key: cord-0035503-3d320c0a authors: nan title: Acute and chronic liver insufficiency date: 2008 journal: Hepatology Textbook and Atlas DOI: 10.1007/978-3-540-76839-5_20 sha: c5a8d880d3c2b91bf58119e0c0fc21a01b03635b doc_id: 35503 cord_uid: 3d320c0a The term “liver insufficiency” denotes a break down in the functions of the liver. The syndrome of functional liver failure covers a wide spectrum of clinical, biochemical and neurophysiological changes. In principle, liver insufficiency can occur without previous liver damage as well as with already existing liver disease. It is characterized by a deterioration in the synthesizing, regulatory and detoxifying function of the liver. This final stage of liver disease terminates in hepatic coma. The term "liver insufficiency" denotes a breakdown in the functions of the liver. The syndrome of functional liver failure covers a wide spectrum of clinical, biochemical and neurophysiological changes. In principle, liver insufficiency can occur without previous liver damage as well as with already existing liver disease. It is characterized by a deterioration in the synthesizing, regulatory and detoxifying function of the liver. This final stage of liver disease terminates in hepatic coma. Serious liver disease can affect the 12 main metabolic functions of the liver, with their 60Ϫ70 even more important partial functions, to widely differing degrees. (s. tab. 3.1) The result is either global insufficiency or partial insufficiency, each with very varied clinical and biochemy y ical symptoms. The failure of certain metabolic functions is responsible to a greater or lesser extent for the development and intensity of liver insufficiency. Impairments in the functions of detoxification and protein metabolism are particularly significant in this respect. The compensated stage does not usually display any signs of liver insufficiency (except possibly jaundice), nor are there any typical ailments. Functional parameters that can be quantified in routine laboratory tests (such as cholinesterase, albumin, Quick's value, bile acids) may still be normal or only minimally impaired in the individual instance. In contrast, liver function tests (galactose, indocyanine green, MEGX, etc.) demonstrate a reduction of liver function which is already quite considerable. The decompensated stage, i. e. manifest liver insufficiency, can present as cellular decompensation (e. g. in the case of acute liver failure due to toxic or inflammatory mass necrosis) or be expressed only in the form of portal decompensation (e. g. in cases of postsinusoidal intrahepatic portal hypertension). • As a rule, chronic liver insufficiency is accompanied by a combined decompensation with a loss in function of the liver cells and, at the same time, the sequelae of portal decompensation (collateral varicosis, encephalopathy, ascites, hepatorenal syndrome, hepatopulmonary syndrome, variceal bleeding). (see chapters 15Ϫ19 and 35) 380 Depending on the time period involved in the course of the disease, acute liver failure without pre-existing liver disease can initially be differentiated by massive liver cell disintegration due to a variety of causes. • In contrast, chronic liver insufficiency with pre-existing liver disease is mostly found in advanced liver cirrhosis with a progressive loss of function. • A sudden necrotising episode can also precipitate the change from chronic and still compensated liver insufficiency into acute liver failure (i.e. "acute-on-chronic" insufficiency) in the same way that acute liver failure which has been overcome may develop into chronic liver insufficiency. (60) Hepatic coma can be subdivided according to its aetiology as follows: (1.) hepatocyte disintegration coma (ϭ endogenous coma due to the loss of parenchyma), (2 ( ( .) liver cell failure coma (ϭ exogenous coma due to metabolic disorders, almost always in the presence of cirrhosis), (3.) electrolyte coma (ϭ so-called "false" coma due to dyselectrolytaemia, almost always iatrogenic), and (4.) mixed forms of coma. (s. pp 281, 284, 386) (s. tab. 15.5) 3 Acute liver insufficiency ᭤ J. W. Morgagni (1761) was probably the first to describe acute yellow atrophy of the liver, i. e. hepatic coma. Acute liver failure can be seen as identical to the "acute yellow atrophy" described by K. Rokitansky in 1842. This acute and severe clinical picture was subsequently termed "bilious dyscrasia" (P. J. Horaczek, 1844), "icterus gravis" (C. Ozanam, 1849), "acholia" (F. Th. Frerichs, 1858), "hepatolysis" (R. Ehrmann, 1922), "hepatodystrophy" (G. Herxheimer, 1935) r r or "liver dystrophy" (R. Böhmig, 1949 ). The terms "hepatargia" (H. I. Quincke, 1899) and "hepatic coma" were used to denote the final stage, which usually sets in at the end of acute or chronic liver failure. • Acute liver failure in the course of acute viral hepatitis was termed "fulminant hepatitis" by W. Lucké et al. (1946) , who also defined a subacute form with a less severe course. (36) Acute liver failure (ALF) is defined as an acute clinical picture with jaundice due to a most severe disorder in the liver function and/or massive liver cell necrosis which, without any pre-existing liver disease, culminates in hepatic coma (ϭ endogenous coma) within 8 weeks. Potentially, the condition is fully reversible (C. Trey et al., 1970) . • In addition, coagulopathy must also be present (D. F. Schafer et al., 1989 ). Clinically, there are three different courses of disease following the onset of jaundice: (1.) fulminant or hyperacute liver failure (ϭ occurrence of hepatic encephalopathy in the 1 st week), (2 ( ( .) acute liver failure (ϭ occurrence of hepatic encephalopathy between the 2 nd and 4 th week), and (3.) subacute liver failure (ϭ occurrence of hepatic encephalopathy between the 5 th and 8 th week). • Surprisingly, however, it could be shown that 30Ϫ40% of the hyperacute forms survived in spite of the development of hepatic coma and cerebral oedema. As opposed to this, the subacute forms displayed a survival rate of only 10Ϫ20% despite a lower frequency of cerebral oedema and better liver function. (s. tab. 20 In the pathological-anatomical context, hepatomegaly due to hyperaemia is often found at the outset. During the further course of disease, this can develop into liver atrophy as a result of parenchymal loss. Histologically, acute liver failure shows a wide range of uncharacteristic changes. (1.) Depending on the underlying cause, the morphological picture of acute necrotizing hepatitis may develop, with extensive confluent cellular destruction. The extent of necrosis, measured by the morphologically evidenced hepatic volume fraction of the still functioning liver parenchyma, yields reliable information on the chance of survival (J. Scotto et al., 1973) . Given a normal value of 85% hepatic volume fraction (HVF) of intact liver cells for each volume unit of the total liver, a decrease to < 30% (threshold 28Ϫ35%) would possibly mean that the patient is unlikely to survive. (2 ( ( .) In acute liver failure caused by toxins or hypoxia, massive fatty degeneration of the hepatocytes can vary substantially. In diffuse fatty degeneration featuring minute vacuoles and damage to the organelles, liver cell necrosis cannot, as a rule, be detected (e. g. acute fatty liver during pregnancy, Reye's syndrome, in association with tetracycline or valproic acid). (3.) Between these two "classical" morphological manifestations, there are also compound forms, i. e. 381 courses of disease with a variety of histological changes of different intensities and combinations. On occasions, it is also possible to identify histological findings which point to a certain cause of the disease. (41, 59) From a morphological point of view, acute liver failure is potentially reversible, so that even complete regeneration can be attained. Precursory cellular necrosis is hence less of a determinant than the capacity to regenerate. There have been reports on the transition from virusinduced acute liver failure to chronic hepatitis. As the final stage of fulminant viral hepatitis (also known as acute liver dystrophy or submassive hepatitic necrosis), a postdystrophic scarred liver ("potato liver") can develop. (s. fig. 35 .14) Cicatricial distortions with a continuing effect, regenerative processes, intrahepatic vascular disorders and hypoxia-related damage lead to the conclusion that a posthepatitic, postdystrophic scarred liver may well be a special form of cirrhosis. ᭤ Neither the functional state of liver insufficiency nor hepatic coma can be recognized histologically. The common target structures for the various causes of acute liver failure are usually the cellular and subcellular biomembranes of the hepatocytes. Among other things, any damage to these biomembranes causes a massive inflow of calcium into the liver cells, which results in a severe disorder of the cell milieu and ultimately in cell death. In oxygen deficiency, the oxidative stress is mainly localized in the extracellular spaces. This is where the Kupffer cells and neutrophils are involved in complex self-stimulating mechanisms, which can lead to the formation of inflammatory mediators and cytotoxic substances. • An important pathogenetic aspect is the "priming effect", which generally results in the increased production of oxygen radicals. The complex process of lipid peroxidation likewise effects massive liver cell damage in the form of self-perpetuation. • Excessive immunological reactions, which occur in acute liver failure due to viral hepatitis, halothane hepatitis, etc., are significant. There are also isolated cases in which biotoxometabolites are produced and may act as neo-antigens. (s. fig. 3 . 11) Consequently, severe damage to liver cells and widespread necrosis are usually the result of a network of altered cellular and humoral reactions, which for their part are often the initial cause of acute liver failure due to their synergistic and interactive effects (H. Popper et al., 1986) . Systemic reactions are responsible for the fact that other organs and functional sequences are equally affected, thus creating a wide spectrum of clinical findings and complications. Acute liver failure is a rare occurrence. About five cases are found out of 6,000 hospital admissions (in the USA a total of ca. 2000 patients per year, in Germany ca. 150). However, there can be wide variations in frequency due to the effect of regional differences on individual aetiology. The causes of acute liver failure are numerous and varied. Diabetes mellitus and overweight (12) are extremely high risk factors. • Primary or secondary hepatitis viruses are deemed a frequent cause, although there are regional and individual variations (e. g. drug 382 dependence, pregnancy) regarding the predominant virus type. • A further common cause (ca. 20%) are drugs (particularly paracetamol, often taken with suicidal intent, and halothane), followed by mycotoxins, alcohol and carbon tetrachloride (such as can be found in cleaning agents or solvents, and also with "glue sniffers"), heat-stroke (up to 10% of cases), Ecstasy, and vascular diseases. (12, 79) (s. tab. 20.2) Paracetamol: The first report on acute liver failure due to paracetamol poisoning was published in 1966 (D. G. D. Davidson et al.). Due to induced CYP II E2, paracetamol is metabolized to the extremely reactive molecule N-acetyl-p-benzoquinone-imine (NAPQI). This binds covalently to cellular proteins. A small amount of NAPQI is neutralized by glutathione; however, with a larger quantity of NAPQI (following an intake of > 10 g paracetamol), the hepatic glutathione supplies are used up, so that the NAPQI becomes highly toxic. The overall picture of acute liver failure is first and foremost determined by the clinical findings. The symptoms are dramatic and subject to swift change. The course of disease can advance within a matter of days or, in a subacute form, take several weeks. (12, 58, 62, 79) General symptoms: The acute clinical picture develops swiftly with conspicuous symptoms, such as fatigability, loss of appetite, nausea, weakness, lassitude, meteorism, apathy and disruption of the circadian rhythm. Encephalopathy: Rapidly, often within one or two days, there is evidence of dysarthria, muscle tremor, finger tremor, lack of concentration and asterixis. Restlessness, hyperkinesis and hallucinatory experiences occur. Even screaming attacks have been observed. These symptoms, which can still be classified under stages I and II, are fully reversible. Nevertheless, lethality of 30Ϫ35% must be anticipated in stage II. In contrast, stage III is clearly less reversible. Somnolence, stupor with confusion, deviant behaviour, hyperreflexia, Babinski's reflex, clonus and spasticity as well as nystagmus are now observed. There is usually still a response to acoustic stimuli. The EEG shows a slowing down of basic activity (0.5Ϫ3.0/ sec.) together with mainly biphasic and triphasic potentials. Lethality rises to over 50%. In stage IV, the patient is in a deep coma. There is evidence of areflexia, an absence of any corneal reflex and loss of tonicity; the brain waves flatten out to an isoelectric line. Irrespective of therapy, lethality is 80Ϫ90%. (s. tab. 15.5) Cerebral oedema: As from coma stage III, cerebral pressure can increase (75Ϫ80% of cases) owing to water retention and/or vasodilation with hyperaemia, yet with a subsequent reduction in cerebral perfusion and hypoxia. Intracranial cerebral compression is > 20 mm Hg. Cerebral oedema is vasogenetic and/or cytotoxic, the latter feature appearing to predominate. Clinical symptoms include disorders in the respiratory rhythm (in particular tachypnoea), hypertension, bradycardia and increased muscular tonus. Singultus implies damage to and impending constriction of the brain stem. The pupils are dilated due to the pressure on the oculomotor nerve. Chemosis can develop, which is a fatal prognostic sign. (2) Intracranial blood circulation sinks rapidly. In 30Ϫ60% of cases, cerebral oedema is fatal. (9, 10, 39, 64, 66, 75, 78) Jaundice: With the foudroyant disintegration of liver cells, a comatose condition can set in within a few hours, even before jaundice is identified. In most cases, however, jaundice is already present. The intensity and time of onset vary. Severe jaundice (> 20 mg/dl) is considered to be a poor prognostic sign. The sweet aromatic smell of the exhaled breath (mercaptan derivatives) is seen as a reliable sign of acute liver failure, but it is not always present. The administration of poorly absorbable antibiotics (e. g. paromomycin) improves the condition of hepatic foetor, and can even eliminate it temporarily. (s. pp 91, 275) Fever: Fever often occurs; it mostly remains at 38°C, but septic temperatures are possible. • In some cases, this may be a question of aetiocholanolone fever, whereby r r aetiocholanolone can also be quantified in the serum. • Bacterial infections likewise cause fever and require appropriate treatment. Toxins may also be responsible for the febrile condition (tissue toxins, endotoxins). (s. p. 761) Liver size: The liver may have normal size or it can be enlarged due to hyperaemia or massive fatty infiltration. A rapid shrinking of the liver to less than 1000 ml in volume ("dystrophy", "acute atrophy") Ϫ requiring sonographic or CT monitoring at the bedside Ϫ is deemed to be a poor prognostic sign. At present, there is no specific laboratory investigation which facilitates the diagnosis of acute liver failure. In view of the severity of this clinical picture, there are, however, a number of laboratory parameters which show marked pathological changes and thus require full diagnostic clarification. Activin A serum levels were elevated, especially in patients with acute liver failure, due to a paracetamol overdose. This did not affect the final outcome, but was possibly a factor in the inhibition of liver regeneration. Serum follistatin was also increased in patients with fulminant liver disease. (27, 35) Furthermore, the laboratory values allow an assessment of the complications involved and an evaluation of the prognosis. (7, 13, 14, 58, 62, 79) Various laboratory values are indicative of severe complications and thus considered to be criteria pointing to a poor prognosis. (s. tab. 20 6. Group-specific component protein: This substance (ϭ α 2 -globulin) is synthesized in the liver and binds actin. GCP is released upon hepatocyte decay; its pronounced reduction in the serum results from the decrease in synthesis in acute liver failure. (57) The course taken by acute liver failure varies in each case as a result of the respective complications, which also decidedly worsen the prognosis. Close-meshed and targeted laboratory investigations can usually identify complications early enough, so that successful therapy might still be possible. Coagulation disorders: Some 35Ϫ55% of patients with acute liver failure are in danger of suffering from serious gastrointestinal bleeding. Extensive cutaneous haemorrhages also occur frequently. In addition, disseminated intravascular coagulation (DIC) sometimes develops. As a result, bleeding and coagulation disorders number among the most frequent causes of death (20Ϫ25%). Pathophysiology is based on the diminished synthesis of coagulation and fibrinolysis factors and inhibitors as well as a decrease in the breakdown of activated factors, a functional disorder of thrombocytes or thrombopenia, and latent consumptive coagulopathy. It is of great help to determine PTT and factor V. A high level of the thrombin-antithrombin III complex (TAT) points to a poor prognosis. The simultaneous development of portal hypertension in individual cases promotes a tendency towards nasopharyngeal and gastrointestinal bleeding. ( Acid-base disorders: Initial metabolic alkalosis (resulting from decreased urea synthesis with reduced bicarbonate consumption) may be superimposed by respiratory alkalosis as an outcome of disorders in lung function. During the further course, metabolic acidosis (with renal insufficiency) and respiratory acidosis (with pulmonary insufficiency) can be expected. In advanced or severe stages of the disease, lactate acidosis may develop in some 50% of all comatose patients owing to restricted gluconeogenesis. Circulatory disorders: In general, acute liver failure is initially accompanied by hyperdynamic circulation. During the further course, approximately 80% of patients develop hypotension, which above all results in a considerable reduction in hepatic, cerebral and renal perfusion. At the same time, peripheral vasodilation is usually evident. Bradycardia, generally resulting from cerebral oedema, worsens the cardiovascular conditions and is considered to be a poor prognostic sign. Ultimately, the patient does not respond to volume expansion and catecholamines. Hypoglycaemia: In 25Ϫ40% of cases, hypoglycaemia develops and can all too easily be overlooked. The cause is seen to be a reduction in liver glycogen content, diminished glycogen synthesis and gluconeogenesis as well as hyperinsulinaemia due to reduced degradation of insulin in the liver. (21) It is often difficult to eliminate such hypoglycaemia, even with i.v. glucose infusions. • Furthermore, there is a danger of hypokalaemia and even hypophosphataemia, necessitating phosphate substitution with continuous monitoring of the serum values of phosphate and calcium (reactive hypocalcaemia is dangerous). The frequency of hyperamylasaemia is reported to be 55% of patients with acute liver failure; in 20Ϫ30% of cases, pancreatitis could be identified clinically and sonographically. The cause is multifactorial. Infections: Because of their greater susceptibility, about 80% of patients with acute liver failure are subject to the threat of bacterial infection, which in 10% of cases is also the reason for their death. The typical signs of an infection, such as fever or leucocytosis, are often absent. Increased levels of procalcitonin (> 0.58 ng/ml) are deemed to be a valid marker of bacterial infection. The respiratory tract and the urinary passages are most frequently affected. Regular bacteriological examinations (sputum or urine as well as catheter after removal) should therefore be carried out. Haemocultures have to be checked for both aerobians and anaerobians. Multiple serological tests may be necessary for aetiological clarification. There is also a certain risk of fungal infections. (51) The survival rate in acute liver failure is 10Ϫ40%. This rate varies widely owing to a number of reasons. There is a better prognosis for poisoning from paracetamol or Amanita phalloides, since successful therapy procedures are already established for these forms of intoxication. Younger patients (10 to 40 years) have a better prognosis. This also applies to HAV infection. A poor outcome can be expected in obesity, Wilson's disease or the Budd-Chiari syndrome as well as in coma stages III and IV (lethality over 80%) due to various complications (e. g. bleeding, renal or respiratory insufficiency, infection) Ϫ especially with younger (< 10 years) or older patients (> 40 years). Acute liver failure which is due to halothane, the application of various medicaments or viral hepatitis (delta superinfection, HEV in pregnancy) likewise has a less favourable prognosis. • Laboratory parameters such as serum bilirubin, higher AFP values (especially during the first three hospital days), coagulation factors, galactose test and cholinesterase have proved helpful in assessing the course of disease, liver function and prognosis. (14, 18, 22, 43, 46, 59, 62, 79) The regenerative ability of the liver is of utmost importance for overcoming such a severe disease. (40) After a regeneration period, an intact cell mass (hepatic volume fraction) of > 45% is required for survival. (41) Various factors are indicative of good regeneration: rising values of α 1 -foetoprotein (and also γGT), HGF, EGF, THFα, TNFα and interleukin-6 as well as a decline in serum phosphorous levels. (14) It was possible to improve regeneration by means of hepatotropic substances, such as insulin and glucagon, so that these substances are also referred to as "goodies" for the liver (S. Sherlock, 1976). Subsequent investigations proved to be contradictory. (23, 81) An increase in the regeneration rate of the liver cells can possibly be achieved either by hepatic arterial infusion of PGE 1 (56) or by silymarin through stimulation of RNA synthesis. (s. pp 44, 896) (s. fig. 3 .5) Chronic liver insufficiency is due to the progression of an already existing chronic liver disease. This generally tends to be advanced cirrhosis of varied aetiology. Basically, however, any liver disease can be a potential cause of chronic liver insufficiency. Alcohol, infections and certain medicaments are also deemed to be common causes. Thus a great number of substances and events can trigger liver insufficiency. The clinical picture of chronic liver insufficiency comprises both a compensated and decompensated form. These two stages of manifest chronic liver insufficiency affect the hepatocellular area or the portal system either exclusively or predominantly (ϭ cellular or portal compensation or decompensation); mostly they occur as a combined form of disease. The resulting spectrum of clinical and laboratory findings will reflect either a global or partial insufficiency of the liver. (s. p. 380) General manifestations of the disease: The clinical picture of chronic liver insufficiency is characterized by a number of symptoms such as fatigue, apathy, lack of appetite, lack of concentration, infirmity, sensation of repletion and meteorism. Clinical findings: Organ-related so-called "minor signs" of liver insufficiency can be observed over a certain period of time. (s. tab. 20.4) Ϫ itching Ϫ skin stigmata of liver disease Ϫ tendency to "bruise" Ϫ nasal haemorrhage and ulorrhagia Ϫ tongue changes Ϫ intermittent acholic stool Ϫ intermittent dark urine Ϫ anaemia Ϫ thrombopenia Ϫ leucopenia Ϫ macrocytosis 6. Fever 7. Splenomegaly Tab. 20.4: So-called "minor signs" of chronic liver insufficiency Constant meteorism ("first the wind and then the rain " ") and intermittent changes in the colour of stools and urine are distinct signs of impending insufficiency. The "blossoming" of spider naevi, an intensification of palmar erythema and tongue changes (e. g. transition of the moist "scarlet tongue" into a dry "raspberry tongue") are common. Obvious features of the blood count are: anaemia (due to bleeding of the skin or mucosa, folic acid deficiency, reduced erythrocyte survival time) and thrombopenia (due to consumptive coagulopathy, dilutional thrombopenia with plasma dilution, immunothrombopenia, sequestration in splenomegaly and toxic inhibition of the bone marrow). Decompensation in chronic liver insufficiency is characterized by the development of severe, life-threatening complications: 1. Ascites and oedema 2. Coagulopathy and bleeding 3. Hepatic encephalopathy 4. Hepatorenal syndrome 5. Hepatopulmonary syndrome 6. Impairment of liver functions Of particular significance is the serious impairment of essential tasks performed by the liver such as the detoxification function (ammonia detoxification, biotransformation, radical scavenger function, clearance abilities of the RES, etc.), the synthesis of vital proteins and the regulation of biochemical systems and substances Ϫ these are considered to be precursors of complicative developments. Any insufficiency of bilirubin metabolism is reflected in increasing jaundice, likewise deemed to be an unfavourable sign with respect to prognosis. The term hepatic encephalopathy (HE) describes the entire field of neuropsychiatric symptoms which can be found in patients suffering from acute or chronic liver disease. The term portosystemic encephalopathy (PSE) stresses the presence of portosystemic shunts, which are as a rule associated with liver cirrhosis. • Hepatic coma (in stages III and IV) is the ultimate and total loss of consciousness (coma ϭ deep, sound sleep). In clinical terms, four or five stages can be defined, but the latent or subclinical stage as well as stages I and II may progress so rapidly that only the comatose final stage is actually determined. Generally, chronic liver insufficiency is seen as a liver failure coma, i. e. exogenous coma. Recurrent hepatic encephalopathy points to the existence of a chronic liver disease, particularly liver cirrhosis. The serum levels of TNF correlate positively with the severity of HE. (see chapter 15) Ascites and oedema are also found in severe hepatic diseases, pointing to serious disorders in the water and electrolyte metabolism. These complications are signs of decompensation in liver cirrhosis or chronic liver insufficiency. Pleural effusion may also be evident. Cirrhosisrelated pleural effusion without concomitant ascites has been described as a rarity. (see chapter 16) All liver diseases resulting in liver insufficiency can also give rise to the hepatorenal syndrome. This syndrome is 386 most frequently found in decompensated liver cirrhosis ("renal insufficiency in the terminal stage of cirrhosis"). It involves massive vasoconstriction of the renal cortical vessels with a critical drop in the glomerular filtration rate (urine production < 500 ml/day, possibly developing into anuresis). At the same time, systemic vasodilation and hyperdynamic cardiac function are generally in evidence. The survival time is very short. Lethality is approx. 95%. (see chapter 17) In 15Ϫ30% of patients with liver cirrhosis, coagulopathy leads to clinically relevant haemorrhagic diathesis. Dangerous and considerable bleeding may occur (nasal, gingival), and there may well be pronounced cutaneous haemorrhages; the latter occasionally occur as sugillations, ecchymoses and petechial haemorrhages (s. This condition describes acute liver failure in cases of hitherto well-compensated liver disease. The result is a sudden deterioration in clinical status accompanied by jaundice as well as hepatic encephalopathy and/or the hepatorenal syndrome. There are a number of causes including (1.) well-known hepatotoxic factors (e. g. superimposed viral infection, alcohol consumption, hepatotoxic drugs, intoxication) and (2 ( ( .) endogenous factors (e. g. sepsis, variceal bleeding, gastrointestinal haemorrhage, diarrhoea, hypoxia). Acute liver failure is frequently the result of a chain of damaging events, like a vicious circle. The clinical and laboratory findings of this sudden deterioration largely correspond to those of acute liver failure (see above). This also applies to potential complications such as coagulopathy, HE, ascites and/or HRS. Except for the treatment of, for example, paracetamol intoxication and Amanita phalloides poisoning, there is no causal therapy for liver insufficiency. All conservative treatment measures are based on four principles: 1. Prevention and treatment of complications 2. Substitution of substances which cannot be adequately produced in the liver as a result of hepatic synthesis disorders 3. Bridging the period of time until toxins have been eliminated, liver functions and regenerative processes have improved or liver transplantation can be carried out 4. Promotion of liver regeneration ᭤ Intensive care: Patients with ALF or decompensated chronic liver insufficiency (e. g. coma stages IIϪIV, refractory ascites, hepatorenal syndrome, disseminated intravascular coagulation, gastrointestinal bleeding) require monitoring and treatment in an intensive care unit, preferably in a transplantation centre. (7, 13, 62, 79) Intensive care involves monitoring the cardiovascular system (blood pressure, pulse, ECG) and respiratory frequency. The patient's y y temperature and urine excretion have to be recorded every hour. The body weight is documented every day using a weighing bed. The water equilibrium should be carefully monitored. Consistent preventive measures against infection must be guaranteed for those patients who are particularly at risk. Regular physical measures for the prevention of pneumonia are a necessity. A moderate head-up position (30Ϫ40°) is recommended. • A central venous catheter (monitoring central venous pressure, parenteral feeding), a nasogastral tube and a suprapubic bladder catheter are positioned for supply and monitoring purposes. Nasal oxygen supply is advisable. The insertion of an epidural intracranial pressure probe is essential for early identification of cerebral oedema. Feeding: Provided the patient does not have a paralytic ileus, enteral feeding via a nasogastral tube is advisable to prevent villous atrophy and thus reduce the risk of bacterial translocation. (s. p. 878) • Parenteral feeding (1,600Ϫ2,000 kcal/day) consists of a continuous intravenous supply of glucose and fat emulsions (MCT). Hypertriglyceridaemia may, in the case of lipid infusions, point to a lipid metabolism disorder, but it can also be due to increased glucose intake, which results in fatty degeneration of the hepatocytes and a corresponding reduction in liver function. Fructose, sorbitol and xylitol must be avoided! The supply of either liveradapted amino acids or branched-chain amino acids is recommended for chronic liver insufficiency Ϫ but not advisable in cases of acute liver insufficiency, because almost all amino acids are elevated in the serum in endogenous hepatic coma. A high daily dosage of watersoluble vitamins (possibly divided into two doses) is important. Administration of zinc is recommended. Electrolytes (Na, K, Ca, Mg) and blood sugar must be carefully monitored, and any deviation from the norm should be corrected immediately. The risk of hypophosphataemia must be eliminated by early parenteral substitution. During refractory episodes, such as those involving the acid-base equilibrium and hyperhydration, haemodialysis is usually indicated. In hypoalbuminaemia, substitution with salt-free albumin is necessary. • With about 75% of patients, artificial respiration is called for, the aim being controlled hyperventilation. N-acetylcysteine is believed to promote the supply of oxygen to the tissues. (73) As a result, this substance, which is free from side effects, was also recommended for cases of CCl 4 intoxication (53) and is even considered helpful in acute liver failure with a different aetiology. H antagonists and omeprazole are recommended. • The timely and repeated administration of fresh plasma (FFB) as well as of antithrombin III has proved to be the most effective measure for balancing plasmatic coagulation disorders. Bacterial infections are extremely common as a result of serious impairment of the cellular and humoral resistance (ca. 80%). Close-meshed bacteriological investigations are required in the frequent absence of clinical signs of infection. This leads to early antibiotic therapy based on an antibiotic sensitivity test. Although an antibiotic prophylaxis is not actually recommended, it should nevertheless be considered in the individual case, since the spreading of an infection has a decidedly nega-tive impact on prognosis. • Administration of selenite (i.v.) may be advisable. Around 30% of patients develop a fungus infection, with a mortality rate of 50%. (s. p. 310) The administration of amphotericin B or fluconazol is an effective prophylactic measure. • Bacterial or fungal infection can also be effectively suppressed by intestinal restimulating of the bacterial flora or intestinal sterilisation by means of neomycin (or paromomycin), a combination of nystatin and gentamicin, or lactulose. (51, 54) (s. pp 285, 288, 310) Essential phospholipids (EPL): In a pilot study, it was possible to achieve recompensation and lasting stabilization in nine out of ten patients suffering from severe liver insufficiency by i.v. administration of a new galenic form of polyenylphosphatidylcholine. (32) • This clinical result accords with other clinical studies and might be supported by the finding that a considerable deterioration in liver function was associated with a deficit of EPL. (15) (s. p. 894) Paracetamol intoxication: Liver damage due to paracetamol (> 10 g) becomes manifest within ca. 48 hours after intake. (s. p. 382) For this reason, it is essential first of all to remove the non-absorbed fractions by gastric lavage and intestinal cleansing. As medicinal treatment, i.v. administration of the glutathione precursor Nacetylcysteine is the therapy of choice (L. F. Prescott et al., 1977) . Dosage is 150 mg/kg BW with glucose as a rapid i.v. infusion (15Ϫ20 minutes), followed by 50 mg/ kg BW over 4 hours and finally 100 mg/kg BW during the next 16 hours (ϭ about 300 mg/kg BW within 20 hours). This therapy has to be commenced as soon as possible (no later than 12Ϫ15 hours after intoxication), even though a hepatoprotective effect can still be achieved up to 36 hours later. A serum concentration of < 200 μg/ml within 4 hours or < 60 μg/ml within 12 hours after intake can be considered prognostically favourable. (s. fig. 20 .3) There is no specific antidote for Amanita toxins. Given timely and appropriate therapy, morbidity and mortality are surprisingly low. • In cases of therapy failure or a critical course of disease, liver transplantation may be indicated. Cerebral oedema: Mannitol (0.5 g/kg BW or 100 ml, each as 20% solution) is used to treat the dreaded cerebral oedema. If renal function is sufficient, this course of therapy can be repeated every one to four hours, as required. Serum osmolality should not exceed 320 mosm/l, and intracranial pressure should not go above 20 mmHg. When renal function is restricted, dehydration must be effected by haemofiltration. Artificial respiration is required (often as PEEP ventilation). Continuous monitoring of the intracranial pressure using an epidural intracerebral pressure probe is extremely helpful. Frequently, there is increased susceptibility to cerebral convulsibility; therefore, phenytoin should be administered at an early stage. Therapeutic application of thiopental (A. Forbes et al., 1989) as i.v. solution (up to 150 mg/hour) calls for intracranial pressure probe monitoring. (22) Other means of lowering the intracerebral pressure include the use of aminophylline, ranitidine, luxus oxygenation and semirecumbent positioning. (8, 17, 34, 65) A prophylactic reduction in pCO 2 down to 25Ϫ35 mm Hg through hyperventilation can be advantageous in the initial stage of a brain oedema. (17, 65) Moderate hypothermia (core temperature down to 32Ϫ33°C, for 10Ϫ12 hours) may be useful in reducing the intracerebral pressure and cerebral blood flow as well as the cerebral uptake of ammonia. (30) Ornithine aspartate (40 g/8 hours as intravenous infusion) (52) and flumazenil are advisable for the treatment of hepatic precoma and coma. Dopamine (2 to 4 μg/kg BW/hr) should be administered early on to stabilize the circulation and renal blood flow. • N-acetylcysteine can be applied during oxygenation due to its positive effect on stabilizing the blood circulation and improving the serum coagulation factors. • Indomethacine reduces cerebral ammonia uptake. The positive results achieved by the application of PGE 1 were reported in 1987 (M. Abacassis et al.). According to a subsequent prospective study, 71% of patients with fulminant and subfulminant hepatitis survived. (56, 63) The effect is attributed to improved arterial flow and regeneration of the liver (0.1 to 0.6 μg/ kg BW/hr by means of perfusor for up to 18 hours, with the dosage gradually being phased out). Lamivudine (100 mg/day) proved to be effective: it was possible to achieve a lasting improvement in liver function and to avoid liver transplantation. No side effects were observed. In view of the loss of complex biochemical liver functions, drug intervention in the metabolic processes of the liver should be as varied as possible Ϫ even the use of therapeutic agents which are not clinically controlled may be biochemically or pharmacologically justified. The most important survival factor in acute liver failure is the patient's age. In the 15 to 25-year age group, 30Ϫ50% of patients survive, whereas those older than 30 years have hardly any chance of survival. It would appear that the good regenerative ability of the liver in young people is the best guarantee for survival. • An attempt must be made at bridging the decompensatory phase by means of optimum intensive care and monitoring of the cerebral pressure as well as by applying clinically proven or indeed new therapeutic procedures or medication until the liver has adequately regenerated or until liver transplantation can be carried out. • Basically, there are three techniques available for bridging the compensatory phase: (1.) extracorporeal systems (2 ( ( .) biosynthetic artificial livers or hybrid organs, and (3.) transplantation of hepatocytes. (86, 87, 97, 98, 108) • It has proved to be much more successful when the serum (ca. 3 l fresh frozen plasma/day) is infused into the femoral artery rather than into the vein. In 1974 patient plasma separated by plasmapheresis was for the first time passed through activated charcoal and artificial resin in order to absorb toxins. In this way, the patient's own purified plasma is reinfused together with the solid components of the blood. This procedure produces fewer side effects and is easy to carry out. 6 . Total body wash-out: This technique is a modification of exchange transfusion. The circulatory system is washed out with electrolyte solutions and then refilled with donor blood whilst the patient is in a state of hypothermia (G. Klebanoff et al., 1972). 7. Haemodialysis: In 1968 temporary improvement could be achieved for the first time by means of haemodialysis in a patient presenting with fulminant hepatic failure (W. M. Keynes). The procedure, however, is not generally recommended. It may be indicated in renal failure, acid-base disorders or with hyperhydration. Following haemodialysis, substitution of reduced amino acids is necessary. This procedure turned out to be of more value than haemodialysis. No dialysate fluid is required. Instead, a solution containing buffered bicarbonate is used to replace the ultrafiltrate. In fulminant hepatic failure, continuous venovenous haemofiltration is recommended because of its advantages for the circulation and metabolism. Heparin or prostacyclin can be used as anticoagulants. 9. Haemodiabsorption: The BiologicDT system is a combination of haemodialysis and haemoadsorption (S.R. Ash et al. 1992 ). (84) Plasma separation was subsequently added to this system (S.R. Ash et al., 1998) . (85) This newly developed BiologicDTPF facilitates direct plasma contact with the haemodiadsorber. The system, which makes use of both a charcoal and a cation exchanger, dialyzes blood across a parallel plate dialyzer with a cellulose mem-brane. So far, results have been disappointing Ϫ only lactate, creatinine and bilirubin were reduced. The aim of albumin dialysis is to remove both soluble metabolites and albumin-bound substances (ABS) from the blood of patients with acute liver failure. (s. tab. 20.5) benzodiazepines fatty acids bile acids phenylalanin bilirubin several peptides carbon hybrids tryptophan copper etc. Tab. 20.5: Albumin-bound substances (ABS) relevant in acute liver failure SPAD: Single-pass albumin dialysis was the first method to be developed. The blood of the patient is extracorporeally dialyzed through an albumin-impermeable membrane against albumin in the secondary circuit. The loaded albumin is discarded. The SPAD method was further developed into a combination of dialysis, filtration and adsorption (ϭ molecular adsorbent recycling system). (105) . The patient's blood is fed through a hollow-fibre filter and dialyzed against an albumin dialysate. The ABS (s. tab. 20.5) pass through the pores in the filter and become bonded. Plasma proteins, hormones and vitamins are not lost. The albumin dialysate is recirculated in a closed circuit where it is fed through a second dialyzer and two adsorber columns which bind the ABS. The albumin dialysate is returned to the hollow-fibre filter. It is dialyzed against a bicarbonate solution in order to remove the excess water and water-soluble substances (ammonia, creatinine, urea, iron, copper) as well as to stabilize the electrolyte and glucose levels and the pH value. The results obtained to date are promising. (95, 103, 106) FPSA: Fractioned plasma separation and adsorption is a very efficient and multifactorial method, employing 390 membranes and adsorbants. (88) It is additionally characterized by the use of microparticles (2.0Ϫ3.5 μm), which are recirculated in suspension using high-speed flow (2Ϫ4 l/min) to optimize the in-line filtration process. In a further development, a special sulfone filter is applied. In the meantime, the Prometheus method has been introduced. (99) Here, the plasma is separated out by an albumin-permeable filter and cleaned in a secondary circuit via an adsorber together with conventional high-flux haemodialysis. Direct contact between the albumin plasma and the adsorber helps to increase the efficiency of this method. These liver support methods serve to detoxify the organism for a limited period of time. They are regarded as supportive measures in intensive care. Survival time has often been prolonged, yet only in isolated cases has the overall life-span of the patient been extended. These methods of treatment, which are costly and involve considerable resources, can only be carried out in medical units that are equipped with all the facilities of intensive care and thus in a position to effect epidural brain pressure measurement, blood purifying processes and liver perfusion methods. • Only young patients between the ages of 15 and 25 have a real chance of survival (40 to 50%), provided they receive optimum intensive care. With patients over 30 years, supportive techniques should only be applied to bridge the time period until a liver transplantation can be carried out. However, conservative treatment may be attempted for four or five days under the following conditions irrespective of age: (1.) there is a chance of regeneration during this period that can be made use of; (2 ( ( .) this period of time does not preclude the patient's chances of liver transplantation (which calls for two to four days' preparation time); (3.) should there be no signs of recovery or regeneration, not even in younger patients (< 30 years), transplantation is nevertheless indicated. • After four or five days, however, severe complications develop, also in younger patients, which render transplantation difficult or even impossible. Especially older patients (> 30 years) should undergo liver transplantation without delay. Temporary substitution of the liver function using hepatocytes (e. g. in haemofiltration systems or bioreactors) is conceivable in acute liver failure, possibly in conjunction with activated charcoal filtration or with plasma separation. The importance lies in bridging the phase of acute liver failure until compensation of the liver function or liver regeneration is achieved. The bioreactor is filled with capillaries in which the patient's blood circulates; some of this blood has already been oxygenated extracorporeally. The efficacy of the system depends on an efficient exchange of the corresponding substances in both directions as well as stable hepatocyte functions. It is possible to use human (allogeneic) or animal (xenogeneic) hepatocytes as well as cell cultures (immortalized cells or tumour cell lines). If human cells are taken, 10 10 hepatocytes per patient are required Ϫ as would be needed for a conventional liver transplant. Regarding the use of animal hepatocytes, there is a possible risk in that no solution has yet been found to the question of zoonosis transmission and there may be an immune reaction to foreign antigens. Bile flow also remains a problem. (92, 100, 101, 109, 110) 1. The binding of microsomal liver enzymes to synthetic carriers is a promising method of temporarily compensating important liver functions (G. Brunner, 1981) r r . Freshly isolated hepatocytes of pigs, immobilized on collagen-coated microcarriers, remained vital in-vivo and in-vitro over a longer period in a perfusion system; they were able to conjugate bilirubin and synthesize proteins. These results provided the basis for developing an extracorporeal bioartificial liver (A. A. Demetriou et al., 1986) . In more advanced systems, plasma was perfused through an activated charcoal column and a fibre system with cultured pig liver cells. (92, 97, 100, 110) • Using a BAL, the plasma is separated by centrifugation and directed into a reservoir in order to increase both the plasma and metabolite flow. By integrating an activated charcoal column, it is possible to effect a greater elimination of toxins. The separated plasma reaches the hollow-fibre bioreactor, where it is perfused through the previously inserted hepatocytes (7 ± 1 hours). • Such a system yielded increased production of coagulation factors in a patient with alcohol cirrhosis (D. F. Neuzil et al., 1993). (s. fig. 20 .5) Attention has recently focused on temporarily replacing the liver function with hepatocytes which have been cultured in the extracapillary space of a cellulose-acetate hollow-fibre unit. Each unit contains ca. 200 g C3A cells, an amount which is necessary for successful perfusion. ELAD has proved efficacious in clinical use. (108) 5. BLSS: The bioartificial liver support system is made up of a blood pump, a heat exchanger to control the blood temperature, as well as an oxygenator and a bioreactor. The hollow-fibre bioreactor generally contains 70Ϫ100 g of porcine liver cells. Initial experience with BLSS is encouraging. (94) 391 6. BELS: The Berlin extracorporeal liver support system consists of a three-dimensional accumulation of approx. 500 g pig liver cells. These cells are linked by means of capillaries and provided with oxygen independently of the patient's blood, so that they function and stay vital for several weeks. (91) The modular extracorporeal liver support system was developed from BELS. In contrast to BELS, however, it consists of three modules: (1.) a cell module with human hepatocytes, (2 ( ( .) single-pass albumin dialysis, and (3.) a dialysis module for constant venovenous haemofiltration. (102) The clinical significance of bioartificial systems largely depends upon whether it is possible (1.) to keep functional hepatocytes alive in extracorporeal systems for an adequate period of time and (2 ( ( .) to make such systems available at short notice for use in emergencies. The idea of extracorporeal liver perfusion (ECLP) for removing toxins by way of perfusion using an animal liver goes back to Andrews (1953) (86, 107) Although the procedure is relatively safe, the results obtained with perfused livers from humans or baboons would appear to be better than is the case with livers taken from pigs. (96) (121) . The transplanted split should be around 1% of the body weight of the recipient. SLT has a higher complication rate than OLT. LDLT: With regard to living donor liver transplantation, SLT has become particularly important in cases where no cadaver organ is readily available. Living donor liver transplantation was first carried out on children. The left lateral segment, usually segments II and III, of the donor's liver is used. Around 5% of OLT candidates are also suitable for LDLT. More than 2,500 living donor liver transplantations have been carried out worldwide. The donor mortality rate is 0.2Ϫ0.3%. (118, 119, 125) In 1991 auxiliary partial orthotopic liver transplantation (APOLT) was successfully carried out for the first time in acute liver failure, with the subsequent possibility of dispensing with the transplant after regeneration of the patient's own liver. (115) The corresponding part of a donor liver is transplanted orthotopically as left lateral segments II and III into the acutely diseased liver. The requisite partial resection of the liver is considered difficult. (124) A European multicentre study (12 centres) achieved equally good results in 30 patients compared to orthotopic liver transplantation with the removal of the native liver (M.-P. Chenard-Neu et al., 1996) . APOLT is intended as a temporary measure in acute liver failure with the aim of discontinuing immunosuppressive therapy after the patient's own liver has regenerated. So far, results imply that more complications are experienced in APOLT than in OLT. The concept of heterotopic transplantation of a complete or even partial ("spliced") donor liver should also be pursued further. Heterotopic transplantation involves placing an auxilliary (additional) organ in the right upper abdomen (O. T. Terpstra et al., 1988). In surgical terms, this technique is considered to be demanding due to the application of the piggy-back method (ϭ anastomosis of the donor liver with the appropriately prepared ostium of the hepatic veins to the infrahepatic caval vein, generally cranial to the opening of the renal vein). • These two methods (APOLT and auxiliary heterotopic liver transplantation) are particularly suitable for juveniles with acute liver failure because they bridge the critical time span preceding the regeneration of the diseased liver. Immunosuppression is thus only required for a restricted period of time. The transplant shrinks or is surgically removed. Acute liver failure induced by Ecstasy was successfully overcome using this technique. (116) It allows the liver function to be compensated and gives the diseased liver time to regenerate. (120) Pigs with human immune system genes are expected to facilitate the production of transgenic donor organs (D. White, 1992) . This is the basis of all endeavours to use transgenic pig liver for the purpose of xenotransplantation (J. Platt, 1993). In the future, genetic engineering should make it possible to eliminate the immunobiological risk of complement-activated, hyperacute rejection. However, the problem regarding the transmission of zoonoses has not yet been resolved. To date, a survival period of 70 days has been achieved with three xenotransplants in ALF and chronic liver insufficiency (J. Fung et al., 1997). Among the experimentally tested transplantation sites are the spleen, kidneys, lungs, pancreas, peritoneum, greater omentum and fatty tissue. Up to now, the spleen has proved to be the most suitable site. The transplantation of foetal liver cells into the spleen may even culminate in a liver lobule-like formation with bile ducts and veins Ϫ however, the functional results have (so far) been no better than with normal hepatocytes. The question of the required number of hepatocytes has still not been resolved: the collapse of a certain liver function (e. g. normalization of factor VIII values in serum) can be compensated by a far lower number of hepatocytes than is the case with total liver failure (e. g. acute liver failure). Calculations made up to now have claimed that there are at least 10 7 Ϫ10 8 liver cells in partially resected liver parenchyma. Indications for the transplantation of hepatocytes predominantly involve those liver diseases in which functional failures occur in the liver cells (not in the bile 393 ducts). • Permanent transplantation would be indicated, for example, in order to eliminate congenital metabolic disorders of the liver cells. In this case, it is possible to use hepatocytes from the patient, with subsequent elimination of the defect by gene technology, as well as hepatocytes from healthy donors. A therapeutic effect lasting for over one year was achieved for the first time in a girl suffering from the Crigler-Najjar syndrome (I. J. Fox et al., 1998). • Human hepatocytes are most definitely more suitable than animal liver cells. The latter may well meet the requirements for a provisional substitute, but not for permanent transplantation. ᭤ Looking into the future, it can be expected that the next few years will witness advances in gene technology (e. g. transgenic animal liver) and molecular biology (e. g. targeted blockade of the immune system against the liver transplant) or even produce new concepts of liver and hepatocyte transplantation. ᭤ It is no longer too bold to pin legitimate hopes on the development of an artificial liver. 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