Clinical Aspects of Liver Diseases 40 Treatment of Liver Diseases

Clinical Aspects of Liver Diseases 40 Treatment of liver diseases

Page: Page: 1 From mythology to provable treatment 844 5.5.3 Pharmacology 859 1.1 In global medicine 844 5.5.4 Indications 860 1.2 In hepatology 844 5.6 Branched-chain amino acids 861 2 Clinical studies 845 5.7 Amino acids of the urea cycle 862 2.1 Types of clinical studies 845 5.8 D-penicillamine 862 2.2 Problems of clinical studies 845 5.9 Somatostatin 863 2.3 Placebo 846 5.10 Terlipressin 863 2.4 Difficulty of evaluation 846 5.11 S-adenosyl-L-methionine 864 2.5 Provability of treatment 846 5.12 Haemarginate 864 3 Principles of liver therapy 847 5.13 Phytotherapeutics 864 3.1 Basic considerations 847 5.13.1 Essential phospholipids 865 3.1.1 Liver therapy 847 5.13.2 Silymarin 867 3.1.2 Liver therapeutic agents 847 5.13.3 Glycyrrhiza glabra 867 3.1.3 Protective therapy of the liver 847 5.13.4 Colchicine 868 3.2 Preconditions 847 5.13.5 Betaine 868 3.3 Aims of treatment 848 5.13.6 Cynara scolymus 868 3.4 Forms of “liver therapy” 848 5.13.7 Bupleurum falcatum 868 3.5 Categories of “liver therapeutics” 848 5.13.8 Phyllanthus amarus 868 3.6 Active substances 848 5.13.9 Schizandra chinensis 868 3.7 Dose adjustment of medicaments 849 5.13.10 Catechin 868 3.8 Significance of quality of life 850 6 Surgical therapy of liver diseases 869 4 Nutritional therapy of liver diseases 850 6.1 Ascites in portal hypertension 869 4.1 Artificial feeding 850 6.2 Bleeding in portal hypertension 869 4.1.1 Enteral feeding 850 6.2.1 Shunt operation 870 4.1.2 Parenteral feeding 851 6.2.2 Block surgery 870 4.2 Diet in malnutrition 851 6.3 Liver resection 870 4.3 Special diets 852 6.3.1 Basic principles 870 5 Drug therapy of liver diseases 853 6.3.2 Classification and indications 871 5.1 Virostatics 853 6.3.3 Regeneration 871 5.1.1 Interferon 853 6.4 Liver injuries 872 5.1.2 Nucleoside analogues 854 7 Liver transplantation 872 5.2 Immunosuppressants 855 7.1 Indications 873 5.2.1 Glucocorticoids 855 7.2 Contraindications 874 5.2.2 Azathioprine 856 7.3 Preoperative diagnostics 874 5.2.3 Cyclosporine A 856 7.4 Preparation of patients 875 5.2.4 Tacrolimus 856 7.5 Surgical aspects 875 5.2.5 Cyclophosphamide 856 7.6 Postoperative features 876 5.2.6 Methotrexate 856 7.7 Aftercare and rehabilitation 879 5.3 Immunostimulants 857 8 Sociomedical aspects 880 5.3.1 Selenium 857 8.1 Health awareness 880 5.3.2 Zinc 857 8.2 Preventive medicine 880 5.3.3 Thymosin 857 8.3 Rehabilitation 881 5.4 Ursodeoxycholic acid 857 8.4 Capacity for work 881 5.5 Lactulose 858 8.5 Self-help groups 883 5.5.1 Chemistry 858 ț References (1Ϫ426) 883 5.5.2 Pharmacokinetics 859 (Figures 40.1Ϫ40.7; tables 40.1Ϫ40.18)

843 40 Treatment of liver diseases

1 From mythology to provable ᭤ Preventive therapeutic empiricism was applied for treatment the first time around 1600, when it was discovered by “therapy comparison” that those seamen of the 1.1 In global medicine East India Company who drank lemon juice as a supplementary beverage did not contract scurvy. This was the basis of (probably) the first “statistic- ᭤ Recommendations and discussions on the treat- al” therapeutic study, which J. LIND carried out in ment of diseases and injuries are as old as medicine 1747 in order to confirm a lemon juice theory in itself. According to our knowledge of earlier times, several groups of people by administering various sub- medicine has its origins in mythological therapy. This stances, including a “placebo”. This theory was also also applies to the treatment of liver diseases. • confirmed by J. Cook in 1776, using a similar study Understandably, “surgical medicine”, especially trau- design. Further therapeutic milestones of medical matology, enjoyed the highest scientific status in history include the comparative studies with digi- antiquity, since the actual “cause” and medical talis (W. Withering, 1785), smallpox vaccine (E. Jenner, “effect” were most obvious in this field. • Mytho- 1798) and mercury treatment of syphilis (J. Pearson, logical ideas and rituals were therefore of minor sig- 1800). Such comparative studies, which were based nificance to the barber surgeon: in general, practical on individual observations, aimed at proving the experience, manual skill and (mostly self-developed) effectiveness of treatments; this development ended appropriate instruments produced the desired result. the epoch of empirical therapy. (2) (tab. 40.1) By contrast, “conservative medicine” was characterized by mythology, steeped in ritual as well as (mantic) divination and, for many epochs, mostly left in the hands of the “priest doctor”. In spite of some- 1.2 In hepatology times astonishingly good diagnostic capabilities and prognostic accuracy, medicine on the whole Ϫ espe- ᭤ During a period of about 3,000 years, hepatology also cially treatment of the patient Ϫ was subject to the experienced these historical medical epochs of therapy, prevailing mythology of the respective epoch. (s. tab. (1.) mythological, (2.) speculative, (3.) empirical, and 40.1) (4.) provable. (s. tab. 40.1) • In addition to cataplasms Ϫ consisting of various herbs, oils or products derived With the gradual rejection of “mythos” and a from animals, mostly prepared and used according to stronger tendency to “logos”, therapeutic measures mythologically related ideas Ϫ cupping, scarification, of a mythological and ritual nature were increasingly enemas, blood-letting and sternutators, the following abandoned. At the same time, however, the absurd materials were also used: dried wolf’s liver with honey, speculative therapy ideas of reached an unimaginable donkey liver with parsley, raw ox liver dipped in honey, level of odiousness. Obscure mixtures, fantastic prep- ox blood, etc. Some highly complex and fantastic arations as well as nauseating and even cruel treat- mythological diets were applied as well. Therapeutic ment methods were more and more propagated and measures were often based on certain mythological applied. An insight into these abnormalities of specu- numbers or ritual-dependent points in time and per- lative medicine is given by K.F. Paullini (1699) in his formed before statues of gods or in connection with ani- book: „Neu-vermehrte, heilsame Dreck-Apotheke“ mal sacrifice. (see chapter 1.) • From the mediaeval (“Revised and Enlarged Curative Dirty Pharmacy”). “dirty pharmacy” came numerous, disgusting therapeutic recommendations for patients with liver disease, e.g. With the coming of the Age of Enlightenment in the consumption of the excrement of certain animals, ear middle of the 18th century, accompanied by a rapid wax, dirt scraped off sheep udders, earthworms, poly- increase in medical knowledge, the calls for con- pods dissolved in wine, or a certain number of live firmed results became more and more urgent. This sheep’s lice. (s. p. 437) • Empirical treatment increasingly led to the advent of empirical therapy, which required made use of substrates of plant origin or extracts of subtle observation, critical analysis, careful examin- Hyoscamus, Cheliodonium, dandelion or milk thistle, ation and, above all, a written record of case histories. etc. To my knowledge, comparative therapeutic investiga- In this connection, surgical empiricism was more tions such as those mentioned above were not performed strongly based on morphological facts and objective in hepatology. Until modern times, treatment of liver methodological experience than the therapeutic diseases remained almost exclusively empirical Ϫ and empiricism of conservative medicine. thus scientifically unproven.

844 Treatment of liver diseases

ried out, as far as possible comparatively, as a retrospec- Mythological therapy tive or prospective investigation. • A retrospective study is a backward-looking review of facts and effects, i.e. Speculative therapy against a time axis, to identify preceding causes. The -pro ؍) data can be collected according to a fixed plan -retrolec ؍) Empirical therapy lective) or generated before the study begins Lack of “Therapeutic tive). Furthermore, a distinction is made between proof nihilism” following the individual course from the time the caus- ؍) Adjuvant therapy ative factor appears through to the onset of effect cohort) and following the individual course from the Provable treatment onset of effect back to the earliest possible point in time .trohoc) (A.R ؍) pharmacological experimental when the causative factor appeared • studies Feinstein, 1977). Thus, a retrospective study is deemed • clinically controlled studies scientifically correct if its execution is justified and the New approaches to treatment methodology is clearly defined. • A prospective study genetic starts from causative factors, observing the effect over biomolecular the course of time. (6, 7, 9) invasive surgical Special cases are the open (non-blind) study on the one Tab. 40.1: Historical epochs of medicine: (1.) mythological, (2.) hand and the crossover study on the other hand. • This speculative, and (3.) empirical therapy, through to (4.) provable means that the controlled clinical study is “fundamen- treatment tally” (i.e. with some exceptions) the sole and most essential tool for obtaining proof of the efficacy of a The occasionally pronounced “polypragmatism” was given substance. If the conditions for a controlled clin- confronted by the opposite extreme of “therapeutic ical study cannot be met, then it must be dispensed with. nihilism” in the sense of treatment based on expect- typology ation. This inevitably led to frustration on the part of The of clinical studies differentiates four types the physician and to resignation on the part of the according to their aims: (1.) pharmacological studies, patient suffering from a liver disease. • Thus, the real- (2.) therapeutic explorative studies, (3.) therapeutic con- ization of provable treatment also became an urgent firmative studies, and (4.) drug-monitoring studies. The challenge in hepatology. purpose of the last-mentioned group is to define the cost/benefit ratio more precisely, identify rare side effects and provide better dosage recommendations. 2 Clinical studies 2.2 Problems of clinical studies The first ethical principles of biomedical research had already been developed in Germany prior to World There is a vast array of literature dealing with still con- War I: relevant instructions were issued by the Prussian troversial aspects of controlled clinical studies. • We Education Office in 1900. At the proposal of the Ger- should be aware that on the one hand, medicine is not an man National Health Board, guidelines for modern exact science and on the other hand, humans do not repre- curative treatment and for the performance of scientific sent a quantifiable model with data on call as needed. studies in humans were issued in 1931 by the Ministry Problems in clinical studies often arise in different fields: of Internal Affairs in Germany. • The following year (1932), P. M artini published his methodology of thera- 1. ethical 4. psychological peutic research, and in 1937 A.B. Hill established the 2. methodological 5. heuristic principles of medical statistics. 3. legal 6. economic

2.1 Types of clinical studies Proof in the strict sense cannot be delivered by a controlled clinical study, which has been called the “sacred Significant contributions have since been made concern- cow”. (5) However, the probability of statistical error in ing the importance, performance and evaluation of clin- terms of the chosen target criteria can be fixed in ical studies. (5, 6) In recent years, statistical and legal advance. In clinical studies, different interpretations of issues in particular have been discussed. (3, 7, 8, 9) • Con- results are still possible, since “intuitive medical obser- trolled clinical studies are rightly called for and they vation and judgement remain indispensable in the indi- are indispensable for avoiding therapeutic misjudgement vidual case” (E. Buchborn, 1982). • The triad of empiri- deriving from “trial and error” and for creating an cism, intuition and logic is necessary in both diagnosis objective basis for official decisions. They may be car- and treatment (R. Gross, 1988).

845 Chapter 40

2.3 Placebo 1. equality of structure A placebo (Latin, “I shall please”) or ADT (ϭ any what 2. equality of observation you desire thing) is a “dummy” without any active sub- 3. equality of representation stance, identical in appearance to the respective active drug and not designed to be effective. This term has Even with great diagnostic effort, no convincing struc- been known since the 14th century. (4) • In medicine, a tural equality is obtainable. Consequently, randomiza- placebo assumes two roles: (1.) as a therapeutic agent in tion alone does not guarantee a valuable clinical study. the practical treatment of patients, intended to have an Despite these problems, three study types should (and “effect” on a disease or a symptom, or exerting such must) be used: effects without the physician’s knowledge, and (2.) as Examination of effect a control substance in clinical studies with drugs. • In 1. ϭ individual cases, even objective changes in physiological change in any one parameter functions and specific effects may be demonstrable. The 2. Examination of efficacy form of administration and the dosage of a placebo, the ϭ cure or improvement of disease physician’s personality (and that of the patient) and the 3. Examination of superiority intensity of the disease situation may lead to a weaken- ϭ improvement of parameters, or cure, or ing or potentiation of the placebo effect. The important improvement of disease by conventional (individual and social) ethical issues associated with therapy vs. new therapy placebo administration concern both the patient and the physician, who have to be informed in general about such procedures. These issues have been clarified by law after being discussed in detail and assessed on the basis 2.5 Provability of treatment of experimental findings. In clinical studies involving drugs Ϫ this also applies to hepatology Ϫ the terms “effect” and “efficacy” have not ᭤ The placebo effect in controlled clinical studies always been appropriately distinguished, but were often should never be regarded as “zero”, even though this (erroneously) considered identical. • The effect of a spe- is, of course, desired (or even imputed) from the cific drug (or “liver therapeutic”) showing changes in statistical viewpoint. any measured parameters or reactions is easier to prove than its efficacy in the sense of cure or improvement of Within the scope of clinical studies, valuable economic disease. Therapeutic efficacy (or efficacy of “liver ther- information on medical procedures can (and should) be apy”) is defined by the difference between the uninflu- obtained. Today, economic assessment assumes a special enced disease course (i.e. possible or usual course) and role in clinical studies, and because of its complex strati- the disease course changed by therapeutic measures (i.e. fication and the general need for rationalization, e.g. in actual course). There is, however, no chance of ever terms of the cost/benefit analysis, it is likely to become observing and assessing the “possible” and the “actual” more and more important. The quality-adjusted life disease course simultaneously. year (G.W. Torrance, 1987) should be included in the The marketability of a pharmceutical preparation is assessment. (s. p. 850) controlled by an act of administration. In this context, three criteria must be satisfied for the licensing of medic- 2.4 Difficulty of evaluation aments, including “liver therapeutics”: Proof of efficacy of a certain (surgical or medicinal) 1. quality 2. safety efficacy therapeutic measure Ϫ and this also applies in hepat- 3. ology Ϫ is very difficult, as it mainly depends on two factors: The term “quality” is defined by the following criteria: purity, identity, content, galenic properties and 1. non-comparability of individual humans temperature stability of a substance. • The term 2. non-comparability of individual diseases “safety” is defined in relation to acute and chronic toxicity, foetal toxicity and fertility, mutagenic and Statistical methods cannot render either non-compar- carcinogenic potential. ability of individual humans or that of diseases compar- able Ϫ at best, they may compensate it by means of As regards the term “efficacy”, no legal definition exists. large patient numbers or are able to assess sameness As a rule, efficacy is defined by the sum of desired under certain circumstances. (1, 5) • Statistical compar- effects with regard to a certain therapeutic aim. Thus, ability of different patient groups can only be achieved in terms of the licensing regulations, the efficacy of a if three requirements are met: drug, including “liver therapeutics”, may be defined as

846 Treatment of liver diseases

“the abstract quality of medicine to achieve therapeutic 3.1.2 Liver therapeutic agents success with proper use, accidental and placebo success In the strict linguistic and hepatological sense, there is having been excluded” (K.J. Henning, 1978). The US Food, no such thing as liver therapeutic agents. However, this Drug and Cosmetic Act defines the term efficacy in a unfortunate term is frequently Ϫ and indeed deliberately similar manner. • Mere proof of quality and safety is Ϫ used rhetorically in publications or for administrative sufficient for medicine that does not have be licensed, reasons. Here, the expression “hepatic agents” (analo- but only registered; no proof of efficacy is required. This gous to cardiac, otologic and diuretic agents, etc.) would applies to homoeopathic remedies, for example. • The be more correct and not so promising in the popular efficacy of medicinal remedies, including “liver thera- sense as the designation “liver therapeutic agents”. • In peutics”, may be regarded as a continuum, i.e. from any case, one ought to be aware of the possible psycholog- “very weak” to “highly potent”. Thus, efficacy is also ical effect of such a term, especially with regard to a proven when the substance is shown to be only slightly “placebo”. (s. p. 846) effective or is only effective in some patients (individual cases). Principally (ϭ exceptions are possible), proof of efficacy is to be provided by controlled clinical studies. 3.1.3 Protective therapy of the liver No proof of superiority of the drug under investigation Similarly, there is no generally protective therapy of the over the standard preparation is required by law. Nor liver. Liver “protection” as such may include active does the licensing procedure check whether there is a vaccination against viral hepatitis A or B, for example, potential need for the drug in question. • Thus the aim and, in a wider sense, also passive immunization after of clinical studies is to provide proof of safety and appro- exposure or general avoidance of typical liver noxae. priate efficacy. This can “protect” the liver from diseases. (12) In in-vitro and in-vivo experiments, certain substances can be studied for their protective effect on the hepatocytes or endothelial cells (including biomembranes and 3 Principles of liver therapy organelles) under the influence of various noxae or 3.1 Basic considerations toxins. Many substances have been shown to display dis- tinct protective properties experimentally under various First of all, two terms need rectifying, since the investigative conditions. Such studies are not, however, superficial yet incorrect use of the designations “liver admissible in humans. • These experimental protective therapy” and “protective therapy of the liver” have properties may also be of therapeutic value in individual rendered it fundamentally more difficult to make cases (e.g. application of silibinin in Amanita poisoning). accurate statements. These terms are relics from the A “liver-protective preparation” must therefore be cap- epochs of speculative or empirical therapy and con- able of protecting the hepatocytes (as well as the sinus stitute the origin of the catchword “therapeutic nihil- endothelium) from a particular liver toxin, or from 2 or ism”. (s. tab. 40.1) 3 clearly defined (or, in the optimal case, all obligate) liver toxins, by administration before or, at the latest, when the damage occurs. The use of a substance in exist- 3.1.1 Liver therapy ing cellular damage would be classified as “therapy” and no longer “protection”. The term protective liver ther- There has never been and there still is not any “liver Ϫ therapy” in the true sense Ϫ and no such therapy will apy clearly implies prophylaxis which, apart from the exist in future either. The liver as the largest biochemical above exceptions (e.g. vaccination), is usually not feas- performance centre of the body is constantly active in ible under the provisions of the respective health in- some 11 major metabolic areas with 60Ϫ70 integrated surance system. (12) partial functions. In order to accomplish the many tasks, about 300 billion liver cells undertake approx. 500 3.2 Preconditions biomolecular reactions daily Ϫ indeed an unbelievable feat. Consequently, it is not possible for drugs to have The question of provability of a certain therapy is also an effect on the liver as a whole. However, therapies for dependent on various factors in hepatology: (1.) know- liver diseases or therapies for hepatological symptoms are ledge of the spontaneous course of a liver disease (not available. With this linguistic correctness, our therapeu- known in individual cases, but only globally assessable), tic efforts in hepatology become realistic and objectifi- (2.) endogenous factors (gender, age, genetics), and (3.) able. There are far more than 100 liver diseases plus exogenous influence (e.g. lifestyle, noxae, patient com- variants and diverse complications. A large number of pliance). These imponderables can scarcely (if at all) be them can be treated successfully with pharmacological integratively assessed or excluded even using subtle stat- regimens Ϫ sometimes with strikingly good results Ϫ as istical methods. Randomization and double-blind clin- well as, of course, by invasive and surgical therapy. ical trials can do no more than balance out these differ-

847 Chapter 40 ences. In order to obtain usable data, certain statistical 3.4 Forms of “liver therapy” conditions should be fulfilled as far as possible: Causal treatment of liver diseases, which is rarely (if Ϫ homogeneous findings ever) feasible, should achieve the complete elimination in of the actual cause(s) (e.g. elimination of the causative Ϫ homogeneous patients noxa, antiviral treatment, gene therapy in hereditary Treatment of pathogenetic primary reac- with liver diseases). • tions Ϫ homogeneous disease (e.g. with interferon, immunosuppressants or penicillamine) is aimed at interrupting the “postcausal” Treatment of disease progression These requirements are difficult to meet even in con- pathogenesis. • inter- trolled clinical studies in hepatology. Moreover, the use venes in the pathological process in a lasting and effi- of medication in liver disease is based on further essen- cient manner and thus prevents or slows down the gen- tial clinical conditions: erally dangerous consequences (e.g. inhibition of cholestasis, fibrogenesis and portal hypertension). • 1. Detailed hepatic diagnosis with exact classification Almost all substances used in hepatology are classed of the liver disease as symptomatic treatment. These substances help (1.) to 2. Identification and elimination of the causative combat malaise and disturbances secondary to the liver noxa(e) disease (e.g. antipruritics) and (2.) to influence the 3. Elimination of concomitant negative factors or structures and functions of the hepatocytes and endo- additional noxae thelial cells as well as the bile capillaries (e.g. antioxidants, essential phospholipids, UDCA, silymarin). (12) Therapeutic uncertainties or differing conclusions regarding drug effects or efficacy may thus be attributed 3.5 Categories of “liver therapeutics” to varying degrees of methodological inaccuracy as follows: A number of substances and preparations are available Ϫ for the treatment of liver diseases. They can be categor- different disease courses ized as follows (s. tab. 40.3): with Ϫ different pathogenesis 1. Prophylactics: e.g. immunoglobulins or vaccines in against hepatotropic virus infections Ϫ different patients 2. Antidotes: e.g. silibinin against Amanita and an poisoning or N-acetylcysteine in paracetamol Ϫ insufficient detailed diagnosis intoxication, haemarginate in acute porphyria were submitted 3. Primary liver therapeutics: e.g. penicillamine, to glucocorticoids, azathioprine, interferon-α, aimed Ϫ joint statistical evaluation at primary intervention in the aetiology or pathomechanism of liver disease. Secondary liver therapeutics: 3.3 Aims of treatment 4. e.g. fat-soluble vitamins in impending deficiency states, drugs to Drug therapy of a particular liver disease or complica- reduce portal hypertension, substances to relieve tive development must have basic treatment aims. The hyperammoniaemia, aimed at secondary primary therapeutic aim is to eliminate the existing prevention of the various sequelae of liver causative factors and pathogenetic mechanisms. The disease. final goal is always the rehabilitation of the liver patient. Tab. 40.3: Categories of liver therapeutic agents (s. tab. 40.2) (s. p. 881)

1. Eliminating or definitively overcoming the cause 3.6 Active substances of disease (as far as possible) as well as promoting and speeding up its cure For several years, (negative) claims appeared in the press stating that the pharmaceutical market was over- 2. Inhibition of inflammatory reactions saturated with more than 600 liver preparations. 3. Curbing of mesenchymal reactions Although the originator of this claim was not identified, 4. Modulation of immunological reactions this utopian number made the rounds. • In fact, there 5. Support/normalization of liver cell functions are merely 25 substances or groups of substances (of 6. Stimulation of hepatic regeneration ȇ chemical or plant origin) listed in the pharmacopoeia. Rehabilitation Here, the various preparations containing the same substance are numbered separately, which gives a total of Tab. 40.2: Treatment aims in liver diseases 90؊100 listed preparations. • It is irresponsible that

848 Treatment of liver diseases some “liver therapeutics” still have an alcohol content of be obtained “empirically”, but because they are not 25Ϫ66 vol.% (particularly homoeopathic and phyto- “statistically” confirmed, they are not “provable”. In therapeutic remedies). (s. p. 60) Although the often this context as well, empiricism, intuition and logic may quantitatively low intake of alcohol in a preparation diverge (s. p. 845), so that statistics, which as such are may be “harmless” (even “3 times daily”), it will usually indispensable, may indeed prove to be an obstacle. cause a relapse in an abstinent alcoholic. In principle, there is no justifiable argument for keeping the alcohol Perhaps the expectations or requirements of “liver ther- content in a hepatological preparation! apy” are too high. With regard to other organs and their respective diseases, established medication often does Some medicaments with special indications are used in not really achieve a “cure”, but merely “functional various liver diseases or in certain complications. They improvements” (e.g. recompensation, inhibition of pro- are not found in the special category of liver therapeut- gression, stabilization in everyday life, improvement in ics (pharmacopoeia), but are listed according to their quality of life, rehabilitation). In principle, these fully main indication. Treatment with some of these active acceptable therapy aims apply to the treatment of liver substances may possibly be accompanied by side effects. diseases as well. (s. tab. 40.4)

Chemical substances (or groups) 3.7 Dose adjustment of medicaments

1. Amino acids of the 10. Immunosuppressants Liver and medicaments are interrelated in three ways: urea cycle 11. Immunostimulants 2. Beta blockers 12. Lactulose 3. Bile acids 13. Nucleoside analogues 1. Medication inducing liver diseases 4. BCAA 14. S-adenosyl-L-methionine 2. Medication for liver diseases 5. Deferoxamine 15. Somatostatin 3. Medication changed by liver diseases 6. D-penicillamine 16. Spironolactone 7. Diuretics 17. Virostatics 8. Glucocorticoids 18. Vitamins (AϪK) Apart from the kidneys, the liver is the most important 9. Haemarginate 19. Zinc excretory organ for drugs. In contrast to other mechanisms of drug elimination, which are relatively well Phytotherapeutic agents (or groups) understood, liver metabolism of drugs has proved Ϫ 1. Colchicine extremely complicated. (s. pp 52 56) Biotransformation 2. Essential phospholipids is influenced by variable and non-variable factors under 3. Glycyrrhizin physiological and pathological conditions. (s. tab. 3.18) 4. Silymarin • Changes in pharmaceutical preparations are alterations 5. Various herbal preparations in the respective properties which occur due to the dis- Tab. 40.4: Active chemical substances (or groups) and phytothera- turbed metabolization function of the liver cells and/or peutic agents used in some liver diseases or their complications hepatic blood flow secondary to liver disease. Addition- ally, drug metabolism may be drastically modified by Active substances with sufficiently proven efficacy in the coexisting hypoalbuminaemia or cholestasis. Liver dis- field of hepatology are only administered as “treatment” eases do not only affect the elimination parameters (e.g. and not as “liver protection” (apart from the prophylact- half-life, clearance), but also absorption (e.g. bioavail- ics mentioned above). These active substances are used ability) and distribution of the drug in the body. A fur- in patients when, according to the diagnosed disease ther factor are the interactions of certain drugs with and the clinical and pharmacological results, they are receptors at the site of action (e.g. increased sensitivity actually indicated. • Thus, it is the existing liver disease of the brain to diazepam in cirrhosis patients). Biotoxo- and/or complication and not the medication budget or the metabolites and lipid peroxidation, which are not nor- patient’s wishes which decides the therapeutic indication. mally typical of a certain medicament, must also be Anything else would go against the principles of a phys- anticipated. • In principle, a dose reduction should be ician or be uneconomical, and legally problematic in considered in severe and chronic liver disease, especially individual cases. when the medicament is used regularly. On the other hand, a dose increase may be required in i.v. administra- “time”, The second dimension of controlled studies, is tion owing to reduced hepatic blood flow and using frequently given insufficient consideration in evaluating medication with a high elimination rate. • Disturbed therapeutic results. In fact, it is only possible to assess drug metabolism may be further aggravated by alcohol whether the substances used in chronic liver disease consumption with its multiple biochemical effects. (s. p. have the required efficacy after an adequate treatment 61) (s. tabs. 28.2, 28.3) period. In the drug therapy of patients with chronic liver disease as carried out by the clinician and general prac- Despite great efforts, it has not been possible so far to titioner, evaluation periods invariably extend over sev- make single dose calculations (1.) for a certain medica- eral years. In such cases, positive or negative results can ment, (2.) in a certain liver disease, and (3.) in a certain

849 Chapter 40 patient. Some drugs have been classified into three 4 Nutritional therapy of groups on the basis of their hepatic extraction rate and liver diseases route as well as their form of administration: drugs with a high, with a moderate and with a low risk of overdos- The Hippocratic idea that “dyscrasia” was the cause of age Ϫ however, such information is given with reserva- nearly all diseases meant that dietetics (ϭ diaita) was tions. The difficulties regarding the correct dose adjust- necessary for the “restoration to normal of the life order”. ment of a medicinal remedy in therapeutic use require (s. p. 6) Even in antiquity, special forms of nutrition careful monitoring of the individual patient, sometimes were of great importance in the treatment of liver dis- also determination of the blood values, or consultation eases. In addition to those dietary prescriptions which with a pharmacologist. (12) were within the reach of everyone (e.g. donkey liver with parsley and honey) (s. pp 7, 844), there were also ᭤ In view of these difficulties, it may be problematic extremely complicated diets for the treatment of jaun- to administer the same dose to all volunteers and to dice which only “kings” could afford (Celsus called jaun- obtain pharmacologically equivalent results in clinical dice the morbus regius). (s. p. 7) • During all historical studies. This might also explain the occasionally great epochs of medicine, dietetic measures have played an variation in study results (despite a carefully chosen essential role in the treatment of liver diseases Ϫ even trial design) and any potential “inefficacy” or un- in the so-called “dirty pharmacy” of mediaeval times. desired effect of the drug. (s. p. 56) (s. p. 844) Because dietetics also assumed such an important role in hepatology, nutrition, i.e. enteral intake of special beverages and food, was mainly based 3.8 Significance of quality of life on mythological and later also on speculative ideas. From the beginning of the 20th century, a mild liver diet Of the two dimensions of life, quantity and quality, clin- was propagated, which in some cases was pursued with ical studies have inevitably paid far more attention to quantity of life scientific meticulousness. The purists issued strict nutri- the former (i.e. length of life). The tional rules for patients concerning liver diets. In those (judged by survival probability, mortality rate or sur- days, we young clinicians often had great difficulty in vival curves) seems to be the most important parameter implementing such guidelines in practical terms. • This for the assessment of treatment efficacy. A review of 99 one extreme was set against the other extreme of thera- publications which had appeared in leading surgical free choice of food Ϫ peutic nihilism, i.e. a by the patient journals from 1981 1986 revealed that in 97% of the (“eat what you like”). (s. tab. 40.1) papers, no mention was made of quality of life after Ϫ surgical procedures in 341 publications on cardiac ᭤ Neither extreme is acceptable Ϫ in fact, certain liver surgery, this was mentioned in only 8% of cases (J. diseases or complicative developments require special oung O’Y et al., 1985, 1987). Obviously, the prolongation of forms of nutrition. life was paramount in fixing therapeutic aims. (1, 10, 11, 13, 14)

Defining and measuring the quality of life has become 4.1 Artificial feeding important in recent years. This also applies to the con- Artificial feeding is indicated when the liver patient is servative or invasive treatment of liver disease, and, in no longer able to, does not want to, or is not allowed to future, more attention will have to be paid to criteria eat anything because of complicative situations. It may for assessing the changed quality of life under certain also be necessary to prevent malnutrition as well as to therapies as well as the choice of certain treatment stra- eliminate manifest dietary deficits rapidly and success- udwig tegies (M. L , 1988). The definition of good life qual- fully. • Artificial feeding may be performed enterally by ity implies that (1.) a person experiences the least pos- nasogastric tubes, gastrotomy or jejunostomy, and par- sible impairment and handicap under a given therapy enterally by central-venous catheter systems. This meas- ϭ ( clinical norm), (2.) this person functions in accor- ure is carried out short term during inpatient treatment dance with existing social roles and derives satisfaction or long term on an outpatient basis at home. from this (ϭ social norm), and (3.) the hopes and expec- ϭ tations of this person are fulfilled ( individual norm) 4.1.1 Enteral feeding (M. Bullinger, 1988). • In one comprehensive survey of the literature, not one single study focusing on the qual- Should artificial feeding be necessary, the enteral route ity of life in liver disease is cited. • Remarkably, a later of application should be given preference. This is feas- study mentioned a significant reduction in the quality ible in 90% of hepatological problem cases. Nutrition of life in patients with chronic hepatitis C. (11) In a fur- consists of high or low molecular weight formula diets. ther study, interferon treatment was not only shown to Feeding may be continuous or in 4Ϫ5 phases. Naso- improve the disease, but also to enable the patients to gastric tubes are harmless even when oesophageal vari- resume their normal daily routine. ces exist. Artificial enteral feeding must correspond with

850 Treatment of liver diseases the principles of energy and metabolism as well as con- 560Ϫ700 kcal). Blood glucose and lactate levels must be taining vitamins, electrolytes and trace elements in opti- monitored. Fats are the most important energy carriers; mum amounts. At the same time, it must be appropriate approx. 20Ϫ50% of the total calorie requirement should with regard to the underlying liver disease. • Enteral be provided in the form of lipids, preferably as MCT/ feeding has significant trophic effects on the intestinal LCT emulsion (1 g fat/kg BW). The latter are also read- mucosa in stimulating local IgA production, improving ily metabolized by cirrhosis patients. (19Ϫ21) In cases of the integrity of the intestinal mucosa as a barrier against acute liver failure (s. p. 383), disturbances in amino-acid bacterial translocation and regulating the physiologic- metabolism generally occur. Amino-acid infusions ally adapted intake of nutritional components, which should be avoided in this disease phase Ϫ coma-adapted are subsequently made available to the liver in a physio- or liver-adapted amino-acid infusions may be indicated logical first pass effect. Serious metabolic disturbances (0.4 g AA/kg BW/day with the possibility of dose in- must be avoided; other complications occur only rarely. crease up to 1.0 (Ϫ1.5) g/kg BW/day). Vitamins, electro- (17, 22, 23) lytes and trace elements must be sufficiently substituted. The adjuvant use of essential phospholipids and ornith- 4.1.2 Parenteral feeding ine aspartate is pharmacologically plausible. The regimen of parenteral nutrition must be monitored daily. Indications for artificial feeding via a central-venous catheter must be considered carefully. As a rule, it is (18, 20) possible only for a brief time, since the application period is limited by several complications: (1.) venous 4.2 Diet in malnutrition thrombosis, (2.) local infection, and (3.) systemic infection (in the usually immunocompromised liver patient). Chronic liver diseases, especially cirrhosis and alcohol- With prolonged parenteral alimentation, (4.) complica- induced conditions, are accompanied by malnutrition in tions in the form of various liver damage must be antici- 50Ϫ80% of cases. The prognosis of the liver disease pated. • The reported frequency of liver damage is largely depends on the nutritional state Ϫ there is also 15Ϫ100%. This generally depends on the duration of a direct relationship between the probability of survival parenteral feeding, but occasionally the composition of after liver transplantation and preoperative malnutri- the infusion solution proves to be inappropriate. La- tion. (17, 19, 20, 23Ϫ27, 29, 32) boratory parameters show increases in GPT, GOT and Causes of malnutrition include: (1.) reduced quantity γ -GT as well as in alkaline phosphatase and bilirubin. and quality of nutrition, (2.) maldigestion and malab- As a rule, these changes are reversible; however, exces- sorption, (3.) accelerated protein breakdown and pro- sive elevations, especially catheter-associated infections, tein loss as well as reduced protein synthesis (PEM), (4.) may necessitate the discontinuation of parenteral feed- increased energy requirement, especially in the case of ing. Deaths have occurred in up to 3% of cases. (15, 16, complications, and (5.) metabolic disturbances (e.g. 18, 21) • Various forms of morphological liver damage insulin resistance, sympathicotonia, loss of metabolic may develop, possibly in combination: efficiency). (s. p. 741) 1. Hepato/splenomegaly 5. Fatty liver The resting energy expenditure (REE) (in kcal) in 2. Cholestasis 6. Steatohepatitis 3. Jaundice 7. Fibrosis chronic liver disease can be calculated according to the 4. Slight to moderate hepatitis 8. Cholelithiasis Harris-Benedict equation, considering the patient’s body weight (W), height (H), and age (A). • Multiplying the The pathogenetic mechanisms of liver disease caused by REE (kcal) by factor 1.2Ϫ1.4 gives the energy require- artificial feeding are not fully understood. Various the- ment under normal daily conditions. ories (؉ (13.7 ؋ W) ؉ (5.0 ؋ H) ؊ (6.8 ؋ A 66.0 ؍ have been postulated: (1.) deficiency of essential Men (؉ ( 9.6 ؋ W) ؉ (1.7 ؋ H) ؊ (4.7 ؋ A 65.5 ؍ fatty acids or essential phospholipids, (2.) exceeding the Women maximum glucose oxidation rate, (3.) lack of important substances (e.g. choline, taurine, glutamine, inositol, The proportions of carbohydrates (4.0Ϫ5.0), fats carnitine), (4.) in individual cases, the presence of toxic (1.0Ϫ2.0) and proteins (0.8Ϫ1.5) (each in g/kg BW/day) metabolic components (e.g. methionine, plant sterols) in patients with chronic liver disease correspond to or newly formed biotoxometabolites. • It must be borne those of an ordinary diet; the basic calorie requirement in mind that cirrhosis patients usually show endogenous is 35 kcal/kg BW/day. • From the metabolic viewpoint, hyperinsulinaemia. A high intake of glucose should thus and in the case of diabetes, daily food intake should be be avoided, as should the additional administration of divided into 3 main meals and 2 snacks. As a prophylac- insulin. The so-called sugar substitutes (e.g. sorbitol, tic measure, it is advisable to restrict the use of common mannitol, xylit, maltit) are not to be recommended. (20) salt to 7Ϫ8 g (because of the very high NaCl content in (s. pp 351, 383) the usual diet). Moreover, a preponderance of lacto- The calculated glucose requirement of the brain is 1.5 vegetarian proteins over proteins derived from meat and mg/kg BW per minute (i.e. 140Ϫ160 g carbohydrates, fish (with their higher production of ammonia) is

851 Chapter 40 recommended. A sufficient intake of vitamins, electro- In liver cirrhosis, a lactovegetarian protein supply lytes, trace elements and roughage should be guaran- always has to be given preference; ammonia-forming teed. (22, 27, 33, 34) (s. p. 741) animal proteins should only be present in the food in low quantities and consumed every few days. Malnutri- Principles of lifestyle tion has to be eliminated by corresponding dietetic measures. In severe cases of disease, artificial feeding 1. Alcohol abstinence (enteral, or for a short time parenteral) may be recom- 2. Avoidance of noxae and toxins mended. (20, 25, 30Ϫ32) (s. pp 742, 850) 3. Reaching and maintaining a normal body mass Haemochromatosis: Iron is ubiquitous in food. A low- index iron diet must be observed consistently (using available 4. Paying attention to the sensitive water-electrolyte food tables). Although a lactovegetarian diet is desir- balance (s. figs. 16.1, 16.3) (s. pp 288, 305, 741) able, attention should be paid to the very high iron 5. Avoidance of malnutrition and undernourishment content of pulses, green vegetables and dried fruit. • (s. pp 587, 728, 851) Black tea (2Ϫ3 cups per day) should be drunk regularly. (s. p. 625) List of instructions: These “principles of lifestyle” Wilson’s disease: With a normal diet, the daily copper should be closely observed by the patient; they apply to supply amounts to 3Ϫ6 mg. In Wilson’s disease, how- every hepatological disease situation. We have always ever, the copper content should be reduced to <1 mg/ included these principles on a list of instructions given day (using the available food tables). As in haemochro- to our patients together with the documentation sheet. matosis, a lactovegetarian diet is important, but atten- (s. fig. 15.3) tion should be paid to the very high copper content of coarse-grained wholemeal products, nuts, cheese (Em- 4.3 Special diets mental, Edam) and cocoa. The intestinal absorption of copper can be reduced further by potassium sulphide (3 Special dietary measures are of major, often even of ϫ 20 mg). (s. p. 616) decisive importance for several types of liver disease or Encephalopathy: The diagnosis of HE, even in the stage associated complications. • Here, too, the false, universal of latency (s. p. 272) (s. fig. 15.3), requires an adjustment claim that “there is no liver diet” is invalid. In the same of protein intake. This applies to both the daily amount way that treatment of a liver condition is indeed pos- (ϭ cutting down) and the type of protein (ϭ only lacto- sible, there are also dietary measures for certain forms vegetarian proteins). No reduction in fats is necessary. or complications of liver disease. • After an exact diag- (26) Carbohydrates should be restricted to 2.5Ϫ3.5 g/kg nosis has been established, there is often a necessity for BW. The return to standard nutrition should correspond dietary therapy depending on the respective hepatolog- to the gradually improving quantitative and later also ical situation. qualitative protein tolerance threshold, varying from At this point, we would like to emphasize once again case to case. Should no nitrogen balance and no that a strict lactovegetarian protein supply must be improvement in the HE symptoms be achieved with adhered to not only in latent encephalopathy, but also lactovegetarian protein intake, supplementation with in (acute or chronic) liver diseases in which insufficient branched-chain amino acids is indicated. The latter also detoxification of ammonia is anticipated. When assess- stimulate muscular protein synthesis and promote the ing the so-called protein tolerance threshold (s. p. 278), formation of glutamine in the brain. However, they are the documentation sheet (s. fig. 15.3) as well as a psycho- not equivalent to substitution by balanced amino-acid motoric test programme (s. p. 203) can be of great help. solutions. Commercially available protein preparations should be low in common salt. (s. pp 277, 732) Metabolic diseases: A fatty liver does not require a low- Ascites: fat diet, but standard nutrition based on general refer- The occurrence of a disturbed water-electrolyte ence values for normal daily routine. With a normal balance in the late stage of latent oedema (s. fig. 15.3) (s. body weight and an increased energy requirement p. 297) requires immediate restriction of the salt intake (<3Ϫ6 g/day) Ϫ depending on the level of natriuresis: (work, sports), the calorie intake has to be adjusted Ϫ accordingly. • In overweight patients, a slow, continuous, the intake of fluid is limited to 1.0 ( 1.5) l/day, especially in hyponatriaemia. An intermittent fruit and rice yet systematic weight reduction should be strived for. Ϫ Coexistent hyperlipoproteinaemia may require support- diet (generally for 1 2 days) is recommended because it ive treatment. Diabetes mellitus must be properly con- is extremely low in sodium, but rich in potassium. trolled. This also applies to concomitant gout. Marked NaCl restriction simultaneously leads to a reduction in protein intake. The use of commercially Cirrhosis: In compensated liver cirrhosis without obvi- available low-salt protein preparations is therefore ous malnutrition or undernourishment, no special diet advisable (e.g. 60 g protein/100 g ϩ 5 mval sodium/100 is necessary, and normal balanced nutrition is adequate. g, or 48 g protein/100 g ϩ 13 g, or 15 g sodium/100 g).

852 Treatment of liver diseases

NaCl restriction is contraindicated in natriuresis of <25 attach themselves to the cell membranes via specific adsorption). Viruses enter the cells by ؍) mmol/day. (s. p. 308) receptors means of endocytosis. The virus coat opens, with the Storage diseases: Some of the genetic metabolic diseases result that viral nucleic acid and enzymes are liberated require special dietary measures, e.g. (1.) disorders of the uncoating). This is followed by transcription of viral ؍) urea cycle are treated by means of a diet similar to that nucleic acid to mRNA, the formation of enzymes (ϭ applied in encephalopathy (s. p. 594), (2.) Gierke’s dis- early-phase proteins) and structural proteins (ϭ late- ease necessitates a high-carbohydrate diet (s. p. 595), (3.) phase proteins) as well as nucleic acids for virus multi- Cori’s disease is treated with formula diets and a starch replication). After maturation, the viruses ؍) plication diet (s. p. 596), (4.) galactosaemia requires a galactose- are released from the host cells by exosomes. • Virostat- and lactose-free diet (s. p. 597), and (5.) in fructose in- ics can therefore have the following points of attack:(1.) tolerance, a fructose- and saccharose-free diet must be prevention of viral attachment to the host cells, (2.) in- given. (s. p. 597) hibition of penetration, (3.) inhibition of uncoating, (4.) inhibition of nucleic acid synthesis, (5.) inhibition of protein synthesis, and (6.) prevention of virus liberation. 5 Drug therapy of liver diseases (s. tab. 40.5)

A great number of different active substances have Due to their various modes of action and viral targets, been discussed in connection with the treatment of some first and second generation virostatics have also the various liver diseases or their complications in the been employed for treating hepatitis viruses. Thus, vari- secondary respective chapters. The effectiveness of these sub- ous virostatics are indicated in infections with hepatotropic viruses stances has either been statistically confirmed in con- (s. pp 112, 464): trolled trials, or they have been tested empirically,or Aciclovir HSV, VZV (EBV) they seem to be pharmacologically plausible for a spe- Amantadine Influenza A, B cific application. • Some of these therapeutic sub- Didanosine HIV stances and their uses are presented in more detail in Famciclovir HSV the following section. Foscarnet HSV, CMV, HIV Ganciclovir CMV, HSV, VZV (EBV) Vidarabine HSV, VZV (EBV) DNA- Reverse Chain Zidovudine HIV dependent trans- break polymerase criptase Virostatics are not indicated in acute viral hepatitis Amantadin Uncoating induced by primary hepatotropic viruses. Their application is, however, recommended in chronic hepatitis B Aciclovir Replication ϩϩand C and B/D. Interferon is the first choice in this Adefovir Љϩ ϩ Famciclovir Љϩconnection. It is also used (as early as possible) in acute Foscarnet Љϩ HCV infection. In infections with hepatotropic viruses, Ganciclovir Љϩ ϩthe following virostatics have already been introduced Interferon Љϩ or are under discussion: Lamivudine Љϩϩ Lobucavir Љϩ ϩ 1. Aciclovir 9. Interferon α, β Vidarabine Љϩ 2. Adefovir 10. Lamivudine 3. Amantadine 11. L-dT Didanosine Transcrip- ϩϩ 4. Emtricitabine 12. Lobucavir Foscarnet tion of ϩ 5. Entecavir 13. Ribavirin Zalcitabine RNA to ϩϩ 6. Famciclovir 14. Tenofir Zidovudine DNA ϩϩ 7. Foscarnet 15. Vidarabine 8. Ganciclovir etc. Interferon Maturation

ϩ Ribavirin Replication 5.1.1 Interferon Tab. 40.5: Some modes of action and points of attack of virostatics Interferons (IFN) were discovered in England by A. Isaacs et al. in 1957. (39) They are low molecular weight 5.1 Virostatics glycoproteins acting as cytokines (so-called intercellular mediators) with clear species-specific effects. Interferon Viruses have no metabolism of their own; they are only type I includes the subtypes IFN-α and IFN-β. They able to replicate in living host cells. Replication can be are formed by nearly all cells, whereby IFN-Ͱ is mainly inhibited by virostatics. Generally, however, viruses can- produced by monocytes and B-lymphocytes, and IFN-β not be completely inactivated; as a rule, this is only pos- mainly by fibroblasts. Both subtypes bind to the same sible by means of the body’s own defences. • The viruses receptor at the target cells and are taken up in the hepa-

853 Chapter 40 tocytes by endocytosis. Prior to degradation, IFN acti- to therapeutic efficacy. It is still unclear which actions vates many genes, thus causing a broad spectrum of pro- or mechanisms assume a central role in the treatment of teins to be synthesized. This explains its multiple chronic viral hepatitis. (40, 42Ϫ45) (s. tab. 40.6) biological effects. The antiviral effect of IFN-α is evident in all the important steps of virus replication. How- 1. Antiviral effects ever, the various cell types form different IFN-α sub- ț Reduction in cellular uptake of viruses types; so far, more than 30 subtypes are known. IFN-α ț Inhibition of intracellular processing of viruses ț and IFN-β have a half-life of (only) 3Ϫ4 hours. Reduction in viral mRNA synthesis ț Reduction in protein synthesis ț Interferon type II includes IFN-γ, which is probably Induction of ribonuclease only produced by T lymphocytes and natural killer cells. 2. Immunostimulation ț IFN-γ is of no importance for the therapy of viral hepa- Induction of substances inhibiting cell division ω and reducing oncogene expression titis. (36) (s. p. 702!) • Recently, IFN- was isolated, but Ϫ cytokines its biological role is not yet understood. Ϫ complement factors (B, C2) Ϫ nuclear proteins Recombinant IFN is produced from a clone of E. coli, ț Increase in the activity of which carries a plasmide that possesses a gene for Ϫ macrophages and natural killer cells Ϫ IFNα . The molecular weight amounts to 19,200 dal- cytotoxic T lymphocytes 2b ț tons. It has a high level of purity (>99%). If antibodies Hypothalamus-mediated fever Increased expression of membrane proteins against recombinant IFN occur, natural IFN may prove 3. ț HLA classes I, II Ϫ antigens useful. Recombinant interferons differ in only one single ț β2-microglobulin amino-acid position: ț Fc-receptor 4. Antineoplastic effect Position 23 Position 34 ț Inhibition of cell division ț Decrease in oncogene expression α IFN- 2a lysine histidine ț Direct cytotoxicity IFN-α arginine histidine 2b 5. Inhibition of fibrosis IFN-α2c histidine arginine Tab. 40.6: Biological modes of action of interferons Lymphoblastoid IFN-α also exists; this is a mixture of natural IFN-α subtypes with different structures of the interferon treatment consensus IFN-α The principles and results of in carbohydrate chains. • Furthermore, a chronic viral hepatitis B and C have been discussed has been developed; this is a genetically modified IFN- in detail. (s. pp 702, 707) α, which has the properties of various IFN-α subtypes. Thus its biological activity is increased (by ca. 30% in chronic hepatitis C, probably due to better receptor 5.1.2 Nucleoside analogues affinity). Nucleosides (e.g. adenosine, cytidine, guanosine, pyrimi- Pegylated IFN: The optimization of biological IFN dine, thymidine, uridine) consist of a nitrogenous purine effects has been achieved by pegylated IFN. The term or pyrimidine base linked to a 5-carbon sugar (ribose or “pegylation” denotes covalent linkage of polyethylglycol deoxyribose). Nucleotides (adenine, cytosine, guanine, (PEG) to IFN. Thus IFN is protected from proteolysis, thymine, uracil), the phosphate esters of nucleotides, and its half-life is extended approx. tenfold (to about 40 form the basis of RNA and DNA. As infectious viral hours). Therefore, this “depot interferon” has an nucleic acids, they are capable of penetrating the cells and improved efficacy due to prolonged persistence in the using available enzyme systems for replication. body. (35, 37, 38, 41, 45) As modified nucleoside components, the nucleoside analogues inhibit the replication of viral nucleic acids. Peginterferon Peginterferon Therefore, they belong to the group of virostatics. They alpha-2a alpha-2b (40 kDa) (12 kDa) are phosphorylated by means of cellular or viral kinases, thus becoming biologically active. As regards their clin- Volume of distribution (units) 8Ϫ12 l 0.99 l ical application as virostatics, it must be ensured that Clearance (units) 94 ml/h 22.0 ml/h endogenous DNA synthesis is not inhibited along with Absorption half-life 50 h 4.6 h viral nucleic acid synthesis. Otherwise, severe mito- Elimination half-life 80 h ϳ40 h Time to maximum 72Ϫ96 h 15Ϫ44 h chondrial lesions with lactic acidoses and irreversible concentration (Tmax) liver damage may occur, possibly with a fatal outcome, Peak-to-trough ratio 1.5 >10 as was the case with fialuridine used in chronic hepatitis B (R. McKenzie et al., 1995). The interferons display multiple biological modes of Many of these nucleoside analogues have already been action. Each of these effects (or their sum) contributes used clinically as virostatics against secondary he-

854 Treatment of liver diseases patotropic viruses, influenza A or HIV infection. (s. p. given successfully as early as 1989 in chronic hepatitis 853). The development of nucleoside analogues is of B. Subsequently, good results were achieved in combi- great importance for the treatment of chronic hepatitis nation with IFN. B and C or D. Their virostatic efficacy can be studied Ribavirin: in chronic hepatitis B using standardized in-vitro sys- (6.) This guanosine analogue was first used experimentally by O. Reichard et al. (1991) and in chronic tems and animal experiments. (50) In hepatitis C, no ndersson such models exist, so that efficacy studies are only pos- hepatitis C by J. A et al. (1991). It is rapidly sible in infected patients. Several new developments have absorbed and distributed in the body, but is excreted slowly (half-life 79 hours). The bioavailability is already been incorporated into clinical studies in hepat- Ϫ ology. They are generally used in combination with 45 65%. As a monotherapy, it only leads to a decrease interferon; in some cases, two nucleoside analogues may in transaminases and a slight improvement in histological activity. Ribavirin may not exhibit a direct antiviral be used together. (45, 50, 52, 55) effect, but can trigger a favourable response to (1.) Famciclovir: After absorption, this guanine deriva- interferon. When combined with IFN, ribavirin proved tive is converted to its active form penciclovir. The bio- far more efficacious in chronic hepatitis C (immunomo- logically active metabolite penciclovir triphosphate, dulation?) without any increase in the typical side effects which effects the inhibition of viral DNA polymerase, is of IFN. (49, 51, 53) (s. p. 707) ϫ only formed in the infected liver cell. The dosage is 3 Amantadine: 500 mg/day. • After discontinuation of this substance, (7.) The antiviral efficacy of amantadine the previous findings usually reappear, i.e. it is only (1-adamantanamine) was reported for the first time by avies effective as an ongoing treatment. It is used therapeuti- W.L. D et al. in 1964. The mode of action consists in preventing uncoating and viral maturation (i.e. inhibit- cally in combination with IFN. (47) (s. p. 705) ing the release of the nucleic acids that have already (2.) Lamivudine: This is a cytosine(cytidine)-nucleoside penetrated the host cell). The active substance is almost analogue. Its effect is based on the inhibition of reverse completely absorbed following oral administration. It is transcriptase in HIV and of DNA polymerase in HBV. eliminated unchanged via the kidney. The half-life is The daily oral dosage is 1 (Ϫ3) ϫ 100 mg/day. After about 15 hours. So far, it has only been indicated to discontinuation of lamivudine, the previous findings combat influenza virus type A. (s. p. 708) recur; here, too, efficacy only exists with continued therapy. A combination with famciclovir seems promising. Its clinical application is mainly in combination with 5.2 Immunosuppressants IFN. Long-term monotherapy over several years may be necessary. (48, 54) (s. p. 704) Immunosuppressants are substances that suppress the immune response. Inhibition or neutralization of the (3.) Lobucavir: This guanosine derivative has proved major part of the body’s defence system is essential in very effective against HBV. The dosage is 1Ϫ4 ϫ 200 (1.) organ transplantation and (2.) autoimmune dis- mg/day. After discontinuation of the one-month ther- eases. The following are considered to be some of the apy, values returned to their initial levels. A combin- most important immunosuppressants: ation with IFN is also recommended for this substance, and indeed has a very good action profile. 1. Antilymphocytic globulin 6. Glucocorticoids Aciclovir: 2. Anti-CD 3 antibodies 7. Methotrexate (4.) After oral application, only about 20% of 3. Azathioprine 8. Sirolimus the applied dose of this guanosine derivative is ab- 4. Cyclophosphamide 9. Tacrolimus sorbed. Aciclovir is mainly eliminated via the kidneys 5. Cyclosporine A (ca. 85% of the dose within 48 hours). Its half-life, which is approx. 3 hours, depends on renal function. The substance is employed especially in HSV and VZV infec- 5.2.1 Glucocorticoids tions. This agent inhibits DNA polymerase (i.e. replication) and effects a chain break. As a monotherapy in The immunosuppressive effect of glucocorticoids is HBV infection, aciclovir only shows moderate efficacy. based on the reduced formation of interleukins 2 and 6 Side effects are rare. with inhibition of T lymphocyte proliferation and on a decrease in IL-2 release. The glucocorticoids are there- (5.) Ganciclovir: This is a guanosine derivative exhibit- fore effective at a very early phase of the immune ing a good action profile in HBV, EBV, CMV and VZV response. • At the same time, phospholipase A2, and infection. Ganciclovir triphosphate inhibits virus repli- thus prostaglandin synthesis, is inhibited, and leucocyte cation. The half-life is about 4 hours. Elimination is via migration is reduced (ϭ anti-inflammatory effect). (60) the kidneys. Only a minor fraction of this substance is The clinical use of glucocorticoids is indicated in (1.) absorbed after oral administration; application (e.g. in autoimmune hepatitis, (2.) immunocholangitis, (3.) PBC CMV infection) is usually intravenous (10 mg/kg BW/ with a progressive course, (4.) florid alcohol-induced day). It has severe toxic side effects. Ganciclovir was hepatitis or progressive alcoholic liver disease with evi-

855 Chapter 40 dence of antihistone B2, and (5.) drug-induced idiosyn- ically, its main indication is the prevention of transplant crasy of the immunological type. In the diseases men- rejection. (57, 62, 64) Occasionally, it has also been used tioned under points (4.) and (5.), the use of in liver diseases, particularly in autoimmune hepatitis glucocorticoids should be reviewed critically. and PBC. (65) As in the case of azathioprine, cholestasis also constitutes a major hepatological side effect when 5.2.2 Azathioprine using cyclosporine. Canalicular damage demonstrated in animal experiments could be prevented by S-adeno- The effect of azathioprine is based on inhibition of T syl-L-methionine. Cyclosporine may cause elevated as lymphocyte proliferation and differentiation of activated well as reduced blood values in combination with many B and T cells. This results in a change in interleukin other medicaments. (68) (s. pp 650, 686) expression. Azathioprine suppressed CD 28-dependent Rac-1 activation, resulting in suppression of bcl-x expression and a consecutive induction of T cell 5.2.4 Tacrolimus apoptosis. These results have important implications for Tacrolimus was introduced for clinical use in 1989 as a the development of novel substances showing higher new, well-tolerated immunosuppressive substance that affinity to Rac-1 with more specific therapy in autoim- can be administered orally or intravenously. Its immune diseases and organ transplantation. (66) Azathio- munosuppressive effect is based on the inhibition of the prine is converted in the hepatocytes to 6-mercaptopu- lymphokinin synthesis of interleukins 2 and 3, inter- rine, the actual active agent. The half-life is 5 hours. It feron-γ and TNF-α as well as a reduction in interleukin- can take several weeks until a steady state is reached in 2 receptor expression. Tacrolimus leads to inhibition of the blood, which explains the delayed effect of azathio- T cell activation, the formation of cytotoxic T lymph- prine (3Ϫ6 months). It is assumed that (due to genetic ocytes, the induction of specific T helper cells and T determination?) the imidazole residue of azathioprine is helper cell-dependent B cell proliferation. Its bioavail- capable of binding sulphhydryl groups, resulting in an ability is about 20%. A number of studies have mean- additional antimetabolic effect. (56) Pharmacological while been published reporting the superiority of tacro- differences are further suggested by a report stating that limus over cyclosporine. (58, 62) Experimentally, treatment failure with azathioprine in autoimmune tacrolimus has been found to effect a decrease in free hepatitis was successfully overcome by subsequent treat- radicals, cytokines, tumour necrosis factor and neutro- ment with 6-mercaptopurine. (63) A short time after the philic infiltration in liver tissue. A possible increase in introduction of azathioprine, results of comparative blood values (hitherto) occurring with about 20 drugs studies with azathioprine and 6-mercaptopurine in and a fall in blood values with numerous other drugs CAH (probably autoimmune hepatitis) were reported. must be considered. Tacrolimus may cause manifesta- (61) • Azathioprine is used clinically in autoimmune tion of diabetes, or even trigger it. Initially only intended hepatitis, immunocholangitis and progressive PBC. as an immunosuppressant against graft rejection (59), Combined use with prednisolone yields even better tacrolimus has meanwhile also been used successfully in results. (63) These two substances administered at a low PSC and autoimmune hepatitis. (67) (s. p. 686) maintenance dosage can ensure remission for many years. (60) Maintenance of remission achieved with azathioprine following discontinuation of prednisolone has 5.2.5 Cyclophosphamide likewise been reported. Hepatological side effects Cyclophosphamide is a prodrug which is converted into include bone-marrow depression, allergic reactions, active metabolites in the liver. Urotoxic side effects must greater susceptibility to infection, cholestasis, destruc- be anticipated; they can be suppressed by the additional tive cholangitis, VOD and nodular regenerative hyper- administration of sodium-2 mercaptoethanesulphonate. plasia. (s. pp 650, 685) • This alkylating substance has a strong immunosup- 5.2.3 Cyclosporine A pressive effect; therefore, it is occasionally used to prevent graft rejection or (at a low dosage) in autoimmune This active substance suppresses the release of interleu- hepatitis. (s. p. 686) kin 1 from monocytes and the synthesis of interleukins α 2, 3 and 4 as well as of TNF- from T helper cells; 5.2.6 Methotrexate T cell proliferation, macrophage stimulation and B cell activation are inhibited. Even at an early stage of the This folic acid antagonist belongs to the group of anti- immune reaction, this leads to the suppression of both metabolites which suppress endogenous substances humoral and cellular immune responses. The body’s (metabolites) and trigger the formation of functionally bacterial defence is still not significantly influenced, as incompetent macromolecules. Because of their largely the phagocytic activity of the RES is barely inhibited by non-specific effect, all rapidly dividing cells are ad- cyclosporine. Bioavailability is about 35% following oral versely affected and toxically damaged. At a low dosage, application; it is almost completely metabolized in the methotrexate has been used in autoimmune diseases. (s. body and eliminated predominantly via the bile. Clin- pp 650, 658, 686)

856 Treatment of liver diseases

5.3 Immunostimulants drase, and especially superoxide dismutase. Zinc metabolism primarily occurs in the liver. It is largely governed Immunostimulants are defined as substances which by hormones (e.g. glucagon, insulin, glucocorticoids, stimulate immunological responses and improve a weak- ACTH, STH, sex hormones) and regulated by interleu- ened immune system. They include interferon, thymus kins 1 and 4 as well as TNF. Its close relationship with factor, interleukins, extracts of microorganisms, chem- the immune system thus becomes evident. (76, 78) ically defined substances (e.g. levamisole, selenium, Among other things, zinc influences thymulin, DNA zinc) and plant-derived substances (extracts from Phyl- and RNA polymerase (ϭ gene expression in cell differ- lanthus, Bupleurum, Glycyrrhiza, Schizandra, etc.). (s. entiation and proliferation) and the mediator functions pp 705, 868) in the immune response. (75) Understandably, zinc deficiency in liver cirrhosis or alcoholic liver diseases may 5.3.1 Selenium well contribute to the patient’s susceptibility to infec- Discovered by J. J. Berzelius as early as 1817, selenium tions or febrile conditions (e.g. spontaneous bacterial was only recognized as being an essential trace element peritonitis) and possibly even the induction of carcino- for humans in 1957. So far, glutathione peroxidase (G.C. genesis. • The multiple biochemical roles of over 200 Mills, 1957) and 5-deiodase (D. Behne et al., 1990) have been zinc-containing enzymes explain the wide spectrum of defined as selenium-containing enzymes. The daily manifestations associated with zinc deficiency in hepat- requirement ranges from 20 to 100 µg, which is met ology. This is of great importance for the pathogenesis mainly by animal protein; in the case of a lactovege- of hepatic encephalopathy and the therapeutic use of tarian diet and a simultaneously increased need (e.g. zinc. (69, 70) (s. pp 90, 269, 278, 787) due to liver cirrhosis or malabsorption), cellular selenium deficiency may occur. (73) Of the 13 selenium pro- 5.3.3 Thymosin teins known so far, only 2 glutathione peroxidases have Of the group of thymosins, a mixture of various thymus been closely defined: one membrane-bound and one hormones (or factors), fraction 5 has been well defined. cytosol-bound enzyme. They are components of an It is already used, for example, for the synthetic manu- antioxidative system in that they catalyze the reduction facture of thymosin-α. Further thymus factors include in hydrogen peroxide, organic hydroperoxides and fatty thymulin and thymostimulin (G.M. Mutchnick et al., 1991). acid hydroperoxides. Further biochemical effects in- • Thymus factors effect the maturation of thymus T clude: stimulation of the immune system (increased cells, which migrate to the lymphatic system as immune activity of the natural killer cells, stimulation of IFNγ cells. The clinical use of thymosin-α is indicated in synthesis, enhanced capability to phagocytize) (72), hep- impaired immune defence with a decreased count or atoprotection (73, 80), detoxication of heavy metals, reduced function of T lymphocytes. (74) Clear effects on regulation of lipid peroxidation (scavenger of free rad- HBV DNA and on transaminases were demonstrated in icals), inhibition of carcinogenesis and tumour growth chronic hepatitis B. (71) • In combination with IFN, (73, 80), etc. (s. pp 50, 51, 787) • Sodium selenite seems good results were also obtained in chronic hepatitis C. to be most appropriate for infections. (s. p. 304) (79) In a recent study, the use of thymosin as monotherapy in chronic hepatitis C did not prove to have any 5.3.2 Zinc beneficial effect. Generally, good tolerance was recorded Zinc is an essential trace element, 98% of which is for this drug. (77) (s. p. 705) deposited in the intracellular space. The various organs differ significantly in their zinc concentration. The total 5.4 Ursodeoxycholic acid body content amounts to 1.5Ϫ4.0 g. The daily zinc requirement ranges between 10 and 15 mg. A high The secondary bile acid 7-keto-lithocholic acid is trans- content of certain amino acids (alanine, cysteine, gly- ported from the intestinal tract via the portal vein to cine, histidine) greatly facilitates the intestinal absorp- the liver, where it is converted to ursodeoxycholic acid tion of zinc, whereas phytate-containing pulses and (UDCA) by bacterial enzyme action. (s. pp 36, 705) (s. cereals as well as chronic alcohol abuse impair its fig. 3.3) • The molecular formula of UDCA is identical absorption to a considerable extent. (106) Zinc is readily to that of CDCA (C24H4O4); however, it has the excreted and hardly accumulates in the body. All in all, hydroxyl group at the C7 atom in the β-position and there are many factors leading to relative or absolute not in the α-position like chenodeoxycholic acid. The zinc deficiency. (s. p. 50) (s. tab. 3.15 ) • Zinc is an essen- tertiary bile acid UDCA thus constitutes the 7β-epimer tial component of about 200 enzymes. It plays a major of the secondary bile acid CDCA. This changes the ste- role in the metabolism of carbohydrates, proteins, lipids, ric arrangement: the molecule possesses a higher polar- vitamin A and alcohol as well as influencing DNA and ity and is thus less able to form micelles. UDCA is RNA synthesis and stimulating the immune system. hydrophilic and only slightly lipophilic, and therefore (110) It activates ornithine carbamoyltransferase, alka- practically non-toxic to the organism. With its molecular line phosphatase, δ-ALA synthetase and carboanhy- weight of 392.6, it constitutes 0.5Ϫ1.0 (Ϫ5.0)% of

857 Chapter 40

human bile. Following oral administration, UDCA is proven or pharmacologically justified. (91, 94, 96, passively absorbed in the jejunum and in the proximal 100Ϫ102) • Practically no side effects are to be expected. portion of the ileum and, through active transport, in From the therapeutic viewpoint, it is possible to achieve the distal ileum; in addition, approx. 20% of the UDCA an improvement in the clinical symptoms (fatigue, pruri- can be absorbed in the colon. In portal blood, UDCA tus, gastrointestinal symptoms, steatorrhoea), especially is transported bound to protein and conjugated in the in cholestasis with decreased values of AP, LAP, γ-GT liver with taurine (to a small extent also with glycine). and bilirubin. (95, 96) • There is a similar improvement These conjugates reach the bile. The half-life is 3.5Ϫ5.8 in further laboratory parameters (transaminases, GDH, days. Like its breakdown product isoursodeoxycholic IgM, cholesterol, etc.) together with an amelioration of acid, UDCA is excreted predominantly in faeces and to histological alterations. (82) Special attention should be a lesser degree in urine. (83, 86, 87, 99, 102) paid when administering UDCA in cirrhosis with asci- Functioning as detergents, hydrophobic (lipophilic) bile acids (cho- tes. (s. pp 233, 241, 651, 658, 686) (s. tabs. 13.10; 40.8) lic acid, chenodeoxycholic acid, deoxycholic acid, lithocholic acid) exert toxic effects on the biomembranes of liver cells and mito- Viral hepatitis chondria. At the same time, these bile acids display an immuno- Acute viral hepatitis (88) suppressive effect and influence the humoral and cell-mediated Chronic hepatitis (82, 101) defence (e.g. inhibition of monocytes). As in the case of PBC, hydrophobic bile acids also induce an excessive expression of Autoimmune diseases MHC-I and MHC-II molecules from hepatocytes and biliary cells. 1. Autoimmune cholangitis 2. Autoimmune hepatitis Modes of action: The mechanisms of UDCA and its 3. Overlap syndrome effects in cholestatic liver diseases are not yet fully 4. Primary biliary cholangitis (85, 94, 100) understood Ϫ even though a number of different effects 5. Primary sclerosing cholangitis (90, 103) have been demonstrated. These include (1.) hepatopro- Cholestatic liver diseases 1. Alcoholic liver disease with cholestasis tective (92, 97, 98),(2.) cytoprotective (89), and (3.) bili- 2. Chemically induced cholestasis ary-metabolic effects (84, 93, 104, 105), as well as (4.) an 3. Cholestasis with complete enteral feeding influence on the immune system. In ligature of the bile 4. Drug-induced cholestasis duct in rats, UDCA was found to reduce the occurrence 5. Secondary sclerosing cholangitis of histological changes and biliary cirrhosis as well as Genetically determined cholestasis of portal hypertension. (98) (s. tab. 40.7) 1. Alagille’s syndrome 2. Byler’s syndrome 3. Cholestasis of pregnancy 1. Inhibition of the enteral absorption of hydrophobic bile 4. Disturbances of the steroid ring acids Ϫ 7α-hydroxylase deficiency Ϫ 4δ-3-oxosteroid-5β-reductase deficiency 2. Induction of bicarbonate hypercholeresis Ϫ β δ Ϫ increase in bile flow (hypercholeresis) 3 -hydroxysteroid-5 -dehydrogenase Ϫ increase in the cholehepatic circulation of UDC 5. Mucoviscidosis (ϭ cholehepatic shunt) (s. p. 36) 6. Recurrent benign cholestasis Organ transplantation 3. Incorporation into the lipid membranes of liver cells and mitochondria, preventing loss of phospholipids and 1. After liver transplantation (81) cholesterol 2. Refractory graft vs. host reaction Ϫ stabilization of membranes Ϫ improvement of bile acid transport Tab. 40.8: Demonstrated, empirically confirmed or pharma- Ϫ amelioration of immunological membrane functions cologically justified indications for the therapeutic use of ursodeoxycholic acid (with some references) 4. Influence on calcium-mediated intracellular signal transfer 5. Interaction with the glucocorticoid receptor 6. Influence on protein kinase C 7. Reduction in MHC-I and MHC-II molecule overproduction (ϭ decrease in T lymphocyte toxicity) 5.5 Lactulose 8. Inhibition of interleukins 1, 2, 4 and 6, TNF-α and immunoglobulin formation 5.5.1 Chemistry α 9. Synergistic effect with IFN- ᭤ Lactulose does not occur in nature, nor is it present in breast milk or fresh cow’s milk. Small amounts of lactulose are, however, Tab. 40.7: Biochemical and pharmacological modes of action of found in heated dairy products, especially in condensed milk (an ursodeoxycholic acid average of 660 mg, up to a maximum of 940 mg, per 100 ml). • The initial substance for the synthetic manufacture of lactulose is Contraindications: The following contraindications lactose. This disaccharide consists of D-glucose and D-galactose, β Lactulose should be observed: acute cholecystitis, acute cholang- interlinked through a -1-4-glycoside bond. • was manu- factured for the first time in 1929 as a keto-analogue of lactose (E. itis, obstruction of the cystic duct and common bile duct Montgomery et al.). As a disaccharide, it is composed of D-galac- as well as frequent biliary colic. tose and D-fructose. The molecular formula is C12H22H11, with a molecular weight of 342.3. Lactulose has a high degree of sweetness Indications: The indications for the clinical use of (0.48Ϫ0.62, compared with 1.0 for sucrose). The pH value ranges UDCA are either already well-documented, empirically between 3.4 and 4.0. (107)

858 Treatment of liver diseases

5.5.2 Pharmacokinetics bonates, and possibly also by retroactive effects of the ᭤ Lactulose can be neither absorbed nor broken down by enzym- lactulose metabolites on the intestinal bacteria with atic or bacterial action in the small intestine; after 1Ϫ2 hours, it potential changes in their metabolism. • The organic reaches the colon unchanged. Lactase activity in the intestinal acids and the bacterial formation of gas as well as the mucosa is not influenced by lactulose. Following oral intake of increase in osmotic pressure account for the laxative Ϫ lactulose, approx. 0.5 1.0% is taken up by the intestinal mucosa effect (F. Mayerhofer et al., 1959). This action occurs through passive diffusion and completely excreted unaltered in the urine. However, its absorption is increased by intestinal disease or within 8 hours of lactulose administration. With a rise damage to the intestinal mucosa following cytotoxic chemother- in the bacterial count of more than 50%, there is also apy. With simultaneous oral ingestion of hyperosmotic solutions, (1Ϫ2 days after lactulose application) a rise in the stool elevated lactulose levels are likewise detectable in the urine. The mass and thus an additional acceleration of defaecation. amount of lactulose thus excreted provides clues to the degree of formation of ammonia damage possibly caused to the intestinal mucosa. After oral • The in the intestine is due to administration of 20Ϫ25 ml lactulose, there is only a slight rise in the breakdown of proteins or amino acids, nucleic acids the blood sugar level of 1Ϫ12 mg%; therefore, no clinically relevant and biogenic amines. The intestinal formation of ammo- aggravation of diabetes need be feared with lactulose therapy, nor nia is inhibited by intraluminal acidosis and promoted are any systemic effects evident. • Lactulose is not demonstrable by alkalosis. Independently of the intestinal flora, in the stool; this suggests that a complete breakdown takes place in the colon due to saccharolytic bacteria. The following bacteria ammonia is also formed in the intestinal mucosa have proved most effective for lactulose catabolism: Lactobazillus through glutamine uptake and the release of ammonia, species, Bifidobacterium, Clostridium perfringens and the Bacte- alanine and glutaminic acid. This metabolic NH3 pro- roides species. An amount of up to 80 ml lactulose can be broken duction with hyperammonaemia was also demonstrable down per day by bacterial enzyme action under physiological conditions. Long-term treatment with lactulose stimulates the forma- in microbe-free and hepatectomized experimental ani- tion of bacterial β-galactosidase, whereby higher bacterial meta- mals. With an intestinal pH value of <6, non-ionized bolization rates of lactulose are achieved. (107) The main ammonia (NH3) diffuses from the blood to the intestine, metabolites include lactic acid, resulting from anaerobic fermenta- while the diffusion of non-ionized ammonia from the pyruvic acid Ϫ tion, and , resulting from aerobic metabolism with intestine into the bloodstream is simultaneously subsequent formation of other organic acids (formic acid, succinic decreased. This results in an elevated excretion of acid, butyric acid, caproic acid, acetic acid, etc.). This leads to a ϩ fall in the pH value in the colon (dose-dependent) to 5Ϫ6. The pH ammonium cations (NH4 ) in faeces and a reduction in value is not in the desired therapeutic acid range until an increase hyperammonaemia. The rapid onset of effect on hyper- in osmotic pressure with an evacuation frequency of 2Ϫ3 times/day ammonaemia following lactulose enemas can also be has been achieved at the respective lactulose dosage. • Degradation of lactulose in the colon with enhanced formation of organic acids explained by the influence on non-ionic diffusion. A results in an inhibition of growth of gram-negative proteolytic further mechanism underlying the lactulose-induced microorganisms which are responsible for the formation of endo- decrease in hyperammonaemia may be based on the fact toxins. There is also promoted growth of saccharolytic bacteria, that lactulose constitutes a valuable carbon and energy creating bifidus flora typical of breast-fed babies (F. Petuely, 1957, source for intestinal bacteria. Bacterial growth is 1986; F. Meyerhofer et al., 1959). (106, 110, 112, 114) thereby promoted and a substantial quantity of nitrogen is included in the protein synthesis of bacteria, which 5.5.3 Pharmacology leads to a measurable consumption of ammonia. A fall in the colonic ammonia level may also be the result of “Wrong idea, good results (the lactulose story)” (U.P. a marked reduction in proteolytic intestinal bacteria by aemmerli H et al., 1969); “Lactulose works, but why?” lactulose. (108, 111, 116) • The therapeutic efficacy of lac- (K.A. Hubel, 1973); “In several aspects lactulose is an tulose in the treatment of hepatic encephalopathy was unusual drug”; “Lactulose is a fascinating hybrid of demonstrated by J. Bircher et al. in 1966. Numerous pub- a nutrient and a drug” (J. Bircher et al., 1988); “Lactu- lications dealing with this indication have appeared. (s. lose is a many splendored thing ... with many other p. 279) Such favourable experience has been further sup- onn beneficial actions in its bag of tricks” (H.O. C , ported by recent studies. (108, 109, 113, 115) • The efficacy 1992). (s. fig. 40.1) of lactulose in endotoxinaemia demonstrated by D. Scev- ola et al. (1979) was later confirmed in various publica- Unchanged lactulose is pharmacologically inert. Its tions and also recently demonstrated anew. (114) Dif- multiple effects are only evident after breakdown by ferent explanations for this anti-endotoxin effect of bacterial enzymes in the colon. (107) • The ability to lactulose have been put forward: (1.) increased removal break down lactulose varies greatly from one bacterial of endotoxins due to higher evacuation frequency, (2.) species to another, and even from strain to strain, blocking of endotoxin receptors by lactulose, and (3.) depending on their enzyme endowment. Therefore, the influence on the number and metabolic performance of quantity and the predominant type of organic acids gram-negative intestinal bacteria. (s. fig. 40.1) formed on breakdown depend on the lactulose dose and the enzyme endowment of the saccharolytic bacteria. A reduction in the cholesterol level due to lactulose was The total acid content of the colon is also influenced by observed by N. Ebner in 1973 and confirmed by D. Conte individual factors, such as the absorption rate into the et al. in 1977. Lactulose can also be used in hepatogenic colon mucosa or the buffering caused by secreted bicar- disturbances of lipid metabolism. • Translocation of

859 Chapter 40

Lactulose

Breakdown by saccharolytic germs in the colon

Organic acids ↑

pH value in the colon ↓ (< 6)

Proteolytic bacteria ↓ Osmotic pressure ↑

1. N-incorporation into bacteria ↑ 1. Transit time ↓ – growth of bacteria ↑ ↓ 2. NH3 production 2. Excretion – proteolytic germs ↓ of toxins ↑ – glutamine in mucosa ↓

3. Fall in NH3 concentration 3. Excretion → ↓ ↑ – intestine blood of NH3 – blood → intestine ↑

Endotoxins ↓ Toxins ↓ Ammonia – production ↓ – excretion ↑ Fig. 40.1: Reduction in the blood – blood level ↓ ammonia levels with a corresponding improvement in the detoxification functions of the liver as a result of multifactorial Improvement in the detoxification functions of the liver influence exerted by lactulose on ammonia metabolism

gram-negative bacteria to the mesenterial lymph nodes Lactulose is administered as long-term therapy. The was significantly suppressed in experimental obstructive indications are derived from its modes of action. (s. jaundice under lactulose treatment compared to the ref- tab. 40.9) erence group without lactulose (114). Furthermore, galactosaemia-induced liver damage and bacterial con- veyance could be prevented by lactulose. (110) 1. Reducing or normalizing hyperammonaemia in ᭤ A therapeutic drop in the pH value to <6 is gen- hepatic encephalopathy erally achieved when evacuation occurs 2Ϫ3 times per 2. Eliminating endotoxinaemia day. In order to guarantee this condition, respective 3. Prophylactic use in cirrhosis (and other chronic quantities of lactulose should be administered in 2 liver diseases) (Ϫ3) daily doses. • In principle, evacuation frequency 4. Decreasing susceptibility to infections in cirrhosis should be “no less than 2 and no more than 4 times by inhibiting the translocation of intestinal bacte- per day”. With this regimen, no major side effects ria need to be feared. 5. Reducing the cholesterol level and influencing lipid metabolic disturbances in primary biliary cholangitis (and other liver diseases accompanied 5.5.4 Indications by hyperlipidaemia) 6. Improving the absorption of calcium in malab- The multiple modes of action of lactulose, which are sorption based on an interplay of several effects, require a sufficiently acidic pH value in the colon. Tab. 40.9: Indications for the therapeutic use of lactulose

860 Treatment of liver diseases

5.6 Branched-chain amino acids Methionine and AAA compete with BCAA for the same transport system at the blood-brain barrier. Lowered BCAA levels in the The cirrhosis patient is in a vicious circle regarding blood therefore favour the passage of elevated methionine and Ǟ AAA concentrations. The influx of these amino acids is increased protein metabolism: cirrhosis hepatic encephalo- by concomitant hyperammonaemia. Ammonia crosses the blood- pathy Ǟ protein restriction Ǟ malnutrition Ǟ catab- brain barrier freely. In the astrocytes of the brain, BCAA effect olism Ǟ. Thus, prolonged protein restriction and an increase in glutamate by transamination with α-ketoglutarate. catabolism may considerably worsen the prognosis of Glutamine formation rises, permitting the removal of ammonia cirrhosis. • In this hazardous situation, the dietary from the brain. Glial swelling could be reduced in animal experiments. • Anabolic protein metabolism in the muscles is responsible and therapeutic use of branched-chain amino acids for (1.) reduction in muscle protein breakdown products which (BCAA), i.e. valine, leucine and isoleucine, is a contribute to the formation of ammonia, and (2.) higher amounts logical therapeutic intervention. of ammonia being taken up by the musculature and converted via glutamate to glutamine, which is harmless. • Hyperammonaemia keto-analogue amino urea cycle in liver cirrhosis cannot be influenced by The is the most important process in bio- acids, which are N-free precursors of protein synthesis. However, logical ammonia detoxication. (s. pp 57, 266) (s. figs. the keto-analogue of leucine can inhibit the breakdown of muscle 3.12, 3.13) • It is directly linked with amino-acid metab- protein, which means that favourable effects might still be achieved by using BCKA in decompensated cirrhosis Ϫ without any dis- olism and thus also with NH2 donors and precursors through specific amino acids and transamination pro- cernible impact on the ammonia level itself. (117, 120, 129) cesses. Here, the major transamination processes are The use of branched-chain amino acids is based on the those involving glutamate and oxalacetate as well as following modes of action (s. tab. 40.10): α-ketoglutarate and aspartate. ᭤ The ammonia hypothesis postulates that a high ammonia con- 1. Compensation of the amino-acid imbalance centration in the tissue inevitably leads to a clear increase in 2. Restoration of the competitive transport mech- glutamine. This results in a marked intracellular decrease in gluta- anisms at the blood-brain barrier mate α (and -ketoglutarate). This glutamate pool can be refilled by 3. Stimulation of glutamine synthesis in the brain, a more intensive degradation of BCAA as NH2 donors. At the same time, transamination effects the formation of branched-chain keto- muscle and liver (ϭ transitory ammonia detoxica- analogues of the respective amino acids. • Succinyl CoA is also tion) facultatively involved, providing α-ketoglutarate via the citric acid 4. Inhibition of ornithine breakdown in the liver with cycle; this is the starting substrate of glutamate prior to transamin- a favourable effect on urea synthesis (ϭ definitive ation. These reactions occur mainly in the muscles. (s. fig. 40.2) ammonia detoxication) 5. Anabolic and anticatabolic effects, especially in AMMONIA muscles 6. Stimulation of the HGF, favouring liver regener- Alpha-ketoglutarate Glutamate Glutamine ation

Tab. 40.10: Modes of action of branched-chain amino acids ADP ATP

BCAA BCKA CO 2 The indication for administering BCAA in patients with hepatic encephalopathy to compensate amino-acid im- Succinyl CoA balance was proposed by J.E. Fischer et al. in 1974, and implemented parenterally. However, oral application of Fig. 40.2: Indirect influence of ammonia on the metabolism of BCAA for an adequate treatment period also has bene- branched-chain amino acids (so-called ammonia hypothesis) (according to E. Holm, 1986) (BCAA ϭ branched-chain amino acids, ficial effects on cirrhosis and HE: (1.) improvement in BCKA ϭ branched-chain keto acids) protein tolerance and the nutritional condition, (2.) improvement in cerebral functions (118, 122), probably ᭤ Branched-chain amino acids apparently stimulate the urea cycle. due to an amelioration of liver function, (3.) stimulation Carbamoylphosphate synthetase, which channels ammonia into of ammonia detoxification with a positive nitrogen bal- the urea cycle, is induced by ornithine and N-acetylglutamate as a ance (118),(4.) reduction in or normalization of AAA two modes of action: cofactor of urea synthesis. Here, BCAA follow levels, and (5.) promotion of glutamine synthesis with a (1.) they stimulate the synthesis of N-acetylglutamate via synthetase formed from glutamate and acetyl CoA, and (2.) they inhibit favourable effect on the cells of the immune system and ornithine-keto acid transferase, which is the enzyme responsible on renal function. • By means of BCAA, it was possible for ornithine degradation, leading to an increase in ornithine con- to prolong the survival time and delay the occurrence Ammonia detoxication is thus stimulated by two regu- centration. • of liver failure in rats with CCl -induced cirrhosis. (123, latory mechanisms. (s. fig. 40.2) 4 126) • However, there are diverging results, which need ᭤ As a rule, cirrhosis patients show reduced plasma BCAA levels further clarification. In principle, the use of BCAA is and unchanged BCAA concentrations in the brain, whereas methi- considered to be a necessary form of supplementary onine and aromatic amino acids (AAA) (phenylalanine, tyrosine, (124, 125, tryptophan) are elevated in the plasma and brain. (s. p. 280) • treatment for catabolic metabolism in cirrhosis The fall in BCAA levels is attributable to its increased degradation, 127, 128, 130Ϫ132), in (also latent) HE and after curative which, in turn, is caused or aggravated by hyperinsulinaemia. resection of hepatocellular carcinoma. (121) (s. p. 280)

861 Chapter 40

5.7 Amino acids of the urea cycle (via α-ketoglutarate), glutamate and other dicarboxylates are taken up almost exclusively by the perivenous As early as 1932, H.A. Krebs and K. Henseleit discovered hepatocytes responsible for glutamine synthesis. In in their investigation of the amino acids that ornithine, addition, aspartate and dicarboxylates are considered to even in small amounts, was capable of increasing urea be activators of glutamine synthesis, a process which is synthesis from (toxic) ammonia. Otherwise, only argi- disturbed in cirrhosis patients. (s. pp 57, 266) (s. figs. nine had a slight effect in this respect. (138) The 3.12, 3.13) following table shows which of the amino acids involved in the urea cycle are available for therapeutic purposes: Aspartic acid is not only involved in the urea cycle, but following oxidative deamination to α-ketoglutarate, it is also a component of the citric acid cycle. An increased quantity of energy is thus Arginine Arginine aspartate made available in the form of ATP for the energy-consuming urea Ornithine aspartate (OA) Arginine malate cycle. The energy cycle is additionally stimulated by transamin- ϭ available Aspartic acid ation of aspartic acid to oxalacetate. The increased channelling of Citrulline aspartic acid into the urea cycle facilitates the release of fumaric ϩ Arginine citrulline Ornithine acid, which is also a substrate of the citric acid cycle, and thus ϩ α ornithine Ornithine -ketoglutarate further enhances the formation of ATP. Moreover, aspartic acid ϭ ϭ available not available at present binds the ammonia which is present in the musculature; as a result, asparagine is formed, and free toxic ammonia is bound. • Aspartic The ammonia-reducing effect of the amino acids involved in the acid is a glucoplastic amino acid and an important initial substrate urea cycle has been strikingly well demonstrated in a variety of for pyrimidine synthesis in liver cell regeneration. Following con- experimental studies by several research groups. In most of these densation with carbamylphosphate and the formation of the inter- studies, ornithine aspartate was used, although arginine, ornithine mediate product L-dihydro-orotic acid, orotic acid, the central pro- and ornithine α-ketoglutarate have also been investigated. (134, duct in the biosynthesis of pyrimidine nucleotides, is formed by 137, 141, quot. 139) • The greatest effect on ammonia reduction oxidation. was achieved with ornithine aspartate, the combination of these two amino acids being more effective than the administration of There are several biochemical and clinical modes of ac- either substance alone. The above results were confirmed in experi- tion associated with ornithine aspartate. (s. tab. 40.11) mental studies by K. Zicha et al. (1968) and G. Hermann (1972).In healthy dogs, the increased ammonia levels due to ammonia over- 1. Increase in urea synthesis by ornithine load were lowered to normal by ornithine aspartate; in dogs with Ϫ substrate of the urea cycle Eck’s fistula, the occurrence of toxic ammonia levels could be pre- Ϫ activator of carbamyl phosphate synthetase vented (C.E. Grossi et al., 1967). Further experimental studies • Ϫ activator of ornithine carbamyl transferase revealed that the liver content of ornithine, citrulline, arginine, glu- Ϫ activator of glutamine synthesis tamate and urea rose following exposure to ammonium chloride in rats. The urea synthesis rate exceeded the norm by 50%, while 2. Increase in glutamine synthesis by aspartate Ϫ glutamate concentration doubled as a result of α-ketoglutaric acid, substrate of glutamine synthesis Ϫ which increased to the highest possible limit. With simultaneous activator of glutamine synthetase administration of arginine or ornithine, hepatic ornithine concen- 3. Increase in the energy balance by aspartate tration increased considerably, and urea synthesis rose by 80Ϫ85%. Ϫ substrate of the citric acid cycle • In healthy volunteers, administration of ornithine Ͱ-ketoglutarate Ϫ formation of oxalacetate led to elevated renal excretion of urea and ornithine α-ketogluta- Ϫ channelling of fumaric acid into the citric acid cycle rate, i.e. a clear stimulation of urea synthesis was attained. 4. Increase in NH3 detoxification in the musculature ᭤ Since the clinical studies of L. Zieve et al. in 1960, the use of these 5. As a component of pyrimidine nucleotide synthesis amino acids or their salts has been indicated in hyperammon- leading to liver cell regeneration aemia. (146) Thus, following protein overload in alcoholic cirrhosis patients, a reduction in ammonia levels was achieved by adminis- Tab. 40.11: Modes of action of ornithine aspartate tering 60 g ornithine α-ketoglutarate. (135, 140) • Since the first clinical use of ornithine aspartate more than 30 years ago (1968), a Ϫ The various modes of action provide the basis for the series of studies has been published. (136, 142 145) This ammonia- therapeutic indications reducing substance is the stable salt of L-ornithine and L-aspartic following of ornithine aspartate: acid with the empirical formula C9H19N3O6 and a molecular weight of 265.3. Bioavailability is 82.2 ± 28.0%. The substance is rapidly 1. Hepatic encephalopathy absorbed, with subsequent splitting into its two component amino Ϫ with improvement in the mental condition and acids. Its half-life is 40 minutes. psychometric test results biomolecular modes of action The of ornithine have been 2. Relief of NH3 intoxication symptoms the subject of several experimental investigations. Ϫ e.g. fatigue, weakness Ornithine activates the enzymes carbamylphosphate synthetase and ornithine carbamyl transferase, which are necessary for the liver-specific process of urea syn- 5.8 D-penicillamine thesis (133, 139); this occurs mainly in the periportal hepatocytes (ϭ definitive ammonia detoxification). Gluta- D-penicillamine is a non-physiological amino acid. It is a dimethyl mine synthesis (binding of ammonia to glutamate) takes derivative of cysteine, which is a structural component of many place predominantly in the perivenous hepatocytes (ϭ proteins. Metabolically, penicillamine is relatively stable. In addition to the amino group (ϪNH2) and the carboxyl group transitory ammonia detoxification). Large amounts of (ϪCOOH), it contains a sulphhydryl group (ϪSH) as a further glutamate are necessary for this. Aspartate, ornithine reactive centre. The underlying biochemical modes of action are:

862 Treatment of liver diseases

1. Chelate formation with heavy metals and aminopeptidases, with a renal excretion rate of about 80%. • The following organ-specific effects are worth mentioning: (1.) 2. Exchange reactions with disulphides inhibition of endocrine and exocrine functions (in the area of the Ϫ with low molecular weight substances pancreas, stomach and small intestine Ϫ especially inhibition of Ϫ with proteins insulin and glucagon release) and (2.) inhibition of the blood sup- 3. Binding with aldehyde ply to the gastric mucosa and splanchnic vessels. Ϫ to pyridoxal phosphate Ϫ to aldehyde groups in collagen and other proteins In oesophageal variceal bleeding, somatostatin is recommended immediately after emergency admission to hos- Penicillamine may effect chelate formation with the pital at the following dosage: an i.v. bolus injection of Ϫ µ µ heavy metals copper, lead, zinc, gold and mercury. This 250 ( 500) g and subsequently 250 g per hour (pos- complex formation is accompanied by simultaneous sibly with 2-minute bolus injections). In this way, sclero- reduction processes, e.g. copper is reduced to copper-1- therapy or ligation is technically facilitated and the ion. From the biochemical viewpoint, an influence on effectiveness of the therapy improved; fewer blood procollagen synthesis is also conceivable, as the amino- ducts are needed. No major side effects have occurred oxydase involved in the formation of collagen contains at this dosage. (152, 154) The bolus injection rapidly copper, so that this enzyme is inactivated through the effects a reduction in portal venous and intravaricose binding of copper to penicillamine. To my knowledge, pressure as well as a decrease in the blood flow in the this process has not yet been confirmed in vivo. • The azygous vein. (151, 153) It is worth noting that intestinal mesenchyma suppression effect of penicillamine with a blood is eliminated more slowly and virtually decrease in the formation of connective tissue is based unchanged, since somatostatin inhibits the release of on the inhibition of the cross-linkage between fibre pro- digestive enzymes and prolongs the intestinal transit tein precursors and hydroxyproline synthesis. However, time. Continued passage of tarry stool may at first be Ϫ it appears that the process of hepatic fibrosis is not erroneously interpreted as an effect of somatostatin influenced. • Of relevance is the reaction with macro- unless systemic problems or a fall in Hb actually suggest globulins, which is accompanied by the breaking of the further bleeding. (s. p. 360) disulphide (S-S) bridges through exchange reactions; this leads to depolymerization. An example of the binding of penicillamine to an aldehyde group is its binding to 5.10 Terlipressin pyridoxal phosphate Ϫ a coenzyme which is formed in α the body from vitamin B . Equally important is the Terlipressin, chemical name N- -triglycyl-8-lysine-vasopressin, 6 consists of 12 amino acids. The molecular weight is 1,377.5, and the reaction of penicillamine with the aldehyde groups of empirical formula is C52H74N16O15S2 ·C2H4O2 ·5H2O. Through tropocollagen, which causes the formation of thiazoli- hydrolytic removal of the glycyl residues, the vasoconstrictor hor- dine, thus preventing synthesis of insoluble collagen. mone lysine-vasopressin is slowly released as an active substance. (150) • Intestinal absorption is rapid and relatively high. Peak concentrations are obtained after 120 minutes. The break- Ϫ down of lysine-vasopressin into inactive metabolites, effected by The half-life is 3 4 hours. The greater part of the orally hepatic and renal endopeptidases and exopeptidases, is almost applied substance is eliminated within 24 hours. In par- total, so that only about 1% is excreted in the urine. • The plasma ticular, diseases with high hepatic copper concentrations half-life is 12 minutes, the elimination time is 40Ϫ180 minutes. The are an indication for penicillamine. • Side effects occur effect persists for 4Ϫ5 hours. The vasoconstriction is particularly frequently; the use of vitamin B may be necessary. intensive in the splanchnic system; as a result, arterial blood flow 6 is reduced, and portal hypertension is lowered (by up to 35% with indications 1 mg terlipressin). (155, 158, 161) The smooth muscles of the The principal for penicillamine are: oesophageal sphincter are contracted with consecutive compres- sion of the existing varices. At the same time, increased peristalsis 1. Wilson’s disease (149) (s. p. 615) occurs, leading to a more rapid evacuation of intestinal blood and of ammonia formed by intestinal bacteria. • The renal blood flow 2. Indian childhood cirrhosis (147) (s. p. 616) is elevated in hypovolaemia. The elevated WHVP and HVPG 3. Primary biliary cholangitis (148) (s. p. 650) become reduced and hepatic arterial blood flow increases. 4. Heavy metal poisoning The following dosage is recommended for acute oesophageal variceal bleeding: 1Ϫ2 mg terlipressin as an 5.9 Somatostatin i.v. bolus (if possible in the ambulance or upon emergency admission) followed by 1 mg as an i.v. bolus every Somatostatin was first isolated from the hypothalamus of sheep for 4Ϫ6 hours for a total period of 2Ϫ3 days. Terlipressin use as a growth hormone-inhibiting factor in 1973 (P. Brazeau et al.). In the same year, its synthetic production was also reported reduces the elevated blood levels of renin and aldos- (H.D. Croy et al., 1973). The molecular weight is 1,638. The empirical terone and increases the GFR. The combined use of formula of this substance, which is composed of 14 amino acids, vasoconstrictor therapy with local mechanical haemo- is C76H106N18O19S2. To my knowledge, somatostatin was used clin- stasis gives the best results Ϫ and a higher chance of ically for the first time in 1974 in a patient with acromegaly (S.S.C. survival. The side effects are slight. (157, 159, 160, 162) (s. Yen et al.). • Since 1979, somatostatin has been recommended for oesophageal variceal bleeding (L. Thulin et al.). Its plasma half-life p. 360) • Application is recommended in the case of the is 1Ϫ2 minutes; the substance is broken down by endopeptidases hepatorenal syndrome. (156)

863 Chapter 40

5.11 S-adenosyl-L-methionine causative factor(s), (2.) use of supportive therapeutic S-adenosyl-L-methionine (SAMe) is present in nearly all body measures (fluid and electrolyte balance, analgesics, anti- cells. About 30% of hepatic SAMe is localized in the mito- convulsants, antihypertensive agents, antiemetics, anti- chondria. It is formed from methionine and ATP by SAMe syn- arrhythmics), (3.) i.v. glucose infusion (approx. 400 g/ thetase (G.L. Cantoni, 1952). Transport from the cytosol to the day), and (4.) haemarginate. (s. p. 607) mitochondria takes place via a specific phospholipid carrier system in the biomembranes. (164, 172) • Metabolically, S-adenosyl-L- Haemarginate is produced from erythrocyte concen- methionine is an important initial substrate for numerous synthesis trate. It compensates the loss of the intracellular haem pathways (164, 167): balance, which regulates haem synthesis. In this way, the 1. Transmethylation: The transfer of methyl groups is of great rele- overproduction of porphyrin precursors is reduced. vance for phospholipid synthesis in the biomembranes and for Haemarginate is relatively stable; following i.v. admin- the synthesis of hormones, nucleinic acids, proteins, porphyrins, etc. (164) istration, it is bound to haemopexin and albumin, and 2. Transsulphuration: The involvement of SAMe leads to the thus made available to the liver cells. (185) • Dosage is 3 formation of glutathione, cysteine, etc. These substances play mg/kg BW/day, administered per daily i.v. infusion (for an important metabolic role in detoxification processes and in about 15 minutes) exclusively in 0.9% NaCl solution the elimination of reactive oxygen intermediates. (100 ml). Haemarginate is stabilized by arginine and 3. Aminopropylation: The transfer of decarboxylated SAMe is contains 96 vol.% ethanol (1,000 mg/ ampoule) as well crucial to the synthesis of polyamines (spermine, spermidine, as propyleneglycol (4,000 mg/ampoule). It is degraded putrescine). Together with ornithine decarboxylase, SAMe determines the synthesis rate of polyamines, which are essential into bilirubin and excreted via the bile. The application for cell regeneration. At 30Ϫ60 minutes, the half-life of SAMe period depends on the degree of severity of acute por- decarboxylase is very short and thus readily adaptable to vari- phyria; as a rule, it extends over 3Ϫ5 days. With success- ous metabolic situations. ful use of haemarginate, the excessive elimination of ᭤ In experiments, SAMe was found to prevent lipid peroxidation PBG and ALA is restored to normal, as is the excretion and to normalize the reduced glycogen content of hepatocytes in of uroporphyrinogen and coproporphyrin. These values liver damage. In further studies, its cytoprotective effect was also confirmed. (163, 166Ϫ171, 173, 177Ϫ181) This protective effect should be monitored in the urine under haemarginate likewise applied to preneoplastic cell damage. The results concern- therapy. (182Ϫ184) • Side effects may appear in the form ing the prevention of cholestasis were impressive. • In cirrhosis of phlebitis. This is, however, rare when haemarginate is or severe liver disease, there is a reduction in SAMe synthetase, administered intravenously into large veins. Minor, clin- glutathione, cysteine and phospholipid methyltransferase (together ically insignificant effects on blood coagulation have with a simultaneous deficiency in phosphatidylcholine formation, accompanied by disturbed membrane fluidity and decreased activ- only seldom been observed. ϩ ϩ 2ϩ ity of Na /K -ATPase and Ca -ATPase). Important: Haemarginate treatment should be initiated The pharmacological effects and therapeutic uses of SAMe in hepat- as early as possible before any neuronal damage, which ology are discussed in a detailed review. (169) • The impressive out- may be irreversible, occurs. come of various experiments led to numerous clinical studies, which, however, also included negative results. (165, 169, 174Ϫ176) On the whole, there was a significant decrease in bilirubin, bile 5.13 Phytotherapeutics acids, alkaline phosphatase and transaminases. Pruritus, a frequent symptom in cholestasis, also showed regression. Plant extracts have been used in the treatment of liver diseases for over 2,000 years. • So far, more than 170 plant-derived sub- S-adenosyl-L-methionine is an interesting substance stances from some 55 plant families have been well documented which deserves further clinical investigation. The recom- regarding their hepatoprotective efficacy. (187) Recently, the mended dosage is 800 mg/day with intravenous admin- Rosmarinus species (186) and Salvia miltiorrhiza (189) were istration or 1,200 mg/day orally. No major side effects added to this list as antifibrinogenetic agents. • In controlled clinical studies, have been noted. The studies available so far suggest the many of these active substances were found to be effective in various liver diseases. Some of them are already following indications: listed in the pharmacopoeia. • Two points should be made here: (1.) in the plant kingdom, there are other substances with spe- 1. Alcoholic liver disease, especially in cholestasis cific agents which would act on liver structures or against liver (s. p. 537) diseases, but have not yet been recognized as such; (2.) more 2. Drug-induced cholestasis (s. p. 554) sophisticated biochemical/biomolecular procedures now allow 3. Chemically induced cholestasis (s. p. 572) more exact characterization and a more precise description of known and previously unknown active substances, so that their 4. Recurrent intrahepatic cholestasis (s. p. 233) targeted therapeutic use may be made possible. (188) 5. Recurrent intrahepatic cholestasis of pregnancy (s. p. 233) Phytotherapeutics are defined by law as substances 6. Gilbert-Meulengracht syndrome (s. p. 221) derived from plants, plant parts or plant components in 7. Compensated liver cirrhosis (s. p. 741) a processed or unprocessed form and used medicinally. As substances, phytogenic preparations are treated in 5.12 Haemarginate the same way as synthetic chemical compounds or substances of other origin. Phytopharmaceuticals must like- The requirements for successfully treating clinically wise comply with the usual safety standards, such as manifest acute porphyria are: (1.) elimination of the quality, harmlessness and efficacy. (s. p. 553)

864 Treatment of liver diseases

Phytotherapeutic agents are used as primary prepar- C1 and C2 positions. The main active ingredient in EPL ations (e.g. tinctures) or as a concentration of various is 1,2 dilinoleoylphosphatidylcholine (DLPC) (40Ϫ52% active substance fractions and as pure substances. of the phosphatidylcholine molecules). Standardization Monoextracts are complicated mixtures of chemical is performed with reference to 3-sn-phosphatidylcholine substances. They contain primary active agents, second- (73Ϫ79%). In the literature, the designation PPC (poly- ary active agents and inert accompanying substances. enylphosphatidylcholine) is also used; this is intended to The main active agents wholly or predominantly deter- emphasize the special fatty acid composition. DLPC mine the therapeutic properties of phytopharmaceut- has a high bioavailability and an affinity for cell mem- icals. Secondary active agents present in addition to the branes. The phosphatidylcholines constitute a typical main active agent(s) may attenuate, potentiate or modify lipid bilayer and are thus the main structural compo- the effects of the main active agent. The overall thera- nent of cellular and subcellular membranes. Moreover, peutic effect generally results from the synergy of several the proportion of phosphatidylcholines with highly constituents. Accompanying substances include cellulose, unsaturated (essential) fatty acids is a decisive factor in lignin and starch as well as various forms of sugar, pro- determining membrane fluidity and thus also the bio- tein and fat. • The active constituents of plants essen- logical membrane functions (see figure 40.3 regarding tially depend on climate, location and other exogenous the multiple functions of phospholipids). Endogenous factors. Therefore, isolating the main active agent is a phospholipids are substituted by EPL, which may be prerequisite for clarifying its composition, synthesis and administered by the oral route or, in a highly purified pharmacosynthetic modification. Should an active sub- form, by the intravenous route. (205, 206, 222) (s. p. 27) stance be unknown or not well-documented, a quantita- (s. fig. 2.19) tively predominant substance (or several substances) amenable to analysis is then defined as the key sub- EPL administration has protective, curative and/or re- stance. This is to ensure that a certain phytopharmaceu- generative effects on the biomembranes of hepatocytes tical preparation is offered at a standardized quality. and sinus endothelia following damage to the cell mem- According to the legal requirements, the key substances brane through toxic, inflammatory, allergic, metabolic may also be defined as so-called “other scientifically or immunological reactions. The cytoprotective effect of proven material”. EPL has been demonstrated in 17 in-vitro and 104 in- vivo experiments including 29 different models and 7 Pharmaceuticals of plant origin also form part of different animal species. They were conducted using rational drug therapy in science-oriented medicine. EPL together with various chemicals (191, 214, 225), alco- They are used in the treatment of certain defined dis- hol (192, 194, 196, 208, 210Ϫ212, 217Ϫ219), narcotic drugs, eases and complaints. The more carefully the various cytostatics, ionizing rays, etc. (s. tab. 40.12) These pharmacological characteristics of phytogenic rem- experiments clearly demonstrated the notable hepato- edies are elucidated, the more reliably their clinical protective and curative effects of EPL in vivo. Remark- effects can be evaluated (e.g. digitalis, rauwolfia, hyo- ably good results were also obtained with EPL as an scyamine, senna). • This is also true of the phytothera- antifibrogenic agent. (191, 207Ϫ209, 213) The earlier EPL peutic preparations used in hepatology. was given, the more pronounced the effects were. Inhibi- tion of lipid peroxidation in the liver membranes was likewise verified. In animal experiments, it could be 5.13.1 Essential phospholipids demonstrated that PPC increases SAMe and GSH levels in alcohol-induced hepatic oxidative stress. (193) Simi- ᭤ Essential phospholipids (EPL) are isolated from the soya bean. This plant was mentioned in the books of Pen Ts’ao Kong larly, it was possible to diminish the antiapoptotic Mu (during the reign of Emperor Sheng Nung, 2838 BC). It action against ethanol-induced hepatocyte apoptosis. was one of the five “holy cereals” considered essential for (215) In a further study, the alcohol-induced increase in human life. • Today, about 800 soya bean species are known. peroxinitrite hepatotoxicity and the concomitant pro- Depending on the species, location and extraction method, the seeds contain 35Ϫ40% proteins, 20Ϫ30% carbohydrates, duction of oxide and superoxide could be prevented by 5Ϫ10% accompanying substances (amines, vitamins, triterpene PPC. (194) Furthermore, it has been shown that PPC saponins, glycopeptides, lectin, flavonoids, xanthines, etc.) and activates enzymes such as triglyceride lipase, which is 12Ϫ18% crude fats. The crude oil contains 90Ϫ95% fatty acid responsible for triglyceride degradation in the liver. (197) glycerides, predominantly unsaturated fatty acids (oleic acid, In addition, dilinoleoylphosphatidylcholine, which is the linoleic acid). Refining crude oil yields 30Ϫ45% phosphatides (soya lecithin). The phosphatides contain 15Ϫ20% phosphati- main active ingredient in PPC, diminishes the activity of dylcholine (“lecithin”), which represents an important constitu- acylcoenzyme A: cholesterol acyltransferase, an enzyme ent of cell membranes and is also involved in lipid metabolism that leads to the storage of cholesterol in the liver. (216) • in the liver (H. Eikermann, 1939). (Detailed account: 190) Based on these pharmacological and clinical data, PPC would appear to be the drug of choice for significantly Essential phospholipids are a highly purified phosphati- reducing or abolishing fatty liver of different origin, e.g. dylcholine fraction containing essential (unsaturated) due to alcohol or obesity, even if the causing noxa can- fatty acids, especially linoleic acid (about 70%), in the not be eliminated, as is the case with diabetes-associated

865 Chapter 40

Intoxications due to chemical substances Intoxication due to drugs

CCl4 acute/subacute 17 1. Paracetamol acute 1 chronic 10 2. Tetracycline subacute 2 CCI4 ϩ ethanol chronic 1 3. Rifampicin subacute 1 Ethanol acute/subacute 14 4. Cholic acid chronic 1 Ethanol chronic 15 5. Indomethacin acute 2 ϩ triton, INH/rifampicin 6. Choline deficiency subacute 1 Cyanate, Carbonyl-Fe acute/chronic 4 7. Anaesthetics subacute 3 Galactosamine acute/subacute 9 8. INH subacute 1 Allyl alcohol acute 5 9. Platidium ϩ/Ϫ CCI4 acute 1 Ethionine subacute 1 Organic solvents chronic 2 Cholestasis intoxication 4 Carbon disulphide chronic 1 Antigen-antibody reaction 1 Thioacetamide chronic 1 Intoxication due to radiation 8 Sodium glutamate chronic 2 Lipid peroxidation due to FeSO4 2 Hexachlorcyclohexane chronic 1 Endogenous oxidative stress 2 Ammonium fluoride chronic 1

Tab. 40.12: Cytoprotective effects of EPL in in-vivo investigations (104 experiments, 29 different models, 7 different animal species) (status 1988: E. Kuntz; status 2000: K.-J. Gundermann)

1. Incorporation of EPL into damaged cell membranes restoration of normal membrane structures

Stability ↑ Cell protection ↑ Physiology ↑ Regeneration ↑ Immunology ↑

– against viruses, – free radicals ↓ – fluidity ↑ – elements rich in – ADCC ↓ toxins, noxae – lipid peroxidation ↓ – flexibility ↑ energy ↑ – MILT ↓ – elasticity ↑ – RNA synthesis ↑ – primary immune – rigidity ↓ – liver cell glycogen ↑ response ↑ – permeability N – mitotic activity ↑ – enzyme activation ↑ – protein activation ↑ – prostaglandins ↑ – stimulation of NA+/K+-ATPase ↑

2. Antifibrosis effect – stimulation of collagenase ↑ – percentage of transitional cells ↓ – peroxidation products ↓ 3. Fat metabolism in the liver formation of lipoproteins ↑ 4. Stabilization of bile ↑ 5. Blood flow properties ↑

Fig. 40.3: Putative and demonstrated hepatic modes of action of EPL in vitro and in vivo. (ADCC ϭ antibody-dependent cell-mediated cytotoxicity, MILT ϭ mitogen-induced lymphocytotoxicity, N ϭ normal)

steatosis. (199, 201, 203) The regenerative effect of EPL on In severe liver insufficiency, we were able to effect a life- experimentally induced liver cell damage was confirmed saving reversal in 7 out of 10 seemingly hopeless cases by biochemical and histological findings. (200) (for fur- by the first ever intravenous application of PPC (3,000 ther details, see 190, 206) (s. tab. 40.12) (s. fig. 40.3) mg/day). (204) • A European multicentre double-blind study showed that EPL significantly increased the rate These results were confirmed in further studies. (195, 221, of IFN-α responders among patients with chronic hepa- 223, 224, 226) It was also discovered that EPL can have titis C as well as reducing the relapse rate. (220) an inhibitory effect on alcoholic fibrogenesis in baboons. (209, 212) The clinical studies which were avail- The modes of action of EPL suggest the following indi- able up to 1988 (190) have meanwhile been supplemented cations: curative, protective/curative and curative/regen- by other investigations. (198, 202, 220) erative therapy (1.) in toxic liver damage and fatty liver,

866 Treatment of liver diseases

(2.) in acute viral hepatitis, acute intoxication, liver The combination of essential phospholipids and silymarin insufficiency, and (3.) as a supportive flanking therapy is of special clinical interest because of the cellular in chronic viral hepatitis and cirrhosis. targets and modes of action of these two drugs. (268Ϫ273) (s. fig. 40.3) (s. tab. 40.13) In patients with 5.13.2 Silymarin chronic hepatitis, a combined EPL-silymarin substance was applied with success (269). Thus, the available results The name “sillybon” was given by ancient Greek of clinical studies suggest the following indications: writers Ϫ and later by Theophrastus (372Ϫ287 BC) Ϫ to a thistle species, without its being defined more Silibinin (intravenous) closely. In “De Materia Medica” by Dioscorides ț Amanita poisoning (about 50 AD), the plant later called milk thistle is Silymarin (oral) described as a medical remedy for the bites of poison- ț ț ous snakes. In his book “Historia Naturalis”, Plinius Toxic liver damage Supportive therapy Ϫ alcohol toxicity Ϫ chronic hepatitis the lder Ϫ E (23 79 AD) was the first to mention the Ϫ drug toxicity Ϫ liver cirrhosis choleretic effect of milk thistle. The extract was Ϫ chemical toxicity recommended as a liver remedy by H. Brunfels (1434) and P.A. Mathiolus (1590), and also in the herbals of 1. Protection of biological membranes from noxae ock onicerus H. B (1560) and A. L (1564). • As a result of • Inhibition of toxin uptake the investigations of F. M ayer et al. (1949) and O. Eichler • Stabilization of biological membranes et al. (1949), the year 1949 can be regarded as the Ϫ influence on phospholipid turnover “hour of birth” of silymarin for liver treatment. Ϫ biochemical interactions with membranes Ϫ decrease in enzyme induction (Detailed account: 227) Ϫ inhibition of phosphodiesterase 2. Support of cellular detoxication mechanisms ᭤ Silymarin is a mixture of three chemically related flavanolig- • Stimulation of superoxide dismutase noids; it is obtained by extraction from the seeds of the milk thistle • Maintenance of the glutathione pool (GSH) of (Silybum marianum Gaertn. or Carduus marianus [L]). These fla- hepatocytes vanolignoids include: (1.) silibinin,(2.) silidianin, and (3.) silicristin. 3. Antioxidative effect Silibinin is the main active constituent. Its molecular weight is • Interactions with free radicals 482.5, the empirical formula is C25H22O10. • The major pharmaco- • Reduction in lipid peroxidation kinetic characteristics are rapid absorption and a calculated Ϫ inhibition of lipoxygenase Ϫ absorbed fraction of 23 47%. Peak plasma concentrations are Ϫ decrease in malondialdehyde Ϫ Ϫ achieved after 1 2 hr. In plasma, 90 95% of silymarin is bound Ϫ diminution of glutathione consumption to protein. The half-life is 6.3 hr. Because of the relatively high Inhibition of fibrogenesis molecular weight, >90% is excreted via the bile. About 10% of 4. the administered dose enters the enterohepatic circulation. With 5. Increase in protein biosynthesis repeated administration, steady state elimination is achieved from 6. Inhibition of cholesterol synthesis the second day; thus there is no accumulation of silibinin. • Sili- Ϫ fall in microsomal hydroxylmethylglutaryl-CoA cristin displays pharmacokinetic properties similar to those of sili- reductase binin, yet with a lower biliary excretion rate (4Ϫ10%). No further information is available on the second minor component silidianin Tab. 40.13: Cellular tackling points and modes of action of sily- (and isosilibinin). (228, 230, 241Ϫ243, 247, 260, 262, 264) marin (Detailed account: 227) ᭤ In addition to an array of general pharmacological findings in 5.13.3 Glycyrrhiza glabra vivo or in isolated organs, specific hepatology-related results have been obtained. A number of studies provided evidence of different Glycirrhizin was used for the first time in hepatology in membrane effects; experimental cholestasis was prevented or 1977 by H. Suzuki et al., who achieved good results in reduced, and the release of histamine or serotonin from mast cells was diminished. Silymarin inhibits the different cytochrome P-450 patients with chronic hepatitis. The main constituents enzymes to a varying extent. (228, 230, 242, 243, 250, 260, 262, isolated from the roots of Glycyrrhiza glabra are triter- 264) Evidence of membranotropia and hepatoprotection is of major pene saponins, including glycyrrhizin (5Ϫ20%), and trit- relevance: respective positive effects have been shown in more than erpene sapogenins. Glycyrrhizin is a conjugate of 1 30 different model studies in over 120 investigations. (232Ϫ236, Ϫ molecule of glycyrrhetinic acid with 2 molecules of 238 240, 246, 249, 254, 255, 258, 259, 261, 265, 267) • The effi- β cacy of silymarin as an antioxidant (so-called radical scavenger) glucuronic acid. It is metabolized by -glucuronidase, was confirmed in recent studies. (229, 237, 251, 253, 255, 257, 266) predominantly in the intestine (by bacteria) and to a Furthermore, an antifibrosis effect (231, 244, 248, 252) and the lesser extent in the liver (by lysosomes). The half-life inhibition of β-glucuronidase (336) have been demonstrated. The is 3Ϫ5 hours, in chronic liver disease 4Ϫ10 hours. The modes of action of silymarin are based on several cellular targets. (s. tab. 40.13) following modes of action are postulated: (1.) it acts as a radical scavenger, (2.) it decreases cell-membrane The clinical studies (approximately 120) available up to permeability, and (3.) it prevents membrane penetration 1988 (227) have meanwhile been supplemented by fur- by viral particles. (276) The antiviral cytoprotective and ther investigations. (236, 242, 246, 256, 263) Silymarin did immunomodulatory effects are based on these modes of not prove beneficial to patients with PBC. action. Although its previously known pharmacological

867 Chapter 40 effects were not considered to be of any consequence 5.13.6 Cynara scolymus for hepatology, glyzyrrhizin has meanwhile surprisingly Cynarine is the main active agent of artichoke extract. proved its worth as a hepatoprotective compound. The It is a cinnamic acid derivative; the substitution pattern agent induces interferon formation and, in this way, also of its aromatic rings is similar to that of dopamine. has an antiviral effect. Good therapeutic results were Caffeic acid is also regarded as a major active substance. recorded in several clinical studies on chronic hepatitis It has not yet been clarified to which constituents the B, NANB and C and for prophylactic use in transfusion known modes of action are attributable: (1.) increase in hepatitis (with administration both before and after choleresis, (2.) inhibition of cholesterol biosynthesis, (3.) blood transfusions) as well as in subacute viral liver fail- hepatoprotection due to antioxidative effects, and (4.) ure (200Ϫ600 mg/day). Glycyrrhizin inhibited HAV rep- activation of the urea cycle. lication and improved the immunological identification of HBsAg; HBeAg-positive patients showed more rapid 5.13.7 Bupleurum falcatum seroconversion. (275, 277) A mixture of glycyrrhizin (40 ϩ ϩ mg) cysteine (20 mg) glycine (400 mg) has also An extract of Bupleurum falcatum with the active agent been used as therapy. • With long-term administration, saiko has for a long time been used in hepatobiliary pseudoaldosteronism may appear, which can be elim- diseases in Eastern Asia. The substance is commercially inated by spironolactone (e.g. 50 mg/day). available in China under the name Sho-Saiko-To. The active components are attributed to the saiko-saponins 5.13.4 Colchicine (M. Yamamoto et al., 1981, 1985). Inhibition of fibrogenesis ᭤ Colchicine is an alkaloid obtained from the autumn crocus (Col- was demonstrated in animal experiments. (292Ϫ294) A chicum autumnale). It is a nitrogen-containing, tricyclic com- good effect was achieved in chronic hepatitis in several pound with a tropolone structure. The results of the pharmacoki- clinical studies. Significantly more rapid HBeAg elimi- netic studies available so far are summarized in a review. (289) nation was attained in children with chronic hepatitis B. Colchicine inhibits the function of the microtubuli (280) and acts as a toxin on cells, mitoses and capillaries. (279, 284, 287, 290) (295) (s. pp 553, 705) Albumin synthesis is apparently only slightly affected. (282) In existing iron overload, further iron uptake is greatly increased by 5.13.8 Phyllanthus amarus colchicine. Trimethylcolchicinic acid proved less toxic. (279) The antifibrotic effect of colchicine is probably based on a reduction Extracts from Phyllanthus amarus and Phyllanthus nir- in collagen secretion and an increase in collagenase activity with uri have been used in India for more than 20 years in elevated collagen breakdown. (286) In existing liver disease, the pharmacokinetics of colchicine is influenced. (288, 289) A poten- acute viral hepatitis, apparently with success. Compared tial antilipid peroxidative effect was observed in experimentally with essential phospholipids, Ph. niruri was equally induced acetaminophen liver damage. (284) effective in improving laboratory values, while Ph. amarus proved to be even more efficacious. Phyllanthus The results obtained from the clinical use of colchicine extracts inhibit HBV reduplication (298, 299) and DNA are controversial. Good results in the prevention of cir- polymerase in HBV and WHV infection (300), whereas rhosis in chronic hepatitis B and, when combined with this effect was not verified in DHV hepatitis. (297) UDCA, in primary biliary cholangitis are counterbal- HBsAg carriers also exhibited a loss of HBsAg in 50% anced by unfavourable results in chronic hepatitis (283, of cases and a significant rise in anti-HBs titres. (296) 291), primary biliary cholangitis (281) and primary scle- These good results contrast with a number of unfavour- rosing cholangitis (285) as well as in alcoholic hepatitis. able experiences, which may be attributable to the fact • A beneficial effect of colchicine on hepatic fibrogenesis that the Phyllanthus species contain varying amounts of should be the subject of further debate. (s. pp 650, 658, active substances in different countries. This was also 743) believed to explain the better efficacy of Phyllanthus 5.13.5 Betaine urinaria compared to Ph. amarus and Ph. niruri. Betaine is a quarternary ammonium compound. This 5.13.9 Schizandra chinensis substance is widely found in nature; it was first isolated from sugar beet (Beta vulgaris). • Like choline and The hepatoprotective efficacy of Schizandra chinensis is methionine, betaine belongs to the group of lipotropic based on its lignoids Gomisines A, C, N, Wuweizisu C substances. Choline plays a major role in the mobiliza- and Schisanthesin D. (302) A rapid decrease in transami- tion of neutral fats in the liver, using them to form nases was verified in chronic viral hepatitis (189 transportable phospholipids with neutral fats. In order patients). (308) Hepatoprotective and anticarcinogenic to be able to give up its methyl group, choline requires effects were demonstrated in experimental studies. (301, Ϫ betaine. Thus it assumes an important function in the 303 307) transmethylation cycle of lipid metabolism, particularly since it is also essential for the resynthesis of methio- 5.13.10 Catechin nine. Within the therapeutic dosage range, betaine is in The active substance (ϩ)-catechin is the main component of the no way toxic. plant Uncaria gambir. In the systematic chemical nomenclature,

868 Treatment of liver diseases

this natural substance is called (ϩ)-cyanidanol-3. Pure (ϩ)-cate- route of liver metastases is also taken into account. • Hjortsjö’s chin is considered completely non-toxic. Catechin is readily concept (C.H. Hjortsjö, 1948) referring to the division of the ante- absorbed and rapidly degraded in the liver. So far, 11 metabolites rior segment into two vertical subsegments could be confirmed by have been identified. Because of its low molecular weight, catechin recent investigations. (332) (s. p. 16 (s. figs. 2.5, 40.4) is mainly eliminated via the kidney. • The following modes of action have been demonstrated: (1.) increase in ATP concentration in the ᭤ During the past 30 years, the surgical treatment of liver diseases liver and (2.) inhibition of lipid peroxidation. This is the basis of or injuries has made enormous progress due to the introduction of the marked hepatoprotective effect. It was used clinically as an more sophisticated techniques, newly developed instruments and adjuvant in acute viral hepatitis, chronic hepatitis and toxic (also anaesthetic procedures as well as better management of intraoper- alcohol toxic) liver damage. The results reported seemed promis- ative haemodynamics. These options regarding superior liver sur- ing. • Although catechin was regarded as totally non-toxic on the gery have only been made possible by the introduction of modern basis of experimental studies, major (unexplained) side effects imaging procedures, endoscopic techniques and angiography. As including haemolytic anaemia, idiosyncratic reactions and even with the use of laparoscopy, these examination methods guarantee deaths occurred (K.A. Neftel et al., 1980; N. Brattig et al., 1981). far more exact presurgical staging than was conceivable in the past. • The preparation, which had already been introduced in many • Since the introduction of TIPS, shunt and block surgery have countries, was thereupon withdrawn from the market. lost some of their importance, both in terms of elective indications and the emergency treatment of complications observed in portal hypertension. In an era of well-managed liver transplantation (which in the meantime is performed at a large number of centres), 6 Surgical therapy TIPS and shunt surgery serve to bridge the time gap until a favourable date for transplantation has been found. • It should be noted that an appropriate shunt operation guarantees a more stable situa- Even in antiquity, liver injuries were considered to be tion than TIPS, especially in the long term. Indeed, shunt surgery, fatal due to the uncontrollable bleeding. Proof of an rehabilitated by C.E. Zöckler et al. (1985), is experiencing a revival enemy’s death was not furnished until his liver could in many places. be presented. (s. p. 5) As far as we know, Celsus (30 Ϫ BC 50 AD) gave the first, remarkable description of 6.1 Ascites in portal hypertension liver surgery, which, due to the high volume of blood, was carried out using a cautery knife. • Surgical treat- Even though conservative therapy proves efficacious in ment techniques for liver diseases were not included 85Ϫ90% of ascites cases, 5Ϫ15% are unresponsive to in textbooks on hepatology until 1965. The two-vol- such treatment. • These patients can be treated success- ume book by F. T h. Frerichs (1861) (s. fig. 1.19), the fully using invasive or surgical measures, since the prog- textbook by H. Eppinger (1937) (s. fig. 5.1) and the two- nosis for ascites which is really refractory is poor. How- volume book by I. Magyar (1961) contained no descrip- ever, in each case, surgical options have to be carefully tions of liver surgery Ϫ apart from the treatment of considered, taking into account all individual facts and echinococcus cysts Ϫ although extensive liver or por- deciding about indications with respect to (1.) perito- tal vein system surgery had been carried out since the neovenous shunt, (2.) TIPS, or (3.) liver transplantation. second half of the 19th century. • The first two methods contribute to recompensation and help to bridge the time gap until liver transplantation can be carried out, whereby the liver function Since the first surgical treatment of refractory ascites should be maintained as effectively as possible. • After by hepatopexy (C.T. Billroth, 1894) and of bleeding peritoneovenous shunt (s. p. 311) (s. figs. 16.12Ϫ16.14) (s. oesophageal varices using resection of the short gas- tabs. 16.14Ϫ16.18) or TIPS (309, 310, 313) (s. pp 259, 314, tric veins (G. Banti, 1894), vast numbers of surgical 362) (s. fig. 16.15), a subsequent transplantation no techniques have been developed in order to manage longer poses a problem. both of these emergency situations.

The attempt to compile a systematic list of all procedures 6.2 Bleeding in portal hypertension is bound to be incomplete despite thorough investigations. However, it is worth the effort to include the ingenious Ϫ The causal spectrum of upper or lower gastrointestinal and seemingly logical Ϫ surgical methods of our worthy bleeding is extremely broad. (s. tab. 19.4) (s. pp 348, predecessors, so that their approaches to the operative 366) The most common sources of bleeding in portal management of ascites or bleeding oesophageal varices hypertension are varices of the oesophagus and stomach are not forgotten. (s. tabs. 16.19 and 19.7!) (s. pp 254, 352), portal hypertensive gastropathy or intestinal vasculopathy (s. p. 257), and intestinal varices. ᭤ An important prerequisite for liver surgery was knowledge of (s. p. 256) It is particularly the unexpected and massive the vascular system, which was first described by F. Glisson in 1654 (s. fig. 1.16) and again by R. Rex in 1888, and which is known in variceal bleeding which is life-threatening and which detail today. • For the segmental classification of the liver, the sys- requires intensive care, i.e. a combination of medication tem according to C. Couinaud (1954) and A. Priesching (1986), using and mechanical measures. Of greatest importance are the branches of the portal vein as orientation, gained prevalence. drugs to reduce portal vein pressure, sclerotherapy or The caudate lobe is designated as segment I. Segment IV is situ- ated on the right side of the falciform ligament (it is exclusively variceal ligation, and (if necessary) balloon tamponade. oriented to venous drainage via the intermediate hepatic vein). (s. pp 358Ϫ359) • Whether or not surgical techniques This sets limits for surgical techniques, and the haematogenous are indicated is determined after definitive haemostasis

869 Chapter 40 and should be based on a critical evaluation of individ- when TIPS or shunt surgery could not be carried out or were ual risk factors and the respective liver status. However, unsuccessful. Devascularization procedures are worth considering as emergency interventions. (s. p. 363) surgical treatment is needed for variceal bleeding which lasts longer than 2 days (requiring a daily supply of >4 units of blood) and which could not be stopped despite 6.3 Liver resection all conservative measures; this also applies to early relapse bleeding. • From a haemodynamic point of view, ᭤ The first liver resection in the form of a lobectomy TIPS, which is a non-surgical connection between the was carried out on a dog by G. Zambeccari as early as hepatic and portal vein, represents a portacaval side-to- 1680. The first resection in humans (removal of an side shunt. This results in a sustained decrease in portal adenoma) was also performed in Italy, but the out- vein pressure. Relapse bleeding is reduced to 10Ϫ20%. come was fatal (A. Lius, 1886). The first successful Such an approach does not complicate subsequent liver resection of a large, benign, pedicled lobular constric- transplantation. TIPS is thought to be the ideal tech- tion was carried out by C. v. Langenbuch (Germany) nique for bridging the time gap before liver transplanta- in 1888, while successful resections were performed tion can be carried out. (310Ϫ312) in the USA by W. W. K een as from 1892.

6.2.1 Shunt operation 6.3.1 Basic principles The importance of surgical treatment for oesophageal or gastric variceal bleeding is still controversial. Nevertheless, according to Definition: A liver resection is defined as the surgical the findings to date, shunt surgery with a relapse bleeding risk of removal of tissue components of the liver in order to 5(Ϫ10)% is deemed to be the best prophylaxis against bleeding, so eliminate a localized disease process. • The left that >50% of Child A and B patients reach their fifth postopera- Ϫ tive year. In the only comparative prospective study carried out so hepatic lobe (segment I IV) contains 40% and the far, the small-calibre, portacaval H-graft prosthetic shunt proved right lobe (segment VϪVIII) contains 60% of the to be superior to TIPS in all relevant aspects. (311) • Good selec- total liver mass. (s. fig. 40.4) Removal of >80% of a tion criteria are: (1.) Child A and B patients, (2.) liver volume healthy liver is (in principle) fatal. • Hyperplasia of the Ϫ between 1,000 2,500 ml (as a close correlation to the O2 con- remaining liver can be expected, while regeneration sumption of the liver), (3.) portal vein perfusion of 10Ϫ30% of the total hepatic blood flow (for a distal splenorenal shunt of >30%) of the resected portion of the liver is also possible. in sequential scintigraphy or duplex Doppler sonography, (4.) selec- tive panangiography to check whether the arteries and veins have Functional reserve: The method of choice and the extent a sufficient length and lumen, and (5.) use of a shunt technique of the resection depend upon the residual function of which does not harm liver function and at the same time facilitates subsequent liver transplantation. The most efficient techniques the remaining liver tissue. As a rule, it is relatively easy have proved to be the distal splenorenal shunt (particularly in high to determine the loss of tissue caused by surgical inter- portal vein residual perfusion) using the same procedure as with vention, but this is not equivalent to the functional loss: splenopancreatic disconnection and gastric transection (319), and on the one hand, the tumourous or diseased tissue the small-calibre mesocaval interpositional prosthetic shunt (especially in cases of decreased portal vein blood flow). Chylous ascites which has been removed had no function and therefore was observed as a rare complication of a distal splenorenal shunt. cannot be evaluated as a functional loss; on the other If, for surgical reasons, these methods cannot be applied, the por- hand, the neighbouring tissue, which was displaced by tacaval side-to-side shunt using a small-calibre stent is now recom- the growth process, might indeed experience functional mended when there is no possibility of liver transplantation. (316) recovery after tumour resection. It should be noted that The partial portacaval shunt is preferred to the direct shunt. (315) The survival rate after 5 and 10 years is reported to be 75Ϫ80% healthy liver tissue usually has to be removed due to the and 65Ϫ70%, respectively. • The outcome of shunt surgery is deter- necessity of allowing a safety margin. This is especially mined by the preoperative liver function and the arterial compensa- true when keeping to the respective segmental bound- tion capacity (which still cannot be measured exactly). The pre- aries. Evaluation of the remaining functional reserve is operative portal vein pressure is obviously not a risk factor during surgery or postoperatively. (314, 317, 318, 320) • Treatment of extremely difficult in a diffusely diseased liver. This is multiple arterioportal fistulas by shunt surgery should be men- above all true in cirrhosis; here, it is first of all necessary tioned as a rarity here. (s. p. 363!) (s. tab. 19.7) to determine the Child Pugh stage. (s. tab. 35.6) Several laboratory parameters (e.g. ChE, GEC, ICG, amino- 6.2.2 Block surgery pyrin 14C test) (339, 340) as well as CT volumetry or 99mTc GSA (339) Ϫ and, in the future, virtual liver sur- Block surgery prevents the portal blood from flowing to the Ϫ oesophagus and thus intervenes directly at the site of bleeding. gery (336) are suitable for assessing preoperative liver However, it does not reduce portal hypertension Ϫ portal vein function and its postoperative functional reserve (even residual perfusion is not decreased. • The numerous methods or though functional values cannot be directly related to three groups modifications may be differentiated into :(1.) simple the functional hepatocyte mass). (321, 333, 334) block operations, in which the oesophagus is divided close to the cardia and re-anastomosed, (2.) extended block operations, which ᭤ Parenchyma setting: When incisions are made in the paren- comprise additional skeletization of the stomach in order to avoid chyma, all structures within the tissue (arteries, portal veins, fundus variceal bleeding, and (3.) the Sugiura method, which also hepatic veins, bile ducts) must remain intact. Apart from the well- includes splenectomy in addition to gastric devascularization and established method called “finger fracture” (W. Anschütz, 1903), oesophageal section. (314) • Block operations are only indicated ultrasonic cutters, water beam dissectors or laser scalpels are used

870 Treatment of liver diseases

nowadays in order to distinguish between hepatic parenchyma and vascular structures. • Haemostasis can be achieved by surgical techniques and electrocoagulation, infrared coagulation, argon beamer or fibrin glue. • The insertion of drainage tubes allows the removal of postoperative lymph, gall, residual haematomas and (possibly) oozing blood. Even if these surgical methods are carefully managed, it is not possible to avoid such fluid discharge completely. • The post-resection methylene blue test helps to reduce the postoperative biliary leakage rate. (335) (s. pp 780, 798!)

6.3.2 Classification and indications

Left hemihepatectomy: This procedure includes segments II, III and IV, i.e. the left liver lobe is removed. • In extended left hemihepatectomy, segment V or VIII is also resected. (s. fig. 40.4) Right hemihepatectomy: This procedure was successfully carried out for the first time by W. W endel (Germany) in 1911 in order to remove a large adenoma. • The technique involves the resection of segments V, VI, VII and VIII, i.e. right liver lobe is removed. • Extended right hemihepatectomy also includes segment IV (left middle segment). (s. fig. 40.4) Lobectomy: In left lobectomy, segments II and III are removed, while in right lobectomy, segments IVϪVIII are resected (whereby the right and left halves of the liver are incorrectly called “lobes”). (s. fig. 40.4) Segmentectomy: This surgical technique involves the removal of a single liver segment or a combination of segments. Both marginal and central segments may be involved. Another surgical option includes going beyond the boundaries of the segments, such as removal of segment V and the lower half of segment IV. • Resec- tion of segment VIII is the most difficult procedure; usually, segment VII is removed at the same time, since the venous blood flow is interrupted in any case. • Segmentectomy IV divides the liver into two parts as far as the vena cava. The cava/gall-bladder line serves as orientation. • Left lateral segment resection involves segments II and III (also known as left lobectomy, see above). • Seg- ment I cannot be assigned to either of the two halves of the liver. Its boundaries are difficult to determine; in general, the anterior boundary is defined by the hilar ramification of the portal vein structures, while the posterior boundary line is deemed to be the vena cava. Segment I varies in size, and sometimes it is nothing more than a thin layer of tissue. • As a rule, it is possible to define the segmental boundaries by targeted puncture of the portal vein oui- branches to show colour contrast in the respective segment and Fig. 40.4: Representation of the liver segments (acc. to C. C naud ϭ ϭ also by intrasurgical sonography. (326) (s. fig. 40.4) , 1954) (ULS upper liver surface, LLS lower liver surface). (327) Left liver lobe: IϪIV (segment I corresponds to the Dorsocranial resection, a special technique with simultaneous caudate lobe and can only be delimited at the LLS; segment IV is hepato-atrial anastomosis, may be indicated in the Budd-Chiari actually located to the right of the falciform ligament). Segment syndrome (G. Bansky et al., 1986; S. Meyer et al., 1988). (s. p. 830) IV is subdivided into an apical part (IVa) and a caudal part (quad- rate lobe) (IVb). Right hepatic lobe: segments VϪVIII. (1 ϭ infe- A wide spectrum of focal lesions of varying sizes pro- rior vena cava; 2, 3 ϭ falciform ligament) (s. figs. 2.1, 2.5) vides the indication for liver resection (323, 325, 328, 330, 331, 333, 337): mal experiment. This observation was confirmed in 1. Benign liver tumour 1931 by animal experiments, in which restoration of the 2. Congenital malformations liver was demonstrated following two-third resection in 3. Focal bile-duct processes the rat. (329) • It has meanwhile been shown that liver 4. Granuloma (tuberculosis, actinomycosis, etc.) 5. Liver metastasis regeneration begins directly after resection with a cas- 6. Malignant liver tumour cade of biochemical and molecular mechanisms. It 7. Parasitic foci becomes measurable three to four weeks later. Numer- 8. Traumatic liver injury ous examinations revealed that the remaining liver reaches its initial, normal size again within 3Ϫ6 months. 6.3.3 Regeneration (324) Even in chronic hepatitis or cirrhosis, the liver demonstrates its regenerative capacity after extensive In 1879 H. Tillmanns first reported the phenomenon of resection, albeit more slowly and to a lesser extent than liver regeneration following a large resection in an ani- a liver with healthy parenchyma. • Regeneration appears

871 Chapter 40

to depend on (1.) regeneration-stimulating factors in the Type Ia: Superficial parenchymal lesions portal blood after resection (e.g. endotoxin) and (2.) the Ib: Deep liver ruptures quantity (and quality or special characteristics?) of the Ic: Visible parenchymal destruction, with or without portal blood flow. • Regulatory factors of growth can bile-duct injury be divided into: (1.) mitogens (which stimulate synthesis Type II: Additional injuries of the porta hepatis (bile ducts, portal vein, hepatic artery) of DNA and mitosis of hepatocytes), such as EGF, Type III: Injuries of the portal vein hilum TGFα, HGF and FGF; (2.) inhibitors, such as TGFβ, Type IV: Liver injuries combined with lesions of the vena cava HPI and some interleukins; (3.) co-mitogens (which enhance the effect of mitogens and reduce the effect of Whereas penetrating injuries are less common today, the inhibitors), such as insulin and glucagon (“goodies of number of blunt injuries has increased, frequently the liver”), TNFα, IL 1, IL 6 and hormones. The geneti- accompanied by liver rupture. A liver injury is involved cally steered interplay of numerous factors in separate in up to 40% of patients with blunt abdominal trauma. phases of development leads to a closely controlled Conservative treatment is recommended as far as pos- regeneration process. What is important for the result is sible in order to avoid unnecessary laparotomy. (353) The the relationship between liver mass and body mass. (322, overall mortality rates were 11.8% and 16.8%, respec- 338, 341) (s. p. 402!) • Regeneration did not occur in a tively. (345, 347) In many cases, the urgency of the situa- portacaval end-to-side shunt under experimental condition does not allow the requisite examinations (e.g. US, tions. Liver cirrhosis induced in animal experiments CT (350, 352), angiography, laparoscopy) to be made Ϫ proved to have regenerative capacity, an observation an emergency operation has to be performed. Such an which was confirmed by clinical findings. It is assumed operation must even be done under shock if the patient that in resection-related regeneration, “other” mecha- does not respond directly to conservative methods. nisms (apart from age) are set in motion than in cirrho- The surgical treatment chosen depends on the type of sis-related regenerative processes. (342) The type and injury, but also on the patient’s condition at the time. extent of the cirrhosis also seem to be important factors Some 40Ϫ65% of all deaths are due to exsanguination, with regard to resection-stimulated regeneration in while 35Ϫ60% are caused by postoperative organ fail- residual cirrhosis. ure. Intra-abdominal formation of abscesses is deemed Complete regeneration of the right liver lobe occurred to be the most common complication. (344, 349) Based in two women following right lobectomy; surprisingly, on the findings available, the following surgical methods the regenerated right lobe showed exactly the same are used: (1.) drainage, (2.) superficial suture with drain- external shape as the original one. (428, 448) This led age, (3.) haemostasis by means of transcatheter arterial to the well-founded assumption that there is both (1.) embolization (346, 348), fibrin glue, infrared coagulator resection-stimulated hyperplasia of the remaining liver or electrocoagulation, (4.) anastomosis techniques (e.g. and (2.) regeneration of its resected part. The causes of intracaval shunt), (5.) hepatorrhaphy, (6.) resection tech- these two developments are still unclear, as is the vary- niques (e.g. debridement, segmentectomy), etc. (343, 344, ing capacity of a cirrhotic liver to regenerate. Several 349, 351) An overall mortality rate of 10.5% was reported different methods of elucidating the regenerative pro- in 1,000 consecutive liver injuries. cesses have been suggested. (322) (s. pp 5!, 402) 7 Liver transplantation 6.4 Liver injuries The first liver transplantation was carried out on a Liver injuries, particularly caused by weapons and dog by C. S. Welch et al. in 1955. (425) • After a five- accidents, have been known ever since the dawn of year period of experimental preparations, T.E. Starzl mankind. There are numerous reports dating from et al. were able to carry out the first orthotopic liver antiquity and later centuries of liver injuries and sur- transplantation for extrahepatic biliary atresia on a 1st March 1963 gical attempts to heal them. • About 1600, F. H ildanus 3-year-old boy in Denver (USA) on ; reported an excision of a prolapsed part of the liver however, the boy bled to death during the operation. Ϫ after trauma Ϫ the patient survived. In 1716 G. Berta Another four transplant recipients lived 6 23 days. succeeded in treating a prolapsed and severely injured (414) • In 1968 R.Y. Calne et al. began carrying out liver in a madman who had cut open his belly with a liver transplantations in Cambridge (England). In knife. • Laparotomy has been used since 1886 to Germany, A. Gütgemann et al. started performing liver ichlmayr manage liver injuries; mortality rates were 60% (L. transplantations in 1968, followed by R. P et Edler, 1887), 81% (F. Terrier, 1896) and 44% (B.T. Til- al. in 1979. While surgical techniques were constantly tun, 1905). undergoing improvement, the problem of organ rejection could not be solved by the substances used at that time (cyclophosphamide, antilymphocytic globu- The following classification is used to assess liver injury lin, azathioprine). (H. Bockhorn et al., 1982):

872 Treatment of liver diseases

It was not until the introduction of cyclosporine A (R.Y. ations may be grouped into eight main categories, subdi- Calne et al., 1979) and the combination of cyclosporine A vided into frequent and rare. In addition, differentiation ϩ prednisolone (T.E. Starzl et al., 1980) that the ultimate is made between safe, possible and limited indications breakthrough was achieved. In 1983, liver transplanta- for liver transplantation. (s. tab. 40.14) tion was recognized as an important option for patients The indication for LT depends on (1.) type of liver disease and (2.) in the final stage of chronic liver disease. • By 1993, a stage of disease, i.e. at what point LT is carried out during the total of 26,500 liver transplantations were reported to course of disease. It should be noted that the preparations neces- have been carried out worldwide (R. Belle et al., 1993). sary for LT should commence as from stage Child B. • Eurotrans- “high urgent” Under the auspices of Eurotransplant, more than plant assigns the status only to patients suffering from acute liver failure or acute transplant failure following LT. 21,000 liver transplantations had been performed by the Patients suffering from acute deterioration of an existing liver dis- end of 1995. Due to the rapidly rising number of centres ease are not included in this category. High urgent registrations (about 300 worldwide), the total number of liver trans- undergo meticulous examination by Eurotransplant. In such cases, plantations was thought to have reached about 80,000 the waiting period is 6Ϫ30 hours. Important parameters regarding an indication for LT in acute liver failure include: (1.) advancing worldwide by the end of 2000. • In Germany, the number encephalopathy, (2.) atrophy of the liver (daily US!), (3.) develop- of liver transplantations rose from 502 in 1992 to 779 in ment of an ascites, (4.) decrease in the transaminases and Quick’s 2004. • The 1-, 5- and 10-year survival rates amount value, and (5.) progressive renal insufficiency. In order to bridge to >90%, >80% and >75%, respectively. However, the the time until a transplant is available, the use of a liver-support Ϫ demand for liver transplantation (LT) is far greater than device can be most helpful. (s. pp 384 386) the supply of donor organs. This lack has practical con- Three indication categories are differentiated according to the over- sequences:(1.) on the indication for LT, (2.) on the all condition of the patient, respective liver function, the effects of development of more sophisticated liver-support devices the liver disease on other organs, and existing risk factors: for bridging a life-threatening situation and for avoiding (1.) Elective indication: The general condition is stable and the nu- LT should the diseased liver meanwhile become restored tritional state is still good or can be improved; liver function is decreasing, but still sufficient; bilirubin is constantly rising; there (s. p. 384), (3.) on the search for alternative transplanta- are as yet no severe extrahepatic complications (e.g. encephalo- tion techniques (e.g. split-liver, APOLT, LDLT) for opti- pathy, ascites, hepatorenal or hepatopulmonary syndrome). mizing the use of cadaveric livers, and (4.) on the (2.) Late indication: The general condition is poor and the nutri- mortality rate among those patients who are waiting for tional state is considerably reduced; liver function is severely com- a suitable organ. • The waiting period currently lies promised and shows increasing deterioration; there are complica- between 6Ϫ12 or even 12Ϫ18 months. tions and additional risk factors. (3.) Emergency indication: Failure of vital functions; severe compli- Ϫ Potential indications for liver transplantation are cations are observed (HE stages II IV, kidney insufficiency, re- spiratory insufficiency). • This situation may develop either (1.) as given in almost any kind of life-threatening liver dis- the final phase of a long-standing, preexisting liver disease or in ease (1.) which has taken a progressive and irrevers- abrupt manner, or (2.) as a high urgent indication in acute liver ible course or (2.) in which a period of time has to failure (361, 362, 370, 408, 417) or acute liver transplant failure. be bridged between the patient’s irresponsiveness to Time of indication: Determining the best time for LT is treatment and the probable reversibility of the dis- very important, but it is also difficult. Although Child- eased liver. The motivation and compliance of the Pugh classification is used as a standard in liver cirrho- patient are prerequisites for LT. sis, it has not proved to be a valuable tool regarding the timing of LT. • Important criteria for determining the best time of indication are: (1.) type of liver disease, 7.1 Indications including its natural course and risks due to complications, (2.) subjective drop in performance of the patient, If the indication for LT is given, the case should be reg- and (3.) progressive deterioration of certain laboratory istered with a liver transplantation centre. The patient is parameters. In this context, a slow but steady decrease then checked regarding the indication, and all contrain- in GPT and GOT to subnormal values points to severe dications should be excluded. Subsequent to phase-1 and irreparable loss of parenchyma. Deterioration of and phase-2 evaluation, the patient is added to the wait- endogenous functional values also suggests that the ing list. Principally, only those patients will be selected final phase is imminent. This is likewise confirmed by forLT(1.) who have a realistic chance of surviving the the fact that the results of exogenous function tests perioperative phase and (2.) whose chances of survival worsen. Such tests are easy to carry out, do not entail are considerably better following LT. Children of <1 side effects, cause little inconvenience and are highly year can also be successfully transplanted. (359, 375, 418) reliable, particularly in combination. (s. tab. 40.15) The The spectrum of indications for liver transplantation has ICG and the aminopyrine 14C breath test have proved widened enormously due to more sophisticated presur- to be valuable transplant control measures. (369) gical diagnosis, more exact evaluation of risk factors, better management of intraoperative techniques and It is important not to miss the right moment for LT. A supplementary measures, improvement in immunosup- long waiting period with conservative therapy generally pressive agents and more qualified aftercare. The indic- leads to an increase in intraoperative risks as well as a

873 Chapter 40

1. Cirrhosis 5. Hepatic tumours Haemophilia Alcoholic cirrhosis Benign tumours Hypercholesterinaemia Autoimmune hepatitis Cystic liver (383, 401) Hyperlipoproteinaemia II Cryptogenic cirrhosis Ϫ echinococcosis (382) Niemann-Pick disease HBV and HDV Ϫ focal nodular hyperplasia Oxalosis HCV Sarcoidosis Porphyria Cholestatic diseases Reye’s disease 2. Malignant tumours Sanfilippo’s syndrome Alagille syndrome Ϫ selected biliary carcinomas Ϫ Sickle cell anaemia Bile-duct atresia selected gall-bladder carcinomas Thalassaemia (β) Bile-duct papillomatosis Ϫ selected hepatic carcinomas Ϫ Tyrosinaemia (358) Biliary cirrhosis after cholangitis selected metastases Urea cycle defects Biliary cirrhosis after PBC 6. Vascular diseases Wilson’s disease (419) Biliary cirrhosis after PSC Wolman’s disease Caroli’s disease (410) Budd-Chiari syndrome Cholangiodysplasia Haemangiomatosis 8. Complications in cirrhosis Cholestatic sarcoidosis Veno-occlusive disease Ascites unresponsive to treatment Graft-versus-host disease 7. Metabolic diseases Hepatopulmonary syndrome α Hepatorenal syndrome 3. Acute liver failure 1-antitrypsin deficiency Aminoacidurias Recurrent varix bleeding Acute episode of a chronic liver disease Severe hypoalimentation Fatty liver of pregnancy Amyloidosis Byler’s disease Spontaneous bacterial peritonitis Fulminant viral hepatitis (371) Retransplantation HELLP syndrome Crigler-Najjar syndrome 9. Intoxications, poisoning (361) Familial cholestasis Acute rejection Postoperative, posttraumatic Fructose intolerance Arterial thrombosis Galactosaemia Chronic rejection 4. Mycosis Gaucher’s disease Initial dysfunction Candidiasis Glycogenosis I, IV (413) Portal vein thrombosis Coccidiodomycosis Haemochromatosis (402) Recidivism of the underlying disease

Tab. 40.14: Indications for liver transplantation: safe, putative and limited indications (as have been published) (with some references)

I. Liver disease primary biliary diseases Ϫ while liver function tests still 1. Type: primary hepatocellular show good values in most cases. primary biliary 2. Natural course Liver transplantation has the following aims: (1.) improvement in life expectancy and (2.) improvement II. Subjective deterioration in condition in the quality of life. III. Changes in laboratory values 1. Enzymatic activity • GPT, GOT < 10 U/l 7.2 Contraindications 2. Endogenous function values • Albumins < 3 g/dl As the management of liver transplantation has • Quick’s value < 40% improved, absolute and relative contraindications have • Cholinesterase < 1,000 U/l been established. Relative contraindications may ques- • Bilirubin > 5 mg/dl tion the success of LT in some cases. Obesity leads to 3. Exogenous function values an increased rate of postoperative complications, but it • Indocyanine green > 5 min. • Galactose elimination capacity < 5 mg does not influence the survival rate. (396, 403) (s. tab. • MEGX 40.16) • Contraindications should also be considered in • Aminopyrine 14C urgent LT due to acute liver failure Ϫ possibly accom- 4. Biliary function panied by necrotizing pancreatitis, septic shock and • Alkaline phosphatase > 1,500 U/l problems with assisted respiration. • Visceral inversion is not deemed to be a contraindication: a successful LT Tab. 40.15: Important criteria in timing liver transplantation was indeed carried out under such conditions by G. B. Klintmalm et al. in 1993. decrease in postoperative survival time. Any complications further worsen the prognosis and put LT into the 7.3 Preoperative diagnostics “late indication” category. (354) • In addition to rising bilirubin and AP values, the consequences of impaired Clinical examination prior to LT comprises: (1.) meticulous anamnesis including all previous findings, (2.) thorough internal bile flow (e.g. undernourishment and malnutrition, examination, (3.) psychosocial and psychiatric assessment, and (4.) catabolism, osteoporosis, malabsorption, hypercholes- broad spectrum of laboratory parameters. The medical “work-up” terolaemia and pruritus) are prognostically relevant in prior to LT takes about 10Ϫ12 days.

874 Treatment of liver diseases

avoid a steal effect. • Although portal vein thrombosis, previous Absolute contraindications operations in the liver hilus and portosystemic shunt surgery are 1. Severe cardiac disease (sometimes considerable) obstacles to liver transplantation, they 2. Severe pulmonary disease are not regarded as contraindications. When there is isolated or 3. Extrahepatic metastases partial portal vein thrombosis, a connection to the portal vein can 4. Malignant secondary disease often be restored by thrombectomy or bypass techniques; the sur- 5. Florid sepsis vival rate is similar to that in patients with a primary open portal 6. AIDS vein. Nevertheless, the conditions for a successful LT are more 7. Severe irreversible brain damage favourable if there is no portal vein thrombosis and the liver hilus 8. Active alcohol or drug abuse does not require special preparatory measures. 9. Anatomical or postoperative anomalies 10. Portal vein plus superior mesenteric vein thromboses 11. Severe osteopenia 7.4 Preparation of patients 12. Poor nutritional state Relative contraindications (1.) During the waiting period, it is important to main- 1. Portacaval shunts tain or even improve the patient’s nutritional status. Pro- 2. Portal vein thrombosis (with open superior mesenteric vein) tein tolerance can be monitored by using simple psycho- 3. Age >65Ϫ70 years (biological age is more important!) metric tests. A protein intake of 1.0Ϫ1.5 g/kg BW/day 4. Condition after complex hepatobiliary surgery would be ideal. Supplementation by branched-chain 5. Chronic renal insufficiency 6. Muscular atrophy amino acids may be helpful. The calorie supply has to be 7. Unstable personality structure adjusted to the optimal requirement of the patient. (s. 8. Unstable psychosocial environment pp 741, 850, 861) 9. Obesity (>100 kg BW) 10. Retransplantation (2.) The daily food intake should be spread over five meals. However, it is almost impossible to achieve an Tab. 40.16: Absolute and relative contraindications for liver trans- optimum supply of water-soluble and fat-soluble vita- plantation. (The relative contraindications should be determined mins. for each individual case) Administration of multivitamin preparations is therefore recommended. Sodium chloride intake should Specific laboratory parameters comprise: (1.) blood group and not exceed 7Ϫ8 g/day. (s. pp 278, 730, 734, 741) antibodies, (2.) HLA typing, (3.) hepatitis serology, including HCV RNA (by PCR) and HBV DNA, (4.) serology, including HSV I (3.) Depending on the patient’s condition, regular and II, EBV, CMV, HIV and varicella, (5.) coagulation status, (6.) muscle training should be carried out daily if possible in thyroid function, (7.) renal function, and (8.) immunology, includ- order to improve anabolism as well as urea and glut- ing ANA, AMA, SMA, anti-LKM and anti-SLA. amine metabolism in the muscles. (s. pp 650, 732) Technical examinations comprise: (1.) thoracic X-ray, (2.) ECG, lactulose (3.) echocardiography, (4.) pulmonary function, (5.) gastroscopy, (4.) The administration of over an extended (6.) EEG, (7.) US and colour-encoded duplex sonography of the period of time (dosage aim ϭ 2Ϫ3 stools per day) is abdomen, (8.) radiology (including CT and angiography of the recommended. (858) • It is advisable to use a combina- coeliac trunk) and right renal arteriography (to exclude high right tion with metronidazole or with non-absorbable antibiot- kidney) as well as MRI cholangiography. With regard to postoperative osteoporosis, bone densitometry is recommended prior ics (e.g. paramomycine) preoperatively in order to sup- to LT. (367) press the gram-negative intestinal flora and thus also the formation of endotoxins. If necessary, antimycotics This extensive programme is, on the one hand, essential for preoperative diagnostics and the documentation of initial findings, while may be administered in addition. on the other hand, postoperative changes in the findings can be (5.) Latent encephalopathy, detectable by psychometric evaluated more easily. • The indication for LT is determined by an interdisciplinary team. If possible, both assessment and registra- tests (s. p. 202), is frequent; experience has shown that tion of cirrhosis patients should be carried out during Child B as it can rapidly become manifest. Of the urea-cycle amino soon as progressive deterioration is observed. • When preoperative acids suitable for therapy, ornithine aspartate has proved diagnostics have been completed, patients grouped in the elective the most successful Ϫ also as an i.v. infusion in the post- category may spend the waiting period at home. However, even if the findings are constant, there is always a risk of acute and operative phase. (s. pp 279, 733) unforeseeable complications. (6.) The relevant literature also recommends vaccination Previous shunt operations and TIPS need to be removed in order against pneumococcus and influenza as well as hepatitis to guarantee that the transplanted liver is sufficiently supplied with B (unless there is already immunity). portovenous blood. In these cases, the portal system is checked preoperatively for thromboses by means of colour-encoded duplex sonography and X-ray techniques. In any case, the confluence of 7.5 Surgical aspects superior mesenteric vein and splenic vein must be free. (391) • The main advantage of portacaval end-to-side anastomosis is its low Compatibility of blood groups thrombosis rate of <5%; in addition, there is no need for a distal shunt ligature. In shunts distal to the hilus (mesocaval, distal splen- Interestingly, compatibility within the blood group system has orenal), no preparation of the liver hilus is required; however, in proved to be the decisive factor in liver transplantation to date. • 10% of cases, these shunts show portal vein thrombosis (in TIPS, Although the HLA system is usually determined (for retrospective up to 15%). • Usually, all surgical shunts are disconnected or evaluation), it is of minor importance according to present know- ligated before the liver transplantation is completed in order to ledge. This is also true of so-called “cross-matching” between

875 Chapter 40 patient serum and donor lymphocytes. No other compatibilities LDLT involving adults, the volume of the donor organ between recipient and donor (apart from body weight, height and should be equivalent to approx. 1% of the body weight thorax size) are known to be required. of the recipient. The respective size of the transplant, which is usually taken from the right lobe, is determined Quality of a donor liver by means of CT volumetry. • After LDLT, bile leaks The quality of the donor liver is of crucial importance for successful (7Ϫ10%) and biliary strictures (16Ϫ20%) frequently LT. First of all, careful and proper organ retrieval by a qualified appear. In such suspected complications, ERC is recom- team is an important prerequisite. Most centres now have such a mended. (364, 376, 383, 392, 395, 411) designated multi-organ retrieval team. • Any information pertaining to the donor (e.g. clinical results, anamnesis, laboratory values, In heterotopic liver transplantation (HLT), the donor donor protocol. current medication, further findings) is listed in the liver is transplanted as an auxiliary (additional) organ Of equal importance in the evaluation of a donor liver are the circumstances leading to the donor’s death (cause of death, inten- into the right upper abdomen, but the recipient retains sive care measures, etc.). • Using more suitable preservation solu- the diseased liver (K. Absolon et al., 1965; J. G. Fortner et tions (Ringer’s lactate, University of Wisconsin solution), the con- al., 1970). This technique is not easy to carry out in terms servation time of donor livers could be prolonged to 15Ϫ20 hours. of surgical requirements; it involves the so-called piggy- Great emphasis is being placed on achieving further improvements in this area. • During removal by the surgeon, the donor liver is back method and is used particularly for young patients assessed macroscopically and by palpation. This requires consider- suffering from acute liver failure. (s. p. 387) able experience, particularly since no other criteria for assessing Auxiliary partial orthotopic liver transplantation the quality of the donor organ are available. (424) The transplant should be almost identical to the recipient’s organ in terms of size, (APOLT) was introduced by G. Gubernatis et al. in 1991. weight and vascular diameter (portal vein, superior/inferior vena In this procedure, segments II and III of the diseased cava). • The use of size-reduced transplants is being further devel- liver are removed, while segments IIϪIV (or sometimes oped as a possible method for the future. only segments II and III) of the donor organ are transplanted. The bile duct is reconstructed as a biliodiges- Types of transplantation tive anastomosis. Full reversibility of the existing liver Normally, orthotopic liver transplantation (OLT) is used; disease is a precondition for the surgical concept of in this technique, the donor liver is implanted at the APOLT. (408, 417) (s. p. 387) site where the recipient’s organ has been removed. The The importance of an adequate supply of zinc is now average survival rate is >90% after 1 year and >80% accepted. In most cases, however, there is already a defi- after 5 years. (s. p. 387) ciency of this important trace element (unless previous medication has remedied the situation). Due to the scale A modified procedure, so-called orthotopic segment liver of the operation, there is a considerable loss of zinc, transplantation (OSLT), has proved successful (H. Bis- which usually cannot be balanced even by intravenous muth et al., 1984); this involves implanting parts of an substitution. Experience has shown that pronounced adult liver, i.e. segments II and III or IϪIV depending and extremely detrimental zincuria may be kept in check on the size of the recipient’s organ, into a young recipi- by i.v. application of potassium canrenoate. (s. p. 787!) ent (“reduced size”). Venous bypass: Insertion of a combined venovenous and portoven- In split liver transplantation (SLT) (R. Pichlmayr et al., ous bypass reduces the negative effects of the anhepatic operative 1989), it is possible to transplant segments VϪVIII, which phase (lasting 30Ϫ120 minutes) by interrupting the blood flow in are left over in OSLT, into an adult. (400) This means that the portal vein and inferior vena cava. This measure allows greater haemodynamic stability during the anhepatic phase. two recipients can be supplied with one donor organ. The surgical splitting of the donor liver subjects the organ to Biliary anastomosis: Reconstruction of the biliary flow is achieved considerable stress, and therefore its quality has to meet by side-to-side anastomosis of the two choledochal stumps or, when primary bile-duct disease is present in the recipient, by anas- particularly high standards. (366, 426) tomosis using a jejunum sling in the Roux-en-Y technique. In living donation (LDLT) (R.W. Strong et al., 1990), seg- Duration of the operation: The duration of the operation varies ments II and III are taken from a parent and trans- greatly owing to the widely differing conditions during surgery. On average, it takes 5Ϫ10 hours. • The blood loss also differs consider- (416) planted into the child. The surgical risk for the ably: 6Ϫ15 units of blood are normally substituted, but this quan- living donor, which was quite high at the beginning, has tity may be much higher in some cases. The number of units of been reduced considerably in the meantime to about blood can be reduced by administering aprotinin, which inhibits 0.24%. The survival chance of the recipient is 27Ϫ92%. fibrinolysis after reperfusion. To date, more than 3000 transplantations of this kind have been carried out worldwide. The technique has 7.6 Postoperative features now been generally established for children. About 5% of all LT patients are also suitable for an LDLT. There- The postoperative phase is characterized by three im- fore, the possibility of such an LDLT should be dis- portant objectives: (1.) monitoring the functional condi- cussed in all those cases where the waiting time for a tion of the transplanted liver, (2.) adjustment of immu- regular LT would prove to be a problem. More than nosuppression, and (3.) early detection and treatment 75% of the donors are free from complications. In of complications.

876 Treatment of liver diseases

Early postoperative phase: Extubation is carried out as development of tolerance to donor tissue. (406, 423) That soon as possible with subsequent regular breathing exer- would mean that a donor liver might, in some cases, be cises and optimal infusion therapy. This takes into spontaneously accepted. As a result, it is possible to account all problems arising from such extensive sur- stop the administration of immunosuppressants. • Usu- gery, e.g. lactate-free volume replacement, stability of ally, after 5-year survival of a primary graft, one third circulation and coagulation, pain therapy, electrolytes, of all patients are able to cease immunotherapy. zinc, vitamins, acid-base balance, energy carriers. Loss of protein is substituted by fresh-frozen plasma and Complications albumin. The onset of bile production and a decrease in lactate values are initial signs that the transplant is Major complications following LT include: (1.) non- stϪ nd functioning well. In addition, factor V and thrombo- function of primary graft (1 2 day), (2.) infection rdϪ th thϪ th plastin time generally increase. Occasionally, ascites can (3 14 day, and longer), and (3.) rejection (5 10 day). The clinical features of these complications are occur. (365) From 7th day, the transaminases fall steadily. Antibiotic prophylaxis, which began during surgery, is similar: nd rd usually discontinued on 2 or 3 day. Oral and bodily liver ϭ large, firm, tender on pressure hygiene as well as monitoring of infection are also part fever of the intensive-care programme. Special surveillance leucocytosis protocols have been carefully designed for this purpose. jaundice Immunosuppression Such findings require immediate and extensive examin- Both the induction and adjustment of immunosuppres- ation: US, Doppler sonography, CT, HIDA scintigraphy sion also follow established protocols, which can, how- and cholangiography. • Further complications are (1.) ever, be executed in various ways. In the meantime, new afterbleeding (10Ϫ15%), (2.) portal vein thrombosis (up immunosuppressants are in use (tacrolimus, sirolimus, to 2.2%) or hepatic vein occlusion, (3.) hepatic artery mycophenolate mofetile, brequinar, leflunomide, etc.). thrombosis or stenosis, (4.) pleural effusion, and (5.) Cyclosporine and tacrolimus include a calcineurine subcapsular necrosis (due to the disproportionate size of inhibitor. Initially, the patients receive triple therapy: donor and recipient liver). Stenosing of the suprahepatic tacrolimus (or cyclosporine) ϩ prednisolone ϩ myco- vena cava is a particularly dangerous condition, which phenolate, occasionally with interleukin-2 receptor can lead to ALF. • The most frequent complication antagonist (e.g. basiliximab, diclizumab). • After 3 affects the biliary system in the form of leaks or stric- months, the patient is given dual therapy, generally with tures (up to 50% of cases). They can be diagnosed with tacrolimus (or cyclosporine) ϩ prednisolone or with the help of T-drain radiology or ERC. (389) tacrolimus ϩ mycophenolate; after a further 6 months, the patient is put on monotherapy with tacrolimus (or Infection cyclosporine). During dual therapy, the dosage of One of the major problems following LT and immuno- prednisolone is reduced slowly until the drug is ulti- suppression are infections. During the early postopera- mately discontinued (except in cases with AIH as an tive phase, the danger of bacterial or fungal infection is underlying disease). (405) • In patients with HCC, immu- particularly great due to high-dosage immunosuppres- nosuppression based on rapamycin appears to be more sion and intensive medical care at a time when the efficacious, since it appears to have an antitumourigenic patient’s physical condition is considerably impaired. effect. • The monitoring of tacrolimus (or cyclosporine) Monitoring of infection, accompanied by optimal is carried out at regular intervals using the respective hygiene and prophylactic measures, is required as well values in the blood. • Long-term follow-up is performed as (possibly) immediate treatment with antibiotics. In by the family doctor or internal specialist and, at certain order to avoid translocation of gram-negative micro- intervals, by the outpatient department of the transplan- organisms, decontamination of the intestinal tract, tation centre. (372) • The toxicity of immunosuppressive already initiated in the preoperative phase, is often con- agents is the main cause of complications (e.g. hyperten- tinued; in addition, the use of an antimycotic agent is sion, kidney damage and even kidney failure, severe recommended (e.g. against candidiasis or coccidi- headaches, altered blood values, nervousness, trembling, oidomycosis). (377, 380, 404, 421) • Viral infections are peripheral paraesthesia, increase in liver enzymes). Such most frequent 2Ϫ4 months after LT. A particular dan- toxicity-related complications may also be due to ger, both in adults and children, may come from new interactions between cyclosporine and other drugs. Dif- infection with or reactivation of CMV (412, 422), EBV, ferential diagnosis of transplant rejection may prove herpes-6 virus, varicella-zoster or Listeria monocyto- difficult. genes. (386) CMV infection is associated with a higher Tolerance: Donor cells have sometimes been detected in rate of rejection. Early diagnosis (by PCR) and early the blood of liver transplant recipients. This chimerism treatment (e.g. intravenous ganciclovir) are required. Of may influence the immune system of the host with the various viral infections, especially condylomas

877 Chapter 40 caused by papilloma viruses are to be feared in the long term, since a high percentage of them can develop into squamous-cell carcinoma. A new form of treatment with imiquimod may prove to be effective.

Transplant rejection Hyperacute form: Transplant rejection may occur as an antibody-related complication within a short period of time after LT. This rare event is caused by donor antigens coming into contact with preformed antibodies in the recipient, which results in damage to the endothelial cells of the arteries with vascular occlusion. The outcome is necrosis of the transplant. Acute form: This condition appears within the first 1Ϫ3 Fig. 40.6: Chronic rejection: stenosing foamy cell arteriopathy postoperative weeks. Some 40Ϫ60% of patients have one or even several rejection reactions of varying inten- is characterized by progressive cholestasis. This form sity, accompanied by discomfort, fever, exhaustion and, may develop after repeated acute attacks or develop occasionally, mild jaundice. Early diagnosis is only pos- insidiously from the beginning. There is a ductopenic sible by detecting an increase in liver enzymes, particu- reaction, whereby the interlobular bile ducts are larly GDH; the diagnosis is confirmed histologically. infiltrated and destroyed by mononuclear cells; ulti- Percutaneous biopsy should be carried out with antibi- mately, the bile ducts disappear. Duct loss can be calcu- otic protection. (385) Histology reveals the presence of lated from the ratio of the number of hepatic arteries to large lymphocytes, plasma cells, macrophages and gran- the number of bile ducts within a portal field (normal ϭ ulocytes in the portal fields in this type of cellular reac- >0.7), whereby 20 portal fields should be examined. At tion. The interlobular bile ducts are damaged, and there the same time, obliterating arteritis develops, with fibri- is subsequent cholestasis. It is possible to observe adher- noid wall necrosis and deposition of foam cells within ence of lymphocytes to the venous and arterial endothe- the intima. (393) The result is portal and periportal lium, resulting in subendothelial inflammation (ϭ endo- fibrosis. (s. fig. 40.6) Differential diagnosis is difficult thelialitis). (s. fig. 40.5) • Therapy is based on pred- and may require repeated biopsies. Chronic rejection nisolone (500 mg i.v. for 3 days). In cases showing no can be graded histologically in a mild, moderate or reaction, the dosage of tacrolimus should be increased, severe form. Therapy with tacrolimus halted progression and, occasionally, mycophenolate (2 x 1g/day) or rapa- in some cases. Tacrolimus and mycophenolate may gen- mycin can be added. In non-responders, therapy with erally bring about a reduction in the chronic rejection OKT3 is recommended (after histology has shown per- response. Should the treatment fail, the only alternative sistent rejection). Thus, an acute rejection does not pose is retransplantation. In this case, an elective indication a risk for long-term prognosis. In most cases, drug ther- for retransplantation is given, since liver functions apy is successful and without morphological residues. remain intact for a relatively long time. • In acute and (357) • Retransplantation is seldom necessary. chronic rejection accompanied by an increase in alkaline phosphatase, ursodeoxycholic acid should be used as supportive therapy. • With regard to unclarified complicative situations, it is essential to determine the level of immunosuppressants in the blood (underdosage? toxicity?). Subsequently, US and colour-encoded duplex sonography as well as CT or MRI are indicated. Radio- logy-dependent interventions may be required. Retransplantation is required in 5Ϫ10% of patients. The main indications are primary graft failure, hepatic arterial thrombosis and chronic rejection. • Results of retransplantation are not so satisfactory as with the first LT: the survival rate is shorter and mortality (usually due to sepsis) is mostly within 6 months. Nevertheless, the prognosis is improving steadily. (407) Fig. 40.5: Acute rejection: portal/periportal inflammation and portovenous endothelialitis (ȇ) (HE) Relapse of the underlying disease Chronic form: This condition is no longer observed very Some 25% of hepatocellular and up to 70% of cholan- often (<5%). It usually sets in 1Ϫ9 months after LT and giocellular carcinomas are subject to relapse within 12

878 Treatment of liver diseases months. Tumour relapse is caused by the presence of 1. Step-by-step reorientation of the individual pa- undetected extrahepatic metastases, which find their tient from the clinical atmosphere to the more way back into the transplanted liver, and on the sup- “normal” daily routine in a rehabilitation centre. pressed state of the immune system. According to some Medical follow-ups, including monitoring of the observations, the probability of relapse depends on the immunosuppressive adjustment. stage of the primary tumour. For this reason, only (selected) early tumour stages are a possible indication 2. Gradual social and cultural reintegration within for LT. • Reinfection of the transplant occurs in the rehabilitation community. 80Ϫ100% of cases due to hepatitis B from extrahepatic 3. Detailed information for the patient regarding reservoirs, most likely in the early postoperative (low- personal hygiene, nutrition, lifestyle, significance defence) stage. Of these cases, about 15% follow a ful- of aftercare, recognizing complaints or abnormal- minant course, about 15% show persistent hepatitis, 5% ities, etc. reach chronic carrier stage, and 20Ϫ25% develop fibros- 4. Improvement in the patient’s nutritional state. ing cholestatic hepatitis with a high rate of viral replica- 5. General physiotherapeutic measures; targeted tion and an unfavourable course. (360) In some patients training of the muscle groups atrophied to a vary- with severe reinfection, cirrhosis can develop within a ing extent in the individual patient. HDV infection few years. may lead to a similar outcome. 6. Psychotherapeutic support (particularly in how to With such a negative outlook, it is important to con- handle the fear of complications), opportunities sider every possibility of avoiding reinfection. The pro- for psychosocial care, discussion of questions re- phylaxis is based on HBIG (10,000 IU intraoperatively lating to the patient’s occupation, etc. and then daily) ϩ lamivudine until HBsAg has disap- peared from the serum. In this way, the risk of reinfec- Tab. 40.17: Tasks and objectives of aftercare and rehabilitation in tion can be reduced to 10Ϫ20%. (s. p. 709) Should rein- specialized clinics fection nevertheless occur (renewed evidence of HBsAg), new nucleoside analogues (e.g. adefovir, entec- Risk of infection: Patients are subject to a high risk of avir, tenofir) are available under certain conditions. (355) infection at public events, when using public transport, •Inhepatitis C, the transplant is reinfected in 90Ϫ100% and particularly during waves of influenza. Interdigital of cases, although only about half the patients display mycosis also presents an infection risk. A further prob- HCV antibodies when immunosuppressives are admin- lem can derive from indoor plants (beware of fungal istered. HCV replication occurs already in the first week spores in potting compost!). Domestic animals similarly after LT. The infection follows a mild course both in constitute a risk factor; it is of particular importance terms of clinical findings and morphology; fulminant that no new pets should be introduced. Towels and bed or cholestatic courses are rare. In 10Ϫ30% of patients, linen must be changed regularly. Shower water, which is chronic hepatitis, or even cirrhosis, appears. Neverthe- usually heated to 60°C in the boiler, should be run for less, in view of the great effort involved in performing an extended period 2Ϫ3 times a week in order to pre- an LT, the use of peg IFNα with ribavirin, and occa- vent legionellosis. Vaccinations with live vaccines should sionally in combination with amantadine, must be con- be avoided. Intake of tap water and non-pasteurized sidered. (s. p. 708) (363, 373, 377, 390, 397, 407, 409, 422) • milk is forbidden as these liquids have a high bacteria HGV infection (generally a result of numerous blood count. Lettuce and vegetables need to be washed several transfusions!) is of no clinical significance. (378) • Alco- times and with particular care. Fruit that is difficult to holic liver disease is followed by relapse within 2 years clean (raspberries, etc.) should not be eaten; preference in about 20% of cases. (368, 399, 415) • Relapses have been is to be given to fruit which can be peeled. Raw steak observed following primary biliary cholangitis (384, 420) tartare must not be consumed. • These numerous re- or primary sclerosing cholangitis (<5%) (374, 381, 387), commendations and warnings are not designed to create autoimmune hepatitis (despite immunosuppression in hysteria, but to help minimize the risk of infection at a 10Ϫ30%) (356, 392) subsequent to BCS (without antico- realistic and, for the patient, comprehensible level. non-alcoholic steatohepatitis. agulant in 100%), or (394) Nutrition: The patient’s diet should comply with the basic principles of physiological nutrition. It is recom- 7.7 Aftercare and rehabilitation mended to take three main and two minor meals per Ϫ day. Foodstuffs causing flatulence and containing LT patients require 7 10 days in an intensive care unit poorly digestible fats (e.g. lard) should be avoided. It is and about 3 weeks in a normal ward of the hospital. important to consider the influence of glucocorticoids The patient is usually fully rehabilitated after 6 months. on appetite as well as their metabolic side effects (e.g. Subsequent to inpatient treatment, follow-up therapy is restriction of sodium chloride, loss of potassium). carried out at a rehabilitation clinic which is specialized in hepatology. Generally, this stationary rehabilitation Medical aftercare: This comprises adjusting and moni- phase lasts 4Ϫ6 weeks and includes various tasks and toring immunosuppressants, providing the patient with objectives. (s. tab. 40.17) all necessary information as well as recognizing and

879 Chapter 40 controlling side effects. • Occasionally, pleural effusion “rehabilitation” of the patient in order to reduce to a has to be monitored and, if necessary, aspirated. Ascites, tolerable minimum any periods in which the individual often evident as a local accumulation of fluid in the is unable to perform efficiently and is also unfit for abdomen, may still be present. • Sometimes, wound care, work. (s. fig. 40.7) treatment of postoperative wound complications or removal of a T-drainage, generally after 6 weeks, may still be required. • The renal function needs to be monitored carefully, even if there is no obvious progressive renal damage. • The vascular system (portal vein, inferior vena cava, hepatic artery) has to be checked by colour-encoded duplex sonography for the occurrence of thromboses, stenoses or aneurysms. Bile leakage or stenoses may appear in the bile ducts. • In 60Ϫ80% of patients, hypertension can be anticipated due to treatment with cyclosporin. In 20Ϫ30% of cases (more often with tacrolimus than with cyclosporine), diabetes mellitus or hypercholesterolaemia develops.

If this wide spectrum of sophisticated rehabilitation measures is carried out with great care Ϫ and with Fig. 40.7: Combination of prevention and rehabilitation in health success Ϫ fewer problems will arise in the aftercare awareness of outpatients when they return to their normal daily routine. The length of stay at a specialized clinic should be tailored to the patient’s individual needs; on average, this lasts 4Ϫ6 weeks. In view of the high costs involved in LT and the great inconvenience to 8.1 Health awareness which the patient is subjected, the rehabilitation ᭤ This term subsumes all factors which reduce potential phase assumes an essential role; follow-up therapy is damage to health. These include protective measures thus both necessary and recommended for achieving promoted by the state, various authorized institutions long-term survival and improved quality of life with and associations as well as by industry, science and the reintegration into the work process. medical professions. Above all, however, every individual should assume personal responsibility for main- outpatient control Inpatient monitoring is succeeded by taining his or her state of health through appropriate protocols. The check-ups are carried out by the family behaviour. • The media must also accept a vital role in doctor or internist in close cooperation with the trans- this context! plantation centre. • The 1-year survival rate after liver transplantation is generally 80Ϫ95%. The 5-year sur- Health awareness with regard to hepatology vival rate varies depending on the underlying disease, Ϫ Ϫ e.g. 70 80% in cirrhotic patients, 45 50% in acute liver • Healthy diet and normal body weight failure, and 35% in malignancies. (379, 388) About two- • Hygiene concerning drinking water and food thirds of the patients begin working again despite a long • Physical/muscular fitness phase of being unable to work due to chronic liver dis- • No alcohol abuse ease. Most liver transplant recipients are very satisfied No medication abuse with their newly acquired quality of life. (398, 399) No drugs • Avoidance of occupation-related damage • Prevention of infections by observance of basic 8 Sociomedical aspects hygiene Health awareness on the part of the individual as well as preventive and rehabilitative medicine in general are exerting more and more influence on developments in 8.2 Preventive medicine the medical world Ϫ and thus also on hepatology. These changes in medical practice are an inevitable and char- These are health measures which are carried out by acteristic feature of a modern society. • Consequently, individuals of their own accord, sponsored by the state, physicians will need to devote more attention to “pre- accepted by medical insurance companies and organiza- vention” in the healthy person in order to keep the cura- tionally feasible; they enable the monitoring and preser- tive phase of any illness as short as possible. And to vation of health as well as the early recognition of dis- an increasing degree, they will also have to undertake eases.

880 Treatment of liver diseases

Prevention with regard to hepatology vocational retraining and additional qualifications, redesigning the workplace to fit the needs of the handi- • Prophylactic vaccinations capped person, reintegration into the work process, per- • Safe blood transfusions sonal support, etc. Occupational rehabilitation also Safe blood products depends on the rehabilitee being adequately motivated. • Prevention of infections Furthermore, it is important to evaluate individual (antibacterial and antiparasitic measures) vocational preferences and prospects of success. Job- • Occupation-related measures related psychological and aptitude tests together with • Regular medical check-ups measures aimed at finding a suitable job must be carried out before a final decision can be made.

Altogether, the measures and objectives of our time 8.3 Rehabilitation do justice to the demands made by Ritter von Buss (a specialist in constitutional law) who coined the term Rehabilitation is designed to reintegrate people with rehabilitation in 1844 with the words: physical or mental impairment into both their profes- sional and personal environment. It comprises aftercare “The diseased who can be cured shall be completely with a social component in the sense that society is rehabilitated, he shall rise again to the position from called upon to help, and thus it is a communal under- which he has descended, he shall regain the feeling of taking. Rehabilitative measures should start as early as personal dignity and thus a new life.” possible during the curative phase. Once the disease has consolidated and as soon as the prognosis offers a realistic perspective, the physician should address the question of rehabilitation. The necessity for rehabilitation 8.4 Capacity for work depends on the severity of the symptoms and/or the psychosocial problems involved. A positive and negative profile of a patient’s capacity for performing certain tasks should be compiled on the Rehabilitation with regard to hepatology basis of the respective disease phase. For the rehabilitation process, it is important to assess the remaining • Adjustment to disease-dependent changes in life- capacity of the individual in combination with any per- style sonal strengths. In addition, liver function and potential Ϫ special diets (e.g. low iron, low copper, MCT) health risks have to be considered. The medical evalu- Ϫ administration of medication (e.g. interferon, ation of the patient’s capacity for work forms the basis immunosuppressants, penicillamine, UDCA) for the respective sociolegal decision. It should be • Introduction of secondary prevention noted, however, that the medical expertise and the legal Ϫ elimination of risk factors (alcohol abuse, over- decision are independent of each other Ϫ such legal weight, faulty nutrition, etc.) terms as “incapacity for work” or “inability to practise Ϫ vaccination prophylaxis the learned profession” must be avoided in the medical • Information about particular risks report. • A patient’s capacity for work also includes fit- Ϫ hepatic encephalopathy, water retention, vari- ness to drive a vehicle (e.g. in cases of encephalopathy) ceal bleeding, side effects of medication, etc. or fitness for public service (e.g. in the educational or • Muscular/physical exercise judicial sector). In severe cases of advanced liver disease, • evaluation is not difficult. However, this is not so easy Psychological guidance for liver transplantees in less severe cases (e.g. diffuse fibrosis, lack of compli- • Assessment of the individual’s remaining capacity cative developments) or low-grade to moderate inflam- for everyday life matory processes. Objectivation of the findings is only • Introduction of occupational rehabilitation meas- possible by extensive diagnostic clarification of the func- ures tion and morphology of the liver Ϫ as well as of other affected organs. The indications for medical rehabilitation are subject to The physician’s assessment of a patient’s capacity for strict legal stipulations. First of all, an expertise includ- work takes into account the individual factors in a cer- ing a detailed medical evaluation is required from a tain type of liver disease and thus forms the basis for physician. In rehabilitation centres specialized in hepa- determining (1.) unfitness for work, (2.) inability to prac- tology, all necessary interdisciplinary diagnostic and tise the learned profession and (3.) inability to earn therapeutic measures are applied. It is important that within the sociolegal framework of the country con- the rehabilitee cooperates actively. cerned. This involves reviewing the overall situation in Measures necessary for occupational rehabilitation are a concrete manner, i.e. whether there is a workplace initiated at the same time. These include options for available that is appropriate to the patient’s capacity for

881 Chapter 40 work. Pension allowances paid due to inability to prac- The above statements can only serve as general criteria tise the learned profession are generally lower than for the physician’s evaluation of patients suffering from those paid due to unfitness for work. Assessment of the liver disease. More detailed information is usually avail- inability to earn does not depend on whether the person able from the insurance provider. Thus it is desirable has recently worked or on current job prospects. It that medical practitioners cooperate closely with socio- should be noted that clearly defined standards of assess- medical specialists, so that it is possible to deal directly ment are required under pension law. Concerning acci- with any application for compensation, disability pen- dent insurance, severe disability and social compensa- sion, etc. tion, the principle of abstract damage assessment Although there are guidelines for evaluating the reduc- applies. The inability to practise the learned profession tion in earning capacity (REC), the actual degree of dis- as well as the inability to earn must be permanent. All ability (DOD) may be assessed differently depending on indications for rehabilitation must be checked carefully the existing disease. In the individual case, the physician and with regard to the relevant conditions. Unfitness for may propose percentage values concerning the disability public service is a term generally used for civil servants, which are higher or lower than the recommended rate. but it also applies to soldiers and persons doing com- • The assessment of chronic hepatitis B and C is of great munity work. importance (H. Selmair et al., 1998), and it should be made The hepatological diagnosis should be as accurate as according to the aetiological-morphological nomen- possible, so that the physician is able to assess the (posi- clature. (s. pp 693Ϫ695) (s. tab. 40.18) tive and negative) capacity profile. In this connection, the insured person is not obliged to tolerate invasive Functional hyperbilirubinaemia 0Ϫ10% examinations (e.g. laparoscopy, percutaneous liver Acute viral hepatitis 100% biopsy). However, the risk of underestimating the reduc- Asymptomatic HBsAg carrier status 0% tion in earning capacity can be detrimental for the in- Chronic active hepatitis dividual. Moreover, the possibility of further deteriora- Ϫ low inflammatory activity 20Ϫ30% Ϫ Ϫ tion of a disease is not included in an assessment; thus moderate inflammatory activity 30 40% Ϫ Ϫ a follow-up report may be required after a certain severe inflammatory activity 50 >70% Ϫ fibrosis (low Ǟ severe) 20Ϫ60% period of time. Scarred liver without complications The original International Classification of Impairment, (depending on the functional reduction) 20Ϫ40% Disability and Handicap (ICIDH) has been revised as the International Classification of Functioning (ICF). Cirrhosis, compensated Ϫ inactive (stable) 40% This new classification requires a precise description of Ϫ moderately active 50% the disease-related impairments of the individual Ϫ distinctly active 60Ϫ100% patient. Subjective complaints should be considered with severe functional reduction 80Ϫ100% although they cannot, of course, be evaluated objec- with shunt surgery 60Ϫ100% tively. Aggravations must be treated with caution. Cirrhosis, decompensated 80Ϫ100% Objective assessment can be based on enzymatic and Fatty liver 0Ϫ10% mesenchymal activity (s. tabs. 5.15; 5.22), serological or Ϫ with hepatitis (low Ǟ severe) 20Ϫ100% immunological findings (s. tabs. 5.17; 5.20), and liver Fatty cirrhosis 40Ϫ100% function tests (s. tab. 5.14). Ultrasound, occasionally Chronic cholangitis 20Ϫ100% colour-encoded Doppler sonography, or even CT give Liver transplantation 100% an impression of the morphological structure of the (after consolidation lasting 2 years liver, especially in cases where patients refused to have with 100% DOD/REC, and later on a biopsy. The assessment programe should also contain no less than 60%) psychometric tests. (s. pp 202Ϫ206) (s. fig. 5.2) Liver lobe resection > 50% Tumour resection 100% The term reduction in earning capacity is used in civil Primary liver cell carcinoma 100% law to assess claims payments. It denotes the difference (within the first 5 years of between the income earned before the accident hap- consolidation, the REC remains at 100%) pened and afterwards, i.e. the actual and proven pecuni- ary loss is determined. Tab. 40.18: Guidelines for assessing the reduction in earning capacity (REC) and the degree of disability (DOD) in liver diseases. The term (severe) disability was defined by the World (If the hepatological picture cannot be classified in relation to a Health Organisation (WHO) in 1980. It contains guide- diagnosis shown in the above table, it should be described and lines for protecting severely disabled persons by law. The classified according to its functional disturbances in line with the above diagnoses) principle of abstract damage assessment applies when determining the degree of disability. A small part of the labour market should be kept open for severely dis- Altogether, three criteria are important in the assess- abled persons. ment of a liver disease:

882 Treatment of liver diseases

enteral nutrition: Proof of a human choline requirement: A placebo- 1. its effects on the patient’s capacity for work controlled trial. J. Parenter. Enter. Nutr. 2001; 25: 260Ϫ268 19. Crawford, D.H.G., Cuneo, R.C., Shepherd, R.W.: Pathogenesis and 2. its connection with a specific damaging event assessment of malnutrition in liver disease. J. Gastroenterol. Hepatol. 3. its rehabilitation potential 1993; 8: 89Ϫ94 20. Fan, S.T.: Nutritional support for patients with cirrhosis (review). J. Gastroenterol. Hepatol. 1997; 12: 282Ϫ286 21. Gaddipati, K., Yang, P.: Hepatobiliary complications of parenteral nut- Medical evaluations are simply opinions of an advisory rition. Gastroenterologist 1996; 4: 98Ϫ106 22. Hasse, J.M., Blue, L.S., Liepa, G.V., Goldstein, R.M., Jennings, L.W., nature; they have to be assessed by administrative and Mor, E., Husberg, B.S., Levy, M.F., Gonwa, T.A., Klintman, G.B.: Early legal experts before a final decision can be made. • The enteral nutrition support in patients undergoing liver transplantation. J. Parenter. Enter. Nutr. 1995; 19: 437Ϫ443 physician, however, is responsible for the medical deter- 23. Kearns, P.J., Young, H., Garcia, G., Blaschke, T., O’Hanlon, G., Rinki, mination of a disease and the resulting diagnosis of M., Sucher, K., Gregory, P.: Accelerated improvement of alcoholic liver disease with enteral nutrition. Gastroenterology 1992; 102: 200Ϫ205 unfitness for work. 24. Kestell, M.F., Lee, S.P.: Clinical nutrition in acute and chronic liver disease. Semin. Gastrointest. Dis. 1993; 4: 116Ϫ126 25. Lautz, H.U., Selberg, O., Körber, J., Bürger, M., Müller, M.J.: Forms of malnutrition in patients with liver cirrhosis. Clin. Invest. 1992; 70: 8.5 Self-help groups 478Ϫ486 26. Leonard, J.V.: The nutritional management of urea cycle disorders. J. Pediatr. 2001; 138: 40Ϫ44 In most countries, there are self-help groups for liver 27. Levine, J.A., Morgan, M.Y.: Weighed dietary intakes in patients with chronic liver disease. Nutrition 1996; 12: 430Ϫ435 patients. Participation in such self-help groups is gen- 28. Marsano, L.S., Martin, A.E., Randall, H.B.: Current nutrition in liver erally beneficial. They are highly valued for their con- disease. Curr. Opin. Gastroenterol. 2002; 18: 246Ϫ253 29. McCullough, A.J.: Malnutrition in liver disease. Liver Transplant. stant availability and their counselling competence. The 2000; 6 (Suppl. 1): 85Ϫ96 patient can remain anonymous and all counselling is 30. Müller, M.J., Böttcher, J., Selberg, O.: Energy expenditure and substrate metabolism in liver cirrhosis. Intern. J. Obes. 1993; 17 (Suppl. confidential. This useful service is offered free of charge. 3): 102Ϫ106 Self-help groups provide the participants with informa- 31. Müller, M.J.: Ernährung bei Leberzirrhose. Internist 1998; 39: 247Ϫ253 tion on all important topics (including the latest devel- 32. Nielsen, K., Kondrup, J., Martinsen, L., Dossing, H., Larsson, B., Stil- ling, B., Jensen, M.G.: Long-term oral refeeding of patients with cir- opments) by means of printed material, special meetings rhosis of the liver. Brit. J. Nutrit. 1995; 74: 557Ϫ567 and reports in the media; in addition, they facilitate a 33. Sarin, S.K., Dhingra, N., Bansal, A., Malhotra, S., Guptan, R.C.: Dietary and nutritional abnormalities in alcoholic liver disease: a com- mutual exchange of experience among the patients. parison with chronic alcoholics without liver disease. Amer. J. Gastroenterol. 1997; 92: 777Ϫ783 34. Siriboonkoom, W., Gramlich, L.: Nutrition and chronic liver disease. References: Can. J. Gastroenterol. 1998; 12: 201Ϫ207 Interferon Clinical studies Bruno, R., Sacchi, P., Ciappina, V., Zochetti, C., Patruno, S., Maiocchi, Brown, R.S.: 35. 1. Strategies and pitfalls in quality of life research. Hepatol- L., Filice, G.: Viral dynamics and pharmacokinetics of peginterferon ogy 1999; 29 (Suppl.): 9Ϫ12 Bull, J.P.: alpha-2a and peginterferon alpha-2b in naı¨ve patients with chronic 2. The historical development of clinical therapeutic trials. J. hepatitis C: a randomized, controlled study. Antiviral Ther. 2004; 9: Chron. Dis. 1959; 10: 218Ϫ248 Ϫ Burkhardt, R., Kienle, G.: 491 497 3. Controlled trials. A social challenge. Eur. J. 36. Dianzani, F.: Biological basis for the clinical use of interferon. Gut Clin. Pharmacol. 1981; 20: 311Ϫ319 Ϫ De Craen, A.J.M., Kaptchuk, T.J., Tijssen, J.G.P., Kleijnen, J.: 1993; 34 (Suppl. 2): 74 76 4. Placebos 37. Foster, G.R.: Review article: Pegylated interferons: chemical and clin- and placebo effects in medicine: historical overview. J. Royal Soc. Med. Ϫ Ϫ ical differences. Aliment. Pharmacol. Ther. 2004; 20: 825 830 1999; 92: 511 515 38. Heathcote, E.J., Shiffman, M.L., Cooksley, G.E., Dusheiko, G.M., Lee, 5. De Dombal, F.T.: The controlled, randomized clinical trialϪsacred S.S., Balart, L., Reindollar, R., Reddy, R.K., Wright, T.L., Lin, A., Ϫ duty or sacred cow? Klin. Wschr. 1980; 58: 649 652 Hoffman, J., de Pamphilis, J.: Peginterferon alfa-2a in patients with 6. Imperiale, T.R.: Meta-Analysis: when and how. Hepatology 1999; 29 Ϫ chronic hepatitis C and cirrhosis. New Engl. J. Med. 2000; 343: (Suppl. 1): 26 31 1673Ϫ1680 7. Rosner, F.: The ethics of randomized clinical trials. Amer. J. Med. 1987; Isaacs, A., Lindenmann, J.: Ϫ 39. Virus interference: I The interferon. Proc. 82: 283 290 Royal Soc. (London) 1957; 147: 258Ϫ267 8. Sackett, D.L., Gent, M.: Controversy in counting and attributing Ito, Y., Takeda, N., Ishimori, M., Akai, A., Miura, K., Yasuda, K.: Ϫ 40. events in clinical trials. New Engl. J. Med. 1979; 301: 1410 1412 Effects of long-term interferon-alpha treatment on glucose tolerance 9. Spiegelhalter, D.J.: Statistical issues in studies of individual response. Ϫ Ϫ in patients with chronic hepatitis C. J. Hepatol. 1999; 31: 215 220 Scand. J. Gastroenterol. 1988; 23: 40 45 41. Lindsay, K.L., Trepo, C., Heintges, T., Shifman, M.L., Gordon, S.C., Hoefs, J.C., Schiff, E.R., Goldman, Z.D., Laughlin, M., Yao, R., Principles of liver therapy Albrecht, J.K.: Bayliss, M.S.: A randomized, double-blind trial comparing pegylated 10. Methods in outcomes research in hepatology: definition interferon alfa-2b to interferon alfa-2b as initial treatment for chronic and domains of quality of life. Hepatology 1999; 29 (Suppl. 1): 3Ϫ6 Ϫ Foster, G.R., Goldin, R.D., Thomas, H.C.: hepatitis C. Hepatology 2001; 34: 395 403 11. Chronic hepatitis C virus 42. Peters, M.: Mechanisms of action of interferons. Semin. 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The wish and the hope expressed by a Babylonian haruspex (a diviner whose predictions are based on inspecting the entrails of sacrificed animals) in the following sentence, which he inscribed as a repeating stereotype on a clay model of a sheep’s liver (ca. 2000 BC) (s. fig. 1.1) (s. p. 2), is dedicated to all patients suffering from liver disease and also to all users of “Hepatology Ϫ Principles and Practice”: “May your liver be smooth”

“In the heart the physician grows, from God he proceeds ... The highest ground of all remedies is love.”

Theophrastus Bombastus von Hohenheim, called Paracelsus (1493Ϫ1541)

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