a hepatitic picture.

Alkaline Phosphatase (ALP):

  • A group of isoenzymes that act to dephosphorylate a variety of molecules throughout the body.
  • Produced in the membranes of cells lining bile ducts and canaliculi.
  • Released in response to the accumulation of bile salts or cholestasis.
  • Non-hepatic production in the kidney, intestine, leukocytes, placenta and bone.
  • Physiological rise in pregnancy or in growing children.
  • Pathological rise in Paget’s disease, renal disease and with bone metastases.

Gamma-glutamyl transferase (GGT)2:

  • Present in liver, kidney, pancreas and intestine.
  • It is found in the microsomes of hepatocytes and biliary epithelial cells.
  • Elevation of GGT in association with a rise in ALP is highly suggestive of a biliary tract obstruction and is known as a cholestatic picture.
  • Subject to rise with hepatic enzyme induction due to chronic alcohol use or drugs such as rifampicin and phenytoin.

Overview of normal liver values2:

Serum total Bilirubin
3-17 micromole/litter
Alanine aminotransferase (ALT)
up to 42 u/l
Asparatate amino transferase (AST)
up to 37 u/l
Serum Alkaline Phosphatase (ALP)
60-306 u/l
Total Protein
60-80 g/l
Albumin
40-50 g/l
Gamma Glutamyltransferase GGT
11-60 u/l

ALP
AST
ALT
GGT
Other
Cholestasis

Primary Biliary Cirrhosis

↑↑

↑↑↑

↑

↑/N

↑

↑/N

↑↑

↑↑

AST:ALT<1.5 suggests extrathepatic
AST:ALT>1.5 suggests intrahepatic

Raised AST:ALT may indicate cirrhosis

Primary Selerosing Cholangitis
Alcoholic liver disease
↑↑

↑/N

↑/N

↑

↑/N

↑

↑↑

↑↑

AST:ALT>1 may indicate cirrhosis
AST:ALT>1.12 indicates risk of oesophageal varices
AST:ALT>2
NAFLD/NASH

Wilson’s disease

↑/N

↑

↑

↑↑

↑

↑↑

↑

↑

AST:ALT<1 unless cirrhosis present

ALP:bilirubin < 4
AST:ALT>2

Hepatitis B/C

Autoimmune hepatitis

↑

↑

↑↑/N

↑↑

↑↑/N

↑↑

↑

↑

AST:ALT>1 indicates cirrhosis
AST:platelet>1.5 indicates at least moderate fibrosis
Enzymes may all be normal
Persistently high transaminases indicate poor prognosis
Ischaemic injury/shock liver

Toxic injury

↑

↑

↑↑↑

↑↑↑

↑↑↑

↑↑↑

↑

↑

Further laboratory tests

Immunoglobulin1

Immunoglobulin measurement is not suitable for general use in liver diagnosis; evaluation may only be useful in combination with other laboratory tests. If ALT levels are persistently high, viral hepatitis serology should be assessed.

Iron/ferritin/copper constellation1

This may be useful for a detailed liver diagnosis and differential diagnosis of cholestasis and jaundice. Plasma protein fraction (α1-Fetoprotein) is useful as a marker of hepatocellular carcinoma.

1. McClatchey, Kenneth D. Clinical Laboratory Medicine, 2nd Edition. Kenneth D. McClatchey. Philadelphia: Lippincott Williams Wilkins, 2002, 1936 pp., ISBN 0-683-30751-7.

2. Hall P, Cash J. What is the real function of the liver ‘function’ tests? Ulster Med J. 2012 Jan;81(1):30-6.

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.