Liver Diseases And Hepatic Encephalopathy


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Liver Diseases And Hepatic Encephalopathy

  1. 1. LIVER DISEASES AND HEPATIC ENCEPHALOPATHY Scientific Product Monograph Merz Pharmaceuticals GmbH Frankfurt am Main
  2. 2. LIVER DISEASES AND HEPATIC ENCEPHALOPATHY Scientific Product Monograph Merz Pharmaceuticals GmbH Frankfurt am Main
  3. 3. CONTENTS Product profile 6 6 Clinical results with Hepa-Merz® 72 6.1 Clinical research with Hepa-Merz® 74 1 Liver function and hepatic encephalopathy 9 6.2 Experimental clinical studies with Hepa-Merz® 75 1.1 Ammonia metabolism and detoxification function of the liver 9 6.2.1 Effects of Hepa-Merz® on ammonia concentration 75 1.2 Liver diseases as the cause of hepatic encephalopathy 13 6.2.2 Effects of Hepa-Merz® on protein synthesis in muscle 82 6.2.3 Effects of Hepa-Merz® on neurometabolites 84 2 Hepatic encephalopathy – clinical picture and pathogenesis 23 6.3 Clinical results with intravenous Hepa-Merz® therapy 86 2.1 Definition and clinical forms of hepatic encephalopathy 23 6.3.1 Hepa-Merz® infusion in comparison with placebo 86 2.2 Precipitating factors in hepatic encephalopathy 27 6.3.2 Meta-analysis of placebo-controlled trials 93 2.3 Pathogenesis of hepatic encephalopathy 30 6.4 Clinical results with oral Hepa-Merz® therapy 96 2.3.1 Neuropathological changes 30 6.4.1 Hepa-Merz® Granules in comparison with placebo 96 2.3.2 Ammonia and the glial hypothesis 32 6.4.2 Hepa-Merz® Granules in the medical practice 100 2.3.3 Additional pathological mechanisms 35 6.4.3 Hepa-Merz® Granules in comparison with lactulose 105 6.5 Summary of results with Hepa-Merz® 106 3 Diagnosis of hepatic encephalopathy 40 3.1 Diagnostic procedures 40 7 Safety and tolerability 108 3.2 Early diagnosis 42 3.3 Criteria for assessing degree of severity 8 Chemistry, toxicology and pharmacokinetics of Hepa-Merz® 110 and monitoring the course of disease 45 8.1 Chemico-physical data 110 8.2 Toxicology 111 4 Treatment of hepatic encephalopathy 51 8.3 Pharmacokinetics 111 4.1 General therapeutic concepts 51 4.2 Dietary therapy 52 9 Basic information 112 4.3 Drug therapy 53 10 Abbreviations 117 5 Mechanism of action and pharmacodynamics of Hepa-Merz® 59 11 References 119 5.1 Mechanism of action 59 5.2 Pharmacodynamic effects in animal experiments 62 5.2.1 Effects of Hepa-Merz® on ammonia metabolism 62 5.2.2 Effects of Hepa-Merz® on metabolism in the brain 64 4 5
  4. 4. PRODUCT PROFILE Hepatic The clinical picture of hepatic encephalopathy (HE) ari- mechanisms contribute to the neurotoxins present in encephalopathy ses as a complication of chronic and, more rarely, acute portal vein blood reaching the brain via the systemic cir- liver disease. It is a potentially reversible functional culation. Once there, neurotoxic ammonia in particular disorder of the brain with neurological and psychiatric disrupts the function of neurones and astrocytes, giving symptoms which may occur with different degrees of rise to the symptoms of hepatic encephalopathy. An severity (HE grades 0-4) and in varying combinations. important aim of treatment is therefore the reduction of Deficits of psychomotor function can be demonstrated the ammonia present in the body by lowering the in the early stages; even at the start, these represent a amount of ammonia produced and increasing its detox- certain risk especially at work and in traffic. At first there ification. are mild non-specific disturbances of sleep, drive, mood and cognitive function. As the condition prog- The active ingredient of Hepa-Merz® infusion concen- L-ornithine- resses, symptoms of psychomotor retardation and neuro- trate, granules and chewable tablets is L-ornithine- L-aspartate muscular disturbances (e.g. asterixis) occur as well as L-aspartate, the salt of the natural amino acids ornithine lowers neurotoxic NH3 disorientation and memory defects. With higher grades and aspartate. Through the mechanism of substrate of HE, the clinical picture is characterised by increas- activation, the two substances stimulate the urea cycle ingly altered levels of consciousness (hepatic coma). (which metabolises ammonia to urea) in the liver and The early diagnosis of hepatic encephalopathy is of glutamine synthesis in the liver, muscle and brain. Urea great importance for the future course of the condition and glutamine (after further metabolism) can be excret- and is possible with e.g. psychometric tests that are ed via the kidneys. L-ornithine-L-aspartate thus activa- easy to perform. tes the two important metabolic pathways in the human body for the detoxification of ammonia. Functional impairment The most common cause of hepatic encephalopathy is of the liver cirrhosis of the liver. Hepatic encephalopathy occurs in L-ornithine-L-aspartate has been used for many years L-ornithine- up to 70% of patients with cirrhosis at some time during for the treatment of conditions associated with impaired L-aspartate the course of their disease. These patients in particular hepatic detoxification (e.g. in cirrhosis of the liver) and is effective should be carefully monitored for signs of hepatic en- its sequelae, when there are symptoms of minimal (sub- and well-tolerated cephalopathy. Increasing structural replacement with con- clinical) and overt hepatic encephalopathy. Hepa-Merz® nective tissue leads to the loss of functioning hepatic is usually well tolerated or very well tolerated. parenchymal tissue and a reduction in the detoxification capacity of the liver. In addition, developing portal In the most recent clinical trials, the efficacy of Hepa- L-ornithine- hypertension leads to the formation of a collateral circu- Merz® infusion concentrate and granules was tested L-aspartate lation through which non-detoxified blood can by-pass against placebo. L-ornithine-L-aspartate showed a sta- evidence-based the liver to reach the systemic circulation. Both these tistically significant effect with respect to an improve- medicine 6 7
  5. 5. 1 LIVER FUNCTION AND HEPATIC ENCEPHALOPATHY ment in mental state (reduction in the HE grade), in- Hepatic encephalopathy is a complication of both chronic creased detoxification (reduction of the ammonia con- and acute liver diseases. The most common underlying centration in the blood) and positive effects on psycho- cause is the reduced detoxification capacity of the motor function (reduction of time required in the number damaged liver in combination with a collateral porto- connection test). With these findings, evidence-based systemic circulation through which ammonia-containing medicine criteria for demonstrating efficacy have been blood by-passes the liver to reach the systemic circula- fulfilled. tion. 1.1 Ammonia metabolism and detoxifi- Summary: cation function of the liver The efficacy of Hepa-Merz® infusion concentrate and granules in the treatment of minimal (subclinical) and overt hepatic encephalopathy in An important function of the liver as a metabolic organ Ammonia production liver disease associated with impaired hepatic detoxification (e.g. in is the detoxification of ammonia produced from nitro- in the intestine, cirrhosis of the liver) has been clearly demonstrated in placebo-control- gen-containing compounds. In the hepatic cells ammo- muscle and kidneys led clinical trials. Treatment with L-ornithine-L-aspartate lowers the nia is converted to urea and glutamine which can be ammonia concentration and thus improves the mental state and psycho- excreted via the kidneys. motor performance. Hepa-Merz® is well or very well tolerated in the The ammonia present in the blood is released endoge- majority of cases. nously during cell metabolism from nitrogen-containing compounds such as proteins, amino acids, nucleic acids and amines, or synthesised by the intestinal flora and absorbed into the blood stream. A large quantity of ammonia originates in the intestines. Mention should be made of both bacterial ammonia production in the large intestine and abacterial degrading of nitrogen-contain- ing metabolites in the small intestine. Ammonia synthesis in the muscles and kidneys contrib- utes to the ammonia concentration in the blood to a smaller extent. Ammonia produced in the muscle in- creases in proportion to the work of the muscle; in resting muscle, ammonia uptake and excretion are approximately in equilibrium. In the kidneys, only a small quantity of ammonia is produced under normal conditions. 8 9
  6. 6. An increase in ammonia synthesis is seen in special type of (reversible) detoxification also takes place in the circumstances e.g. on treatment with diuretics and in brain and the liver. hypokalaemia. Glutamine is broken down in the kidneys by the action In the liver itself, large quantities of ammonia are also of glutaminase to give glutamate and ammonia; gluta- produced during protein breakdown. This is immediate- mate is further converted to a-ketoglutarate by the ly detoxified, however, so that the liver does not contrib- release of a second ammonia molecule. The ammonia ute to the blood ammonia concentration when its function released in the kidneys can be excreted in the urine; a is intact. small quantity is re-absorbed. Ammonia Ammonia is physically dissolved in the blood and is in metabolism equilibrium with ammonium ions (NH3/NH4+); this is pH- Urea in the body dependent. With a rise in the pH (alkalosis), the propor- tion of diffusible toxic ammonia (NH3) increases. Under physiological conditions there is a natural equi- Small intestine Large intestine librium between ammonia production and ammonia detoxification. The normal non-toxic serum levels in the peripheral blood are in the region of 30 µmol/l. The highest ammonia concentrations are found in the portal vein blood, which carries the ammonia produced in the intestinal tract. Muscle Liver Figure 1.1 summarises the pathways involved in the Glutamine metabolism of ammonia in the human body. The liver is the most important organ to detoxify am- monia produced in the large and small intestine, Urea muscles and kidneys. Most of the urea produced there is excreted via the kidneys, with a small proportion Kidney being excreted via the gastrointestinal tract. Urea Some of the ammonia present in the human body is detoxified in the muscles. Glutamine is produced from Fig 1.1: Ammonia metabolism in the body ammonia and glutamate. Apart from muscle tissue, this 10 11
  7. 7. Ammonia Some 70-80% of the ammonia present in the portal These highly specialized cells, also referred to as scav- detoxification vein blood is removed during passage through the liver. enger cells, form only 5-10% of the liver parenchymal in the liver This is due to the synthesis of urea and glutamine. cells. Urea synthesis and glutamine synthesis take place in Summary: two different cell systems organized sequentially in the A large proportion of the ammonia present in the blood comes from the hepatic acinus (Figure 1.2). gastrointestinal tract, with contributions in the internal milieu from mus- cles and kidneys. Ammonia-containing blood is transported through the portal vein to the liver where it is detoxified by the formation of urea and glutamine. Functional units of periportal and perivenous hepatocytes in Periportal hepatocytes Perivenous hepatocytes the acini of the liver control the ammonia concentration in the blood. Cytosol Cytosol Mitochondrion Mitochondrion Glutaminase 1.2 Liver diseases as the cause of hepatic encephalopathy Carbamyl phosphate Glutamine synthetase Glutamine synthetase I The most common liver disease that causes hepatic encephalopathy is cirrhosis of the liver. This can also Glutamine arise as the result of other liver diseases (e.g. hepatitis, Urea fatty liver). Genetic enzyme deficiencies and acute liver failure are much less common causes of hepatic en- Glutamine Glutamine cephalopathy. Urea Hepatic encephalopathy is a relatively frequent complica- Hepatic encephalopa- Figure 1.2: Detoxification of ammonia in the liver. Formation of urea and glutamine in periportal and tion of cirrhosis of the liver, particularly if there is a collat- thy is a common com- perivenous hepatocytes (after Häussinger, 1990) NH4+: Ammonia; Cbm-P: Carbamyl phosphate; Orn: eral portosystemic circulation. Hepatic encephalopathy plication of cirrhosis Ornithine; Cit: Citrulline; Arg-Suc: Arginine succinate; Arg: Arginine can be demonstrated in 30-70% of these patients. The of the liver pathology of cirrhosis of the liver consists of destruction of In periportal hepatocytes, ammonia is converted to urea the normal parenchymal structure and replacement of the in the urea cycle. In the subsequently activated perive- parenchyma with nodular connective tissue. This is a nous hepatocytes, the ammonia is metabolised to glu- common chronic liver disease with a prevalence of about tamine by the action of glutamine synthetase. 1%. 12 13
  8. 8. Cirrhosis: The cause of cirrhotic changes in the liver in more than Haemodynamic consequences of cirrhosis causes and half of the patients is chronic alcohol intoxication. In a of the liver degree of severity third, cirrhosis is the result of hepatitis. More rarely there is a metabolic cause (e.g. Wilson’s disease, haemo- The connective tissue changes with resultant loss of Portal hypertension chromatosis, alpha-1-antitrypsin deficiency etc.) vital hepatic parenchyma increase the vascular resis- and toxic NH3- or vascular cause (e.g. chronic right ventricular failure) tance of the liver leading to the development of portal concentration in or an unexplained disease process. Progression of hypertension. Raised pressure in the portal vein induces the brain cirrhosis is more or less the same whatever the aetiology. the formation of a collateral circulation between the por- The degree of severity of cirrhosis is usually expressed tal system and other veins, known as a portosystemic by the Child-Pugh classification, stages A, B and C, shunt. Portal vein blood by-passes the liver through which takes into account the laboratory parameters of oesophageal and abdominal varices, rectal varices, bilirubin, albumin and the prothrombin time as well as abdominal wall vessels and intrahepatic collaterals to ascites and encephalopathy (Table 1.1). hepatic veins. This means that portal vein blood which is particularly rich in ammonia (due to absorption of the ammonia produced in the gastrointestinal tract) flows directly into the systemic circulation, by-passing the liver through these collateral vessels. Because of the resultant hyperammonaemia, muscles and the brain take up greater amounts of ammonia to compensate; this gives rise to toxic ammonia concentrations in the Parameter Number of Points 1 2 3 brain. Encephalopathy Grade 0 Grade I/II Grade III/IV Reduced ammonia detoxification in the liver Ascites none slight severe Bilirubin (mg/dl) ≤2 2–3 >3 At the same time, the loss of functioning hepatic tissue Bilirubin (µmol/l) (≤34) (34–51) (>51) has an effect on the detoxification capacity of the liver. Albumin (g/dl) >3,5 2,8–3,5 <2,8 Ammonia can no longer be broken down in sufficient Prothrombin time (seconds above standard) 1–3 4–6 >6 quantities. Urea synthesis and glutamine synthesis are or INR <1,7 1,8–2,3 >2,3 reduced in patients with cirrhosis. In contrast, there is Table 1.1: Assessment of hepatic function reserve based on Child-Turcotte criteria, modified by Pugh. increased activity of glutaminase, which converts gluta- Addition of the points gives the Child-Pugh stage: A (5-6 points), B (7-9) and C (10-15) mine into ammonia, i.e. release of ammonia is greatly increased in the cirrhotic liver (Figure 1.3). 14 15
  9. 9. % synthesis rate/wet liver weight Percentage ± SEM Normal state Haemodynamic causes Metabolic causes µmol/hxg Control 500 Fatty liver ** Cirrhosis 400 300 Urea Urea Urea Glutamine Glutamine Glutamine 200 NH + 4 NH + 4 NH + 4 100 ** ** * ** 0 Urea synthesis Glutamine synthesis Glutaminase activity *p<0,01 **p<0.0005 vs control Figure 1.3: Activity of urea synthesis, glutamine synthesis and glu- Figure 1.4: Pathophysiology of hepatic encephalopathy in cirrhosis taminase in biopsies of histologically-confirmed normal liver tissue, of the liver (after Gerok, 1995) fatty liver tissue and cirrhotic liver tissue. The data are based on the calculation of synthesis rate per wet liver weight (µmol/h x g). The Data on the incidence of subclinical hepatic encephalop- synthesis rate of control liver tissue corresponds to 100% (after Gerok, 1996) athy vary, ranging from 30% to 80% (Häussinger and Maier, 1996). Early stages in particular often remain Figure 1.4 gives an overview of the factors playing a role unrecognized. in portosystemic encephalopathy – pathological hae- modynamics and reduced detoxification in the liver. Fatty liver (steatosis) is the most widespread liver dis- Fatty liver and Both mechanisms contribute to the increased ammonia ease in the population. It may be the result of various cirrhosis in the blood and the occurrence of hepatic encephalop- conditions (e.g. diabetes mellitus, disorders of lipid athy. metabolism) or toxic effects (alcohol, drugs, industrial toxins). The most common cause is toxic damage due The clinical course of cirrhosis of the liver is generally to alcohol misuse. chronic and progressive. The most important complica- tions are bleeding from oesophageal or abdominal var- An increased deposit of triglycerides in the hepatic cells ices, ascites, jaundice, clotting disorders, renal failure is characteristic of fatty liver. Firstly small deposits can and hepatic encephalopathy. On average, about 40% be seen (fine droplet fatty change). As the condition of patients with cirrhosis develop overt hepatic en- progresses, the size of the fat droplets in the hepatic cephalopathy during the course of the disease. cells increases (large droplet steatosis). 16 17
  10. 10. The fatty deposits lead to an overall enlargement of the Non-alcoholic steatohepatitis (NASH) also belongs in Non-alcoholic liver. the group of non-alcoholic fatty changes in the liver, steatohepatitis (NASH) with a spectrum ranging from steatosis through steato- Symptoms of a fatty liver include sensations of pressure hepatitis and steatofibrosis up to cirrhosis. and fullness in the right side of the upper abdomen and frequently also pain in the region of the liver, as well as Inflammation of the liver may have various underlying Hepatitis and cirrhosis flatulence, fullness, nausea and reduced performance. causes. The most important of these are hepatitis vi- of the liver The enlarged liver is usually easily palpable through the ruses, autoimmune processes and drugs. On occasion abdominal wall. Results of liver-specific laboratory tests the cause may not be identified. Chronic hepatitis may may occasionally be abnormal, depending on the extent develop into cirrhosis of the liver and hence be an indi- of liver damage and loss of function. rect cause of hepatic encephalopathy. With fatty liver the detoxification function may already be Viral hepatitis is the most common. Table 1.2 gives an limited. Studies have shown that urea and glutamine up-to-date overview of hepatotropic viruses (Caspary synthesis are reduced in fatty livers (see Figure 1.3). 2001). As a rule, acute viral hepatitis heals without caus- Values lie somewhere between those in cirrhotic tissues ing cirrhosis. Hepatic encephalopathy may occur in and those found in healthy livers. It is therefore probable fulminant viral hepatitis even without cirrhosis. In chron- that minimal hepatic encephalopathy is also present in ic hepatitis, cirrhotic changes in the liver arise as part of patients with fatty livers, or can develop under the the inflammatory process. Chronic viral hepatitis can influence of additional precipitating factors (see section therefore be an indirect cause of hepatic encephalop- 2.2). athy. Hepatitis B, for example, becomes chronic in some 10% of cases and a number of these patients go At first these processes are reversible with the removal on to develop cirrhosis. In contrast, hepatitis C follows of the cause, i.e. in most cases misuse of alcohol. With a chronic course in some 80% of cases and often continued presence of the toxin, the process frequently develops into cirrhosis of the liver. progresses with increasing fibrosis developing into cir- rhosis of the liver. The effects of alcohol may also give rise to inflammation of the liver with hepatic cell necrosis and cell infiltration – alcoholic hepatitis – which may also develop into cirrhosis of the liver. 18 19
  11. 11. HAV HEV HBV HDV HCV Normal CAH IIa CAH IIb CAH cirrhosis Picorna- Calici- Hepadna- Delta- Flavi- n=50 n=44 n=41 n=37 Virus family viridae viridae viridae viridae viridae 160 * Genome RNA RNA DNA RNA RNA * Incubation time (days) 14–45 14–60 30–180 30–180 14–180 Ammonia (µg/dl) 120 * Transmission faecal-oral faecal-oral parenteral parenteral parenteral Diagnositics (acute infection) anti-HAV anti-HEV HbsAg anti-HDV anti-HCV 80 IgM IgM anti-HBc-IgM IgM HCV-RNA Becomes chronic no no <5 % <10 % 50–80 % 40 (adult) (co-infection) arterial 90 % <80 % venous 0 (perennial) (super-infection) Cirrhosis of the liver – – 20–30 % 30–40 % 20–30 % Figure 1.5: Arterial and venous plasma ammonia concentrations in with chronic hepatitis different stages of chronic active hepatitis (mean ± standard devia- Oncogenicity no no yes ? yes tion). The statistical significance * (p<0.05) refers to the comparison with normal controls (after Müting et al., 1988). Notifiable disease* I, D I, D I, D I, D I, D CAH: chronic active hepatitis Table 1.2: Characteristics of hepatotropic viruses (after Caspary 2001); I = illness; D = death; *Obligation to notify disease in accordance with §3 of the Federal Infectious Diseases Protection Law Fulminant viral hepatitis in particular but also drug-induc- Acute liver failure ed toxic reactions may rarely lead to acute liver failure which has a dramatic clinical picture. This is defined by In less common autoimmune hepatitis, loss of immunologi- the combination of severe liver insufficiency and alter- cal tolerance leads to self-destruction of the liver. The ation in the level of consciousness with hepatic en- etiology and mechanisms are mostly unclear. The cephalopathy. The diminution in liver function is character- inflammatory process leads to loss of functioning paren- ized by a rapid fall in clotting factors, with a sharp rise chyma and to fibrotic changes in the liver. in transaminases and accompanying jaundice. The appearance of hepatic encephalopathy is an unfavour- In chronic hepatitis, the reduced detoxification capacity of able prognostic sign. Various classifications of the the damaged liver tissue appears even before cirrhosis degree of severity of acute liver failure have been de- develops. A study on patients with chronic hepatitis showed fined based on the interval between the appearance of that even before the formation of a by-pass circulation – jaundice and encephalopathy. In general it can be said associated with progressive liver damage – there is an in- that the more quickly hepatic encephalopathy follows crease in the blood ammonia concentration (Figure 1.5). the signs of jaundice, the worse the prognosis, i.e. 1 week 20 21
  12. 12. 2 HEPATIC ENCEPHALOPATHY – CLINICAL PICTURE AND PATHOGENESIS in hyperacute forms and more than 4 weeks in sub- 2.1 Definition and clinical forms of acute. hepatic encephalopathy The symptoms of encephalopathy in acute liver failure Hepatic encephalopathy (HE) is a metabolically induc- Definition of hepatic do not basically differ from hepatic encephalopathy due ed, potentially reversible, functional disturbance of the encephalopathy to other causes. However, there is a risk of cerebral brain which may occur during the course of chronic and oedema and fatal cerebral herniation as a result of acute liver diseases (see section 1.2). The term encom- raised intracranial pressure. The prognosis in acute liver passes a syndrome of individual neurological and failure is poor; mortality without a liver transplant is psychological components that may occur in different about 80%. combinations and with varying degrees of severity. The symptoms and signs of hepatic encephalopathy do not basically differ from encephalopathies of other genesis; the definition therefore includes a concurrently demon- strable liver disease. Occasionally, portosystemic encephalopathy (PSE) is Summary: classified as a subgroup of hepatic encephalopathy. The most common liver disease which causes hepatic encephalopathy This refers to encephalopathy in cirrhosis of the liver in is cirrhosis of the liver. The typical picture of disease includes liver cell combination with portosystemic collateral circulations damage with reduced detoxification capacity in combination with colla- (see section 1.2). However, this form cannot basically teral portosystemic circulations. Other liver conditions may develop into be distinguished from other forms of hepatic encepha- cirrhosis during the course of the disease e.g. fatty liver or hepatitis. In lopathy. acute liver failure, hepatic encephalopathy may occur without cirrhosis or portosystemic shunts. The clinical picture of hepatic encephalopathy is very Clinical picture and variable and can be associated with impairment of intel- degree of severity lectual and psychomotor functions as well as changes in personality and level of consciousness. Clinical pro- gression varies greatly: acute, episodic, fluctuating and chronic forms are possible. Hepatic encephalopathy is divided into five degrees of severity according to the West Haven criteria, on the basis of clinical symptoms and signs as well as the findings of psychometric tests (Table 2.1). These 22 23
  13. 13. divisions are based largely on the mental state of the Minimal (subclinical) encephalopathy is present in 30- patient; they range from HE grade 0 with no distur- 70% of people with cirrhosis. The burden of this distur- bance of consciousness to deep coma with HE grade bance depends on the demands made on the individu- IV. al. Diminished performance may be of particular importance in manual work (e.g. operating conveyer belt) and driving a car. Reduction in the quality of life HE grade State of conciousness/ Behaviour Neuromuscular and personal safety may be associated even with HE intellect symptoms grade 0 (see section 3.2). Minimal clinically normal but clinically normal but disturbance of fine Typical symptoms and signs of HE grades I-IV are pre- Overt hepatic subclinical abnormal pathological abnormal pathological motor function and psychometric tests and psychometric tests sented in Table 2.1. The degree of severity of hepatic encephalopathy I reduced concentration and personality changes disturbance of fine encephalopathy can progress very quickly. prolonged reaction time, motor function Neuropsychiatric symptoms of overt hepatic encepha- sleep disorders, fatigue (reduced alertness) lopathy are extremely variable. The first clinical indica- II retardation, lethargy marked personality asterixis, slurred tions are, for example, sleep disturbances, loss of drive changes, temporal speech and mood swings as well as loss of fine motor func- disorientation tions. Poor attention span, lack of concentration and III disorientation, somnolence, bizarre behaviour, hypo- and hyperreflexia, stupor delusions asterixis, convulsions reduced mental agility can be taken as signs of dimin- IV coma ceased areflexia, loss of tone ished cognitive function. As these are non-specific, they are often not recognized as signs of hepatic encepha- Tab. 2.1: Degrees of severity of hepatic encephalopathy: Classification of the mental state according lopathy. With HE grade II, symptoms of psychomotor to West Haven criteria (modified after Conn and Bircher 1994) retardation with disorientation and memory defects appear. Characteristic flapping tremor (asterixis) is a sign of neuromuscular disorder, as are ataxia, dysarthria Minimal hepatic In the stage of minimal (subclinical or latent) hepatic and increased reflexes. Occasionally, hallucinations and encephalopathy encephalopathy – HE grade 0 – the patient has no delusions occur. complaints and on direct questioning has no symptoms Changes in personality – often the intensification of a belonging to grade I. Sleep, concentration, fine motor previously existing characteristic – may be pronounced. functions, general performance and mood are not In the later stages of hepatic encephalopathy, alter- affected. Even so, results of psychometric and neuro- ations in the level of consciousness determine the psychological tests show subtle abnormalities, provid- clinical picture. HE grade IV is characterised by deep ing evidence of cerebral disturbance in the sense of coma with response only to painful stimuli. retardation of psychomotor functions. 24 25
  14. 14. Hepatic Hepatic encephalopathy may also occur in acute liver 2.2 Precipitating factors in encephalopathy in failure, e.g. with fulminating hepatitis (see section 1.2). hepatic encephalopathy acute liver failure This is basically indistinguishable from the symptoms seen with chronic liver disease; however, the distur- A great variety of factors can precipitate or exacerbate Many precipitating bances of cerebral function appear more abruptly and hepatic encephalopathy (Figure 2.1). Often there is factors progress more rapidly. States of delirium, restlessness interplay of several factors. The severity of the cirrhosis and seizure tendency are more common than with and the extent of collateral circulation do not necessar- other forms of hepatic encephalopathy. ily determine the likelihood of encephalopathy. Hepatic encephalopathy may be induced by a certain combina- tion of precipitating factors even in patients without recognizable impairment of liver function and no mark- ed portosystemic shunt volume. Summary: The definition of hepatic encephalopathy encompasses the liver disease Increased ammonia in the brain Volume deficiency and the cerebral dysfunction. Assessment of the severity of the condition • Increased ammonia production: • Diuretics is made clinically on the basis of the mental state (HE grade in accordance Protein-rich diet (in forced mobilization of ascites) with West Haven criteria). With the minimal or subclinical form (HE grade GI bleeding • Vomiting 0) there are no obvious clinical deficiencies but the results of psychomet- Hypokalaemia • Diarrhoea ric tests are abnormal. Increasing deterioration of the level of conscious- Constipation • Bleeding ness becomes apparent with HE grades I-IV, reaching deep coma by HE Infection grade IV. • Increased passage of ammonia Drugs into the brain: Metabolic alkalosis Transjugular intrahepatic porto- (esp. diuretics) systemic stent shunt (TIPS) Vomiting Hypoxia Figure 2.1: Precipitating factors in hepatic encephalopathy (after Caspary 2001) The majority of precipitating factors is associated with increased nitrogen or an increased number of nitro- genous metabolites in the blood. 26 27
  15. 15. The common precipitating factors of azotaemia, bleed- Hepatic encephalopathy may also be precipitated TIPS and hepatic ing from shunt varices, infections and protein-rich diet, following the creation of a transjugular intrahepatic encephalopathy lead to increased nitrogenous compounds that are bro- portosystemic shunt (TIPS) as a therapeutic measure. ken down to ammonia which cannot be sufficiently Encephalopathy becomes overt in about a quarter of detoxified because of impaired liver function. At the TIPS patients. The main indications for a TIPS are same time there is decompensation of ammonia detox- haemodynamic problems, especially prophylaxis of ification. recurrent bleeding from oesophageal or abdominal Hypovolaemia, aspiration of ascites, diuresis, hypoka- varices. If there is not already severe hepatic encephalop- laemia or hyponatraemia may lead to disturbances of athy (grade II-IV), the risk of encephalopathy has to be fluid balance, acid-base balance and electrolyte con- accepted, since these haemodynamic complications are centrations. As a result, more ammonia may be produc- difficult to treat and potentially fatal. Elderly patients ed in the kidneys, hepatic and renal blood flow be (>60 years of age) are particularly at risk. The patho- reduced and detoxification in the liver impaired. Di- physiological changes responsible for the manifestation uretics also directly inhibit urea synthesis in the liver. of hepatic encephalopathy in patients with shunts are Metabolic acidosis also adversely affects urea synthe- described in section 1.2. sis. Other factors that commonly precipitate overt hepatic encephalopathy are sedatives and tranquillisers, espe- cially benzodiazepines. These substances have a neu- rodepressant action and in this way may promote hepat- ic encephalopathy. Since these drugs are metabolized in the liver, impaired hepatic function prolongs their half- Summary: lives; this means that a relative overdose may occur All conditions that increase the ammonia concentration in the blood – by even when normal dosages are taken. Sedative drugs increasing ammonia production or disrupting detoxification – are pos- should therefore be prescribed for patients with cirrho- sible precipitating factors in the manifestation of hepatic encephalopa- sis only in special circumstances. thy. Neurodepressant agents (e.g. benzodiazepines, alcohol) may like- wise precipitate hepatic encephalopathy. When a TIPS is created as a Alcohol induces hepatic encephalopathy not only by therapeutic measure, the risk of hepatic encephalopathy must also be causing cirrhosis of the liver; it may also act as a precip- accepted. Elderly patients (>60 years of age) are particularly at risk. itating factor through its neurodepressant effects. 28 29
  16. 16. 2.3 Pathogenesis of hepatic chromatin. These pathological changes indicate a key encephalopathy role for the astrocytes in the pathogenesis of enceph- alopathy (Figure 2.2). Explanation of the pathogenesis of hepatic encepha- lopathy requires investigation of the relationship be- tween liver function and cerebral function, two highly complex systems. Results are frequently not easy to interpret and give rise to further questions. The many symptoms and signs and their variability with respect to the degree of severity and progression make it dif- ficult to find a common pathomechanism that explains all the forms of encephalopathy. Despite intensive scientific research, it has not yet been possible to completely elucidate the pathophys- iological mechanisms of hepatic encephalopathy. However, it is certain that increased ammonia con- centration in the blood contributes to the pathogene- sis. There is probably synergy with other pathome- chanisms. Figure 2.2: Alzheimer type II astrocytes Alz: Alzheimer astrocyte, N: normal astrocyte 2.3.1 Neuropathological changes Swelling of Hepatic encephalopathy is basically a reversible dis- astrocytes turbance of cerebral function. Damage to neuronal The astrocytes are important components of the blood- cells is not seen. In neuropathological studies, how- brain barrier. The uptake of substances from the blood ever, changes can be identified in the morphology of into the brain requires the transastrocyte transport the astrocytes. In acute liver failure, the astrocytes are mechanism. Astrocytes are in close contact with neuro- swollen. In cirrhosis of the liver, neuropathological nal cells and are involved in the metabolic processes of changes can be seen, which are described as Alzhei- neurotransmitters and regulation of ion concentrations mer type II astrocytosis. These astrocytes are charac- in the brain. terized by large swollen nuclei and margination of the 30 31
  17. 17. 2.3.2 Ammonia and the glial The mechanism of neurotoxicity of ammonia in the brain Neurotoxicity hypothesis has not yet been completely explained. There is experi- of ammonia mental evidence of disturbances of the cerebral energy Pathogenetic An increased ammonia concentration in the blood cer- metabolism and neurotransmission, direct modulation significance tainly contributes to the manifestation of hepatic en- of neuronal activity and an indirect effect on the neu- of ammonia cephalopathy. There is no pathogenetic concept in rones via the astrocytes. On the basis of recent studies, which ammonia does not play a key role. The following functional disturbance of the astroglia with resulting points in particular support this: dysfunction of the neuronal cells is possibly the most important neurotoxic mechanism of action of ammonia. • In most patients with hepatic encephalopathy, the ammonia concentration in the blood is raised. Accumulation of glutamine (a product of ammonia Ammonia and Only 10% of patients have normal levels. detoxification) in the cells is the main cause of the astro- glial swelling • In cases of hyperammonaemia, lowering the cyte swelling. Only these cells contain glutamine syn- ammonia concentration leads to improvement in thetase, an enzyme capable of detoxifying ammonia in the symptoms. the brain (Figure 2.3). • Hepatic encephalopathy occurs far and away most commonly in patients with cirrhosis of the liver and portosystemic collateral circulations, in whom insufficiently detoxified blood – especially with respect to ammonia – reaches the brain. NORMAL HYPERAMMONAEMIA • There is a certain correlation between ammonia concentration and the severity of the hepatic SYNAPSE ASTROCYTE SYNAPSE ASTROCYTE encephalopathy. Gln Gln • Conditions where the ammonia is raised can pre- Gln Gln NH3 Gln NH3 Gln cipitate or exacerbate hepatic encephalopathy, while a fall in ammonia concentration improves Glu NH3 NH3 Glu NH3 NH3 Glu Glu the clinical symptoms and signs. Glu Glu In animal experiments hyperammonaemia induces GLU-RECEPTOR GLU-RECEPTOR changes that are also seen in liver patients (e.g. cerebral oedema and raised intracranial pressure) as well as Figure 2.3: Diagrammatic representation of glutamate-glutamine cycle in the glutamatergic synapse numerous neurochemical changes similar to those and the influence of hyperammonaemia found in humans. (Gln = glutamine; Glu =glutamate; (1) = glutaminase; (2) = glutamine synthetase) 32 33
  18. 18. Other substances such as cytokines and benzodiaze- may arise. There may be changes in the permeability of pines or conditions such as hyponatraemia may be the blood-brain barrier with symptoms of raised intra- synergistic to the ammonia effects and thus contribute cranial pressure. In addition, effects on the activity of ion to the astrocyte swelling, or may even be the main channels, disturbances of neurotransmitter and recep- cause of this change. tor functions, and damage to the neuronal energy sup- ply are to be expected. The glutamatergic neurotrans- Figure 2.4 gives an overview of the different factors mitter system that controls cognitive function is contributing to the pathogenesis of hepatic encepha- probably involved in the process; due to the increased lopathy. consumption of glutamate needed to detoxify ammo- nia, glutamate deficiency results in the glutamatergic neurones. Frequently it cannot be determined how Changes in post- Changes in Changes in the much the functional changes in neuronal activity are synaptic receptors neurotransmitters blood-brain barrier due to direct toxic effects of ammonia and how much to indirect effects of the glial swelling. Swelling and functional disturbance of the astroglia 2.3.3 Additional pathological Neurotoxin ammonia/amino acid imbalance mechanisms Impaired liver function Besides the role of ammonia and the concept of glial swelling, there are indications that additional patho- mechanisms exist. These may be synergistic or may Figure 2.4: Interplay of various pathogenetic factors in hepatic encephalopathy even determine the manifestation of hepatic encepha- In acute liver failure, glial swelling occurs with clinically lopathy. overt cerebral oedema. Findings from recent studies have shown that there is also a disturbance of cell vol- There is evidence for considering the neurotoxic effects Other endogenous ume homeostasis with glial swelling in chronic liver dis- of other endogenous substances – for example, mer- neurotoxins eases and hepatic encephalopathy (Häussinger et al, captans which are formed during the breakdown of 2000). sulphur-containing amino acids (e.g. methionine) by bacteria. These substances are responsible for the Many potential functional disturbances of the glial cells characteristic foetor hepaticus. They inhibit Na+/K+ themselves and of the glial-neuronal communications ATPase and potentiate the neurotoxicity of ammonia. 34 35
  19. 19. Phenols are also neurotoxins; they lead to coma in ani- that the concentrations of aromatic amino acids in the Neurotoxicity mal experiments. They are derivatives of the amino brain also increase while the branched-chain amino of ammonia acids phenyl alanine and tyrosine, and are formed in the acid concentrations are reduced (Figure 2.5). gastrointestinal tract. Short and medium chain fatty acids are produced by the physiological intestinal flora during the break- NH3 down of fatty acids, and can also be formed in the liver itself. They inhibit Na+/K+ ATPase and urea synthesis in the liver. In addition, there is some evidence that these compounds increase the tryptophan uptake into the brain and thus affect transmitter metabolism. Glutamate Glutamine Glutamate Glutamine Increased The blood-brain barrier is a complex physiological permeability of the functional unit which protects the brain from metabolic blood-brain barrier disturbances in the rest of the body. In acute liver Glutamine Glutamine failure, the permeability of the blood-brain barrier is increased in a non-specific manner. Certain changes in Figure 2.5: Diagrammatic representation of ammonia and amino acids exchange. Ammonia taken up into the brain is converted to glutamine, which is exchanged for the branched-chain amino acids the blood-brain barrier are also seen in chronic liver fail- (BCAA) and aromatic amino acids (AAA) present in the plasma, which use the same transport system. ure. The transport capacity for neutral amino acids is In the case of portosystemic encephalopathy, increased levels of ammonia in the blood lead to raised concentrations of glutamine in the brain. The higher AAA to BCAA concentration ratio in the blood increased but reduced for basic amino acids, ketone promotes the entry of AAAs into the brain through exchange with glutamine (after Conn, 1994) bodies and glucose. At the same time, the ammonia- dependent rise in intracerebral glutamine formation increases the uptake of neutral amino acids into the brain. The selective changes in permeability that can be The aromatic amino acids are substrates for neuro- observed are possibly related to the glial swelling. transmitter synthesis – tyrosine and phenyl alanine for dopamine, and tryptophan for serotonin. The excess Amino acid imbalance In chronic liver disease, the blood shows a typical supply of substrates may mean that substances such and “false neurotrans- amino acid distribution profile. The quantitative rela- as tyramine, octopamine and phenyl ethanola- mitters” tionship between aromatic (tyrosine, phenyl alanine, mine are formed via secondary metabolic pathways. tryptophan) and branched-chain amino acids (valine, These act as “false neurotransmitters” by competing leucine, isoleucine) shifts towards the aromatic amino with the normal transmitters for the same receptors and acids. On the basis of this observation, it is assumed thereby disrupting neuronal activity. 36 37
  20. 20. GABA-ergic On the basis of the therapeutic neurodepressant effects transmission of benzodiazepines, which are notable precipitating fac- Summary: tors for hepatic encephalopathy, the hypothesis has Every last detail of the pathogenesis of hepatic encephalopathy has not been proposed that so-called endogenous benzodiaze- yet been fully elucidated. Ammonia certainly plays a key role. The asso- pines and related substances (endozepines) which can ciated glial hypothesis, which assumes an underlying mechanism of dis- be found in the blood and brain as well as in plant prep- rupted interaction between the altered astrocytes and other cellular ele- arations and foodstuffs, contribute to the pathogenesis ments of the brain, brings the various findings together in a of hepatic encephalopathy by their agonistic actions on comprehensive manner. The concept of synergistic mechanisms be- the GABA receptors. Gamma-aminobutyric acid tween the observed influencing factors is plausible and correlates with (GABA) is an important inhibitory neurotransmitter in the the variable symptoms and signs to be seen in hepatic encephalopathy. brain and GABA receptors are to be found on neurones and astrocytes. Activation of the GABA-ergic system has a neurodepressant effect. Serotonin, The increased uptake of tryptophan into the brain leads noradrenaline to an increased formation of serotonin. The density of serotonin receptors decreases while their affinity increases. Changes regarding the neurotransmitter noradrenaline are also seen in hepatic encephalopathy, which may possibly have pathogenetic significance. Zinc, manganese Results of recent studies have suggested an associa- tion between hepatic encephalopathy and the trace elements zinc and manganese. It has been shown that the activity of enzymes in the urea cycle is reduced when there is zinc deficiency. NMR studies in patients with hepatic encephalopathy have indicated deposits of manganese in the basal ganglia. The question of how relevant these findings are to pathogenesis remains open. 38 39
  21. 21. 3 DIAGNOSIS OF HEPATIC ENCEPHALOPATHY 3.1 Diagnostic procedures In alcoholics with cirrhosis of the liver, Wernicke-Korsakov Differential diagnosis syndrome and delirium tremens from alcohol withdraw- Diagnosis of hepatic The diagnosis of hepatic encephalopathy is made on al must in particular be included in the differential diag- encephalopathy on the basis of the clinical picture (see West Haven criteria) nosis of hepatic encephalopathy. Subdural haematoma the basis of the and must be considered in every patient with neuro- and other vascular processes, space-occupying clinical picture psychiatric disturbances and liver disease. The diagno- lesions, intoxication, encephalitis, hypothyroidism and sis is easy in known cases of cirrhosis of the liver or ful- metabolic disorders such as hypo- or hyperglycaemia, minating hepatitis but presents difficulties when the liver uraemia and hyponatraemia have all to be considered disease has not yet been diagnosed. as well. Clinico-chemical blood tests may be worthwhile in re- vealing a hitherto unsuspected liver disease or hyper- With hepatic encephalopathy, changes in the EEG are Electrophysiological ammonaemia syndrome, but have only limited rele- visible as abnormal slowing of the baseline activity investigations vance in the diagnosis of hepatic encephalopathy. although this is not pathognomic. Similar changes can be seen with uraemia, CO2 poisoning, vitamin B12 defi- The following summary proposed by Gerber and ciency, hypoxia or hypoglycaemia. In addition, it is dif- Schomerus indicates the relevant laboratory tests that ficult to evaluate changes because a reference EEG is may be useful in this context (Table 3.1). not usually available for the patient. It is often the case that no clear boundary can be drawn between normal Liver function tests Drug screening (urine and blood) and pathological. Similar restrictions exist in respect to • Transaminases (GOT, GPT) investigations with evoked potentials (VEP, P300). And Alcohol levels • Cholestasis parameters these methods are also relatively time consuming and Blood gas analysis (AP, γ−GT) expensive. Electrophysiological methods are therefore Fasting ammonia concentration not of prime importance in the diagnostic work-up of • Bilirubin • Total proteins with Cultures overt symptoms. electrophoresis/albumin (blood, urine, sputum, faeces) • Prothrombin time Hepatitis and HIV The main indication for imaging procedures in the Imaging techniques differential diagnosis of hepatic encephalopathy is the (CT, MRI etc.) Blood glucose Ascites (cells and culture) exclusion of other cerebral processes, especially Electrolytes Blood picture, C-reactive protein, cerebral haemorrhage. If symptoms corresponding to (with calcium and phosphate) erythrocyte sedimentation rate bleeding etc. are present, these imaging techniques Creatinine, urea are first-line investigations. Table 3.1: Laboratory tests in hepatic encephalopathy (after Gerber and Schomerus, 2000) 40 41
  22. 22. Using specific test procedures and a standardized test Reduced fitness to Summary: drive, a study conducted recently by a research group drive in patients with Hepatic encephalopathy is diagnosed on the basis of the clinical picture. at the University of Hamburg, in collaboration with the subclinical hepatic The necessary investigations for the differential diagnosis of this condi- Föhrenkamp clinic of the Mölln BfA rehabilitation centre, encephalopathy tion include laboratory tests, imaging procedures and occasionally elec- showed that patients with cirrhosis of the liver and sub- trophysiological examinations. clinical hepatic encephalopathy were not completely fit to drive. Not only was their ability to drive a car severe- ly restricted but also the ability to adapt their driving 3.2 Early diagnosis behaviour to the general rules of the road, as can be seen in Figure 3.1 (Wein et al., 2002). Diminished Early recognition of hepatic encephalopathy is of partic- performance in ular clinical relevance, i.e. diagnosis in HE grade 0. subclinical hepatic Disturbances of consciousness are not yet noticeable Marks encephalopathy with minimal or subclinical hepatic encephalopathy but 5 SHE Group of patients with cirrhosis of the liver BF observing pedestrians without subclinical hepatic encephalopathy SI checking safe to proceed impairment of intellectual function already exists. This is SHE+ Group of patients with cirrhosis of the liver GEB observing speed with subclinical hepatic encephalopathy restrictions important to the patient for two reasons: KK Clinical control subjects BH observing obstacles 4 RB observing rules BL signalling • Recognition of incipient hepatic encephalopathy is an ZF rapid merging GEA adaptation of speed indication of the decompensation of the underlying 3 OW orientation by signposts VB observing right of way cirrhosis and the necessity of treatment. ABH maintaining distance • Even the existing limitations represent a risk to the 2 SP keeping in lane EP parking patient at work (especially manual occupations) or SE getting into the correct lane driving a car. AB hill starts 1 BEA obeying traffic lights BF SI GEB BH RB BL ZF GEA OW VB ABH SH EP SE AB BEA Reductions in performance such as slower reaction Figure 3.1: Test drive: Marks gained in driving categories (after Wein et al., 2002) times, inaccurate perception of geometric shapes and Note: Marks in school reports etc. in Germany are scored with 1 being the highest reduced visual selection abilities, which are at first bare- ly noticeable, are important at work or driving a car. In addition, there are personality changes such as reduc- ed emotional stability, loss of self-control and self-criti- Diminished function in minimal hepatic encephalopathy Psychometric cism as well as a tendency to dissimulate (Häussinger is best identified with the aid of psychometric tests. procedures in and Maier, 1996). The risks of a road traffic accident or Moreover, these tests are relatively easy and cheap to subclinical hepatic an accident during manual work are thereby increased. administer (see section 3.3). encephalopathy 42 43