BACKGROUND: Kava hepatotoxicity in 20 patients from Germany has been debated worldwide following a regulatory ad hoc causality assessment and ban of kava, an anxiolytic herbal remedy obtained from the rhizome of Piper methysticum Forster. AIMS: We assessed causality with a quantitative structured causality analysis in all 20 cases of patients with liver disease, presented by the German regulatory agency that assumed a causal relationship with the use of kava extracts. METHODS: The quantitative scale of CIOMS (Council for International Organizations of Medical Sciences) in its updated form was employed for causality assessment and quality evaluation of the regulatory data presentation. RESULTS: The regulatory information is scattered and selective, and items essential for causality assessment, such as exclusion of kava independent causes, were not, or only marginally, considered by the regulator. Quantitative causality assessment for kava was possible (n=2), unlikely (n=12), or excluded (n=6), showing no concordance with the regulatory ad hoc causality evaluation. CONCLUSION: The regulatory data regarding kava hepatotoxicity is selective and of low quality, not supportive of the regulatory proposed causality; but instead, is an explanation of the overall causality discussions of kava hepatotoxicity. We are proposing that the regulatory agency reports data in full length and reevaluates causality.

Kava is a perennial shrub native to some islands of the South Pacific and has been cultivated for centuries to prepare a psychoactive beverage from its rhizoma by means of extraction. Subsequently, kava extracts are commonly used as herbal anxiolytic drugs also in many other countries all over the world including European ones and the USA. Toxicological and clinical studies have shown that kava extracts are virtually devoid of toxic effects with the exception of rare hepatotoxic side effects reported in few patients. When assessed primarily by the British regulatory authority MCA but also by us, a critical analysis of the suspected cases (n = 19) in Germany reveals that only in 1 single patient a very probable causal relationship could be established between kava treatment and the development of toxic liver disease due to a positive result of an unscheduled reexposure test, whereas in another patient there might be a possible association. Out of the remaining 17 cases 12 patients were not yet assessable due to insufficient data and in 5 other cases a causal relationship was unlikely or could be excluded. The German regulatory authority might therefore well be advised to provide now additional information for those 12 patients with so far unsatisfactory data, facilitating a more appropriate assessment of causality. Nevertheless, in the meantime physicians and patients should continue to keep an eye on possible hepatotoxic side effects in the course of kava treatment, to stop the treatment alredy at first suspicion and to start with a careful diagnostic work up ruling out all other causes.

Kava extracts are obtained from the rhizoma of the kava shrub (Piper methysticum) and contain various pyrones which are used as herbal anxiolytic remedies for generalized anxiety syndromes of low and intermediate grades. The commonly recommended daily dose of 60-120 mg kavapyrones and the duration of the therapy of up to 3 months should not be increased without consultation of a physician and were not followed by most patients, since herbal drugs are considered by the population not only as effective but also as safe. Whereas kava extracts are well tolerated by most patients and rare side effects are rapidly reversible upon drug discontinuation, there are suspected hepatotoxic reactions reported during the last years in temporal and not necessarily causal association with a therapy with kava extracts. Almost 80 % of the patients took kavapyrones in overdose (maximally 480 mg/d) and/or for a prolonged time of more than 3 months up to 2 years. Additional risks factors include co-medication with up to 5 other chemically defined or herbal drugs with in part potentially hepatotoxic properties as well as a genetic deficiency of the hepatic microsomal cytochrome P450 2D6. Severe clinical courses with liver transplantation and possible fatal outcome occurred in 7 patients with overdose and/or long duration of the therapy with kavapyrones. Preventive measures should therefore include a dose of 120, maximally 210 mg kavapyrones per day for 1 month, maximally 2 months, as well as a prescription by a physician. Laboratory test (ALT and gamma-GT) should be done before and during the therapy, and co-medication and alcohol consumption should be avoided. With these measures the hepatotoxic risks under the treatment with kavapyrones might be minimized which are also available via internet and from abroad with possible severe consequences when taken without medical supervision.

About 1000 drugs produced world-wide may lead to clinically relevant hepatotoxic reactions which are unpredictable at normal doses and occur at various frequencies. Among these are well established therapeutic drugs which have been in use for years or decades as well as newly introduced drugs, the number of which is steadily increasing. For the development of drug-induced liver disease, various pathogenetic mechanisms, many risk factors and variable latency periods are known. The histological picture may imitate practically all known non-toxic liver diseases from which toxic liver disease needs to be differentiated. Patients under drug therapy require regular medical follow-up with regard to the development of toxic liver disease since the prognosis is only good with early recognition and immediate withdrawal of the alleged drug. Specific therapeutic modalities to prevent toxic liver disease are limited to paracetamol overdosage which is treated by the application of N-acetylcysteine. For other drug-induced liver diseases characterised by a prolonged course, therapy with ursodeoxycholic acid or steroids may be helpful. When fulminant drug-induced liver failure occurs, liver transplantation is the therapy of choice with a better prognosis than a conventional therapy. Despite this therapeutic option more than 40 different drugs are known to have caused lethal forms of toxic liver disease. Physicians have therefore to be alert to early recognize drug-induced liver disease and to withdraw the drug at first suspicion of the diagnosis.

Vague upper abdominal pain, weight loss (10 kg) and recurrent bouts of fever had been present for several months in a 77-year-old woman. Abdominal ultrasonography in the region of the head of the pancreas and duodenum had demonstrated several lymphomas, some of them with "air streaking". This finding suggested penetration from the duodenum to neighbouring lymph nodes. Plain film of the abdomen did not show free air, but at gastroscopy a covered perforation into the surrounding lymph nodes was found. At first lymphoma or Crohn's disease were considered in the differential diagnosis. But the finding of acid-fast bacteria in a biopsy from the pelvic crest suggested intestinal tuberculosis with dissemination. This diagnosis was confirmed by the direct demonstration of Mycobacterium tuberculosis in gastric juice. Under tuberculostatic treatment with daily 0.3 g isoniazid, 0.45 g rifampicin, 0.8 ethambutol and 1.5 g pyrazinamide, as well as 50 mg prednisolone to prevent stricture, the size of the tuberculous ulcer had markedly decreased within 2 weeks. Follow-up gastroscopy after 6 months showed almost complete healing without stricture. However rare, gastrointestinal tuberculosis should not be forgotten in the differential diagnosis because it can imitate a large variety of gastrointestinal diseases.

In order to achieve a hyperthyroid state, rats were treated for 7 days with thyroxine (150 microgram/100 g BW) or triiodothyronine (10 microgram/100 g BW). This regimen resulted in an enhanced activity of the microsomal ethanol oxidizing system. In addition, a decrease of hepatic alcohol dehydrogenase activity was observed under these experimental conditions, whereas hepatic catalase activity remained unchanged. These findings suggest that if chronic ethanol consumption simulates a functional "hyperthyroid hepatic state", increased rates of ethanol metabolism observed following prolonged alcohol intake might therefore be attributed at least in part to an induced activity of the microsomal ethanol oxidizing system in the liver.

Progress in the understanding of drug-induced liver injury (DILI) is clearly hampered by the lack of specific markers of the disease. In this scenario, recrudescence of the liver injury upon re-exposure to the suspicious drug is considered the more reliable evidence of DILI. On-purpose re-exposure, however, entails both practical and ethical issues because the bulk of situations in clinical practice are non-immunoallergic DILI in which a provocation test frequently would give negative results. Besides, deliberate re-exposure with a drug that is not considered vital or essential is potentially harmful and, hence, hardly justified in DILI, and rechallenge is more commonly described in an unintentional basis. The causes, characteristics and consequences of rechallenge have been specifically addressed recently. For causality assessment, a positive rechallenge test carries the strong value, and is accordingly scored by clinical algorithms. Such clinical scales, however, reward drugs that are associated with a positive rechallenge response, but might be considered biased against those where re-administration fails to elicit a response or, more commonly, for which no rechallenge is attempted.

In the present condition of the technique of cultivation of tissues, the only possible way of studying leucocytic secretions was to grow colonies of leucocytes in a medium of known properties and to examine the modifications of these properties under the influence of the living cells. The method was far from perfect, because the secretions were mixed with serum and accumulated for 48 hours in a medium where they probably underwent partial destruction. But an approximate idea of certain of the qualities of the secretions, although not of their quantity, could be derived from the experiments. In the fluids extracted from the cultures, we attempted to detect the presence of the leucocytic secretions through their physiological effects on homologous and foreign cells. Two kinds of substances were sought, those which act on homologous cells, and those which destroy foreign erythrocytes. The secretion by leucocytes of substances necessary to the nutrition of other cells was considered as probable long ago. Renaut thought that the main function of the white blood corpuscles was to bring to the fixed cells of the tissues the food material which they need. While the existence of physiological relations between leucocytes and tissue cells could be considered as almost certain, their nature had remained practically unknown. It was probable, however, that the substances secreted by leucocytes were analogous to the growth-activating and unstable substances which are found in embryonic tissues, leucocytes, and certain adult tissues. When connective tissue was aseptically inflamed, or when an aseptic peritoneal exudate contained many leucocytes, aqueous extracts of both connective tissue and peritoneal exudate were found to have acquired the power of stimulating cell proliferation. These experiments showed that leucocytes could bring to the tissues some activating substances. But it remained to be ascertained whether leucocytes, while they are alive, could secrete similar substances either spontaneously or under the stimulus of a foreign factor. Leucocytes are supposed to be, as is well know, the origin of the substances which protect the organism against infection. Although the problem of the origin of alexin and antibodies has been investigated by many experimenters, it is not yet completely solved. It was of interest, therefore, to ascertain whether leucocytic secretions could increase the natural hemolytic effect of hen serum on sheep or rabbit erythrocytes, and whether these secretions would become more active under the influence of a foreign protein. The substances which destroy foreign cells are not necessarily different from those which act on homologous cells. The word substance is used for simplicity of description and may be taken as meaning only a given property of an unknown substrate. A comparison was made of certain properties of sera extracted after 48 hours incubation from media containing leucocytes and from media containing no leucocytes. The serum from the leucocytic cultures was always found to be more favorable to the growth of homologous fibroblasts than the serum from the culture media incubated without leucocytes. The natural hemolytic power of the serum on sheep erythrocytes was found to be increased in about SO per cent of the experiments. In other experiments, we found that when two culture media free of cells were placed, one in an incubator at +38 degrees C. and the other in a refrigerator at +5 degrees C. for 48 hours, the serum from the incubated medium partly lost its hemolytic action on sheep or rabbit erythrocytes, while that from the refrigerated medium remained normal; at the same time, the inhibiting action of the incubated medium on homologous fibroblasts had increased very much. This effect of incubation indicates that certain unstable constituents of serum are destroyed by heat. Then the changes found in the properties of the serum from cultures of leucocytes are due to the fraction of the activating substances which has not been destroyed by incubation at 38 degrees C. A quantitative study of the secretions is, therefore, impossible with the present technique, which can furnish only qualitative indications about the substances set free by the leucocytes. We have ascertained also whether a medium containing leucocytes and kept in the refrigerator undergoes any change under the influence of the cells while they are in a condition of latent life. Gabritschewski dishes with and without leucocytes were placed in a refrigerator at a temperature of about +5 degrees C. After 48 hours, the hemolytic power on sheep erythrocytes of the serum from the leucocytic cultures had increased slightly and its inhibiting action on the growth of homologous fibroblasts had decreased. Then certain substances favorable to the growth of homologous cells and toxic for heterologous cells were diffused by the leucocytes into their medium. But the action of these substances was weaker than in the case of the cultures kept in the incubator. This experiment showed that leucocytes under certain conditions diffuse alexin or natural hemolysins which originate from them at the same time as the substances which activate homologous cells. In other experiments, although leucocytes were frozen at -10 degrees C., treated with distilled water, or extracted with saline solution, they did not yield any hemolysin. To summarize: Leucocytes, cultivated in plasma, always secreted substances which increased the rate of growth of homologous cells. Less frequently, they set free substances which hemolyzed foreign erythrocytes. The growth-promoting substances are analogous to those contained in embryonic tissues, and probably represent some of the foodstuffs brought to fixed tissue cells by leucocytes. They may possess the function of rejuvenating cells which have ceased to multiply when the cicatrization of a wound or the repair of a fracture requires a resumption of tissue activity. According to this hypothesis, the leucocytes brought to the surface of a wound by the process of inflammation would not only oppose bacterial invasion, but also bring to the tissues the material necessary to cell multiplication. It seems that in some cases regeneration is started by substances brought to the tissues by other cells. Loeb thinks that in Tubularia, when endodermic cells gather at the end where a new polyp is about to be formed, the substances given off by these cells are responsible for polyp formation.(6) There may be an analogy between this phenomenon and the secretion by leucocytes of growth-activating substances at the surface of a wound. If we assume that leucocytes in vivo set free their secretions in the blood stream, certain variations of the growth-inhibiting action of normal serum can be better understood. The rate of proliferation of homologous fibroblasts is much slower in the serum of an old chicken than in that of a young one. When the serum is heated at 56 degrees and 70 degrees C. for (1/2) hour, it becomes still more inhibiting. A substance favorable to cell activity has disappeared. It is therefore permissible to suppose that the growth-inhibiting power of serum and its variations are due to the antagonistic action of two substances, one growth-promoting and thermolabile, and the other growth-inhibiting and thermostable, the activating substance being always weaker in its effect than the inhibiting one. We know that activating substances can be extracted from embryonic tissue, from muscle and gland tissues, and from leucocytes of the adult animal, and that they are thermolabile and very unstable. Leucocytic secretions seem to have some of the properties of leucocytic extracts. It is probable that the activating substances which disappear from the heated serum are secreted by leucocytes and other cells. An increase of these secretions, then, would diminish the inhibiting action of serum on homologous fibroblasts. On the contrary, a decrease of the secretions in the serum would increase its inhibiting effect on homologous cells. The strong inhibiting action of serum in old age would be due partly to a reduction in the amount and activity of the substances secreted by leucocytes and tissue cells in the humors of the organism. Leucocytes also secreted in vitro substances which were toxic for foreign cells. Although the results were not constant, the serum appeared to become slightly more hemolytic for sheep or rabbit erythrocytes, under the influence of the leucocytes. The hemolysis of rabbit corpuscles by hen serum is due, according to Hyde,(9) to a complex sensitizer alexin, and not merely to alexin, as Bordet thought. When a foreign protein was added to the culture medium, the leucocytic secretions increased, as was shown by the action on homologous fibroblasts of sera taken from cultures of leucocytes with and without casein. The presence in the medium of the cultures of leucocytes of only 0.1 per 1,000 casein did not markedly modify the action of their serum on the proliferation of fibroblasts. When the concentration of casein in the leucocyte cultures reached 1 per 1,000, the growth of chicken fibroblasts in the serum extracted from the Gabritschewski dishes became more rapid. But there was no parallel increase of the hemolytic action of the serum upon sheep erythrocytes. We found that chicken serum containing 0.1 per 1,000 casein was barely toxic for homologous fibroblasts, while it became markedly inhibiting when the casein concentration reached 1 per 1,000. Probably, there is a relation between the toxicity of the medium, the increase of leucocytic secretions, and the time of the increase. The change brought about by casein in the equilibrium of the system composed of the cells and their medium determines the secretion by the leucocytes of substances which increase the activity of homologous cells and oppose the inhibiting effect of the foreign proteins. This reaction of the leucocytes is immediate, and may represent the first defense of the organism against a factor which disturbs its equilibrium. Possibly it differs from the specific cell reaction which leads to the production of antibodies. It is known that antibodies develop more slowly. Hemolysins were detected in cultures of bone marrow 4 days after the addition of antigen. The immunization of fibroblasts against foreign proteins has been shown by Fischer to begin after 4 days. If leucocytes behave in the organism as they do in vitro, we may assume that before the appearance of antibodies, they respond to the presence of an antigen by setting free growth-promoting substances and possibly alexin. This immediate reaction of the leucocytes against a disturbing factor, and the resulting production of substances which increase the activity of homologous cells, might be partly responsible for the results observed in the treatment of certain diseases by the injection of foreign proteins. It may be concluded that, under the conditions of the experiments: 1. The serum obtained from cultures of leucocytes is less inhibiting for homologous fibroblasts than the serum from media without leucocytes. In some experiments, its hemolytic action on sheep or rabbit erythrocytes is also increased. 2. The addition of casein to leucocytic cultures brings about a decrease in the inhibiting effect of the serum on homologous fibroblasts. 3. The increase in the activity of homologous fibroblasts in serum obtained from leucocytic cultures is probably due to growth-promoting substances secreted by the leucocytes. The presence of a foreign protein under certain conditions determines a more abundant leucocytic secretion.

The work reported in the preceding sections justifies, we think, a number of definite conclusions. In addition to this, some of the experiments indicate a line of thought which may lead to considerable alteration in our conceptions, both of phenomena of bacterial hypersensitiveness and of infection. 1. In guinea pigs two fundamentally different types of intradermal reactions may be observed. One of these is the immediate, transitory reaction which develops in animals sensitized against proteins (horse serum, etc.) and may be regarded as one of the manifestations of general protein hypersensitiveness, or anaphylaxis; the other is the tuberculin type of skin reaction which develops more slowly, leads to a more profound injury of the tissues and is independent of anaphylaxis as ordinarily conceived. 2. The tuberculin type of hypersensitiveness (as well as probably the typhoidin, mallein, abortin reactions, etc.) does not develop at all in guinea pigs sensitized with proteins, like horse serum, etc. While this form of hypersensitiveness may eventually be induced with materials not bacterial in origin, it has been observed up to date only as a reaction of bacterial infection. 3. Methods of treatment with protein material from bacterial cultures which sensitize guinea pigs to anaphylactic reactions with the bacterial extracts, do not sensitize them to the tuberculin type of reaction. Such sensitization is easily accomplished only by infecting the animals with living organisms. No reliable method of sensitizing guinea pigs to such reactions with dead bacterial material has as yet been worked out, though a few hopeful experiments have been obtained with massive injections of large amounts of the acid-precipitable substances (nucleoproteins?) from bacterial extracts. 4. In animals made hypersensitive to the tuberculin type of reaction by infection with living bacteria, the reaction may be elicited by intradermal injections of bacterial extracts from which all coagulable proteins, nucleoproteins, and Bence-Jones proteins have been removed, as well as this can be done by boiling with acid, etc. This proteose residue alone suffices to elicit such reactions. The exact chemical nature of the so called proteose residue must be further studied and analyzed when we have had opportunity to produce bacterial extracts in large quantity. These points seem incontrovertible on the basis of our own experiments, as well as those of other workers. There thus seem to develop two definite forms of hypersensitiveness in guinea pigs infected with bacteria, typical anaphylaxis in which the protein material of the bacterial cells is concerned, which develops late and which can be induced by repeated injections of dead bacterial material, and a hypersensitiveness to non-protein constituents which differs from the former, both in the laws that govern sensitization and in the manifestations which follow injections into the sensitized animals. While there is virtual agreement among immunologists concerning the essential mechanism of protein anaphylaxis, its dependence upon an antigen-antibody reaction, and the dominating rôle played by the sessile antibodies, the mechanism of hypersensitiveness to tuberculin and similar bacterial substances is still a problem of much uncertainty. The most striking difference between the two phenomena lies, as we have seen, in the criteria of sensitization, in that hypersensitiveness to the tuberculin type of reaction can hardly ever be induced by any of the ordinary methods of preparation with the constituents of dead bacteria, but develops promptly (7 to 10 days) in the course of actual infection with living organisms. The considerable specificity of such reactions forces the conclusion that the sensitizing substance must, in some way, be derived from the infecting microorganisms. The idea that the failure of sensitization with dead culture materials is perhaps due to the elaboration in the body of infected animals of bacterial products not represented in extracts of test-tube cultures is rendered unlikely by the fact that in the tuberculin-sensitive, infected animals, we can produce the reactions by the application of such dead extracts. It is neither logical nor in keeping with biological experience to assume that one substance will sensitize to reaction with another. This mistake was made early in the study of anaphylaxis in another connection and caused considerable delay of progress. Krause has shown that tuberculin sensitiveness may be blunted in infected animals by massive, but sublethal injections of tuberculin, and we have obtained some indications of the same thing. Moreover, others as well as ourselves have seen tuberculin reactivity decline in guinea pigs and in man in the stages of very severe infection. These facts would eliminate any assumption of mere cumulative injury as explaining this type of reaction, and stamp it as a mechanism at least analogous to ordinary anaphylaxis. The only remaining possibility to explain the difference between infected animals and those treated with dead bacterial constituents would be to assume that the difference must lie in the manner in which the sensitizing substance is administered to the animals, and that sensitization with the proteose residue materials depends upon criteria of sensitization differing in regard to the time and quantity factors from those governing protein sensitization. If one considers the relatively simpler chemical structure and perhaps physically greater diffusibility of the materials concerned in this reaction, one might readily expect such differences in the methods needed for sensitization. In keeping with such a line of reasoning our experiments have shown that the tuberculin active materials are constantly and rapidly being diffused out into the culture fluid from growing organisms, in quantities greater than can be extracted from similar amounts of the dead bacteria. It seems reasonable to assume from this that the same thing may happen in the animal body harboring a growing focus. And it would seem quite likely that the association of the tuberculin type of reaction with actual infection may depend upon the fact that sensitization to these non-protein substances depends upon a constant steady absorption of large amounts of the material. Moreover, the only hopeful experiments on the artificial production of tuberculin sensitiveness in guinea pigs obtained by us were those in which massive doses of the nucleoprotein material injected into guinea pigs gave rise to a moderate skin sensitiveness. Does the so called proteose residue form antibodies, and, if so, are substances analogous to antibodies involved in the tuberculin type of hypersensitiveness? The failure to transfer passively this form of hypersensitiveness to normal animals with the blood and tissues of tuberculin-sensitive ones would suggest that no antibodies are involved. But this is not conclusive on the basis of available experimental facts. We are inclined to believe that antibodies of a sort are involved, for the following reasons:(a) In our experiments with the uteri of highly sensitive extract-treated guinea pigs and of tuberculous guinea pigs, we have occasionally had positive reactions when the proteose residue alone was used.(b) We believe that these proteose substances are entirely analogous to the substances studied by Avery and Dochez (22) in the urine and blood of typhoid and pneumonia patients. They obtained precipitin reactions against homologous immune sera with the urine of infected cases concentrated by evaporation after boiling with acetic acid to remove coagulable proteins.(c) Petroff, with whom we discussed this proteose residue early in our work, has produced it, and tells us that he has obtained precipitin reactions with it by titrating it against the serum of a sheep treated for a long time with tubercle bacillus products. In suggesting an antibody response to a non-protein antigen we are aware that we are opposing what has been regarded as a well established doctrine in immunity; this is justified, or at least mitigated, we believe, by the consideration that reactions of the antigen-antibody type are the only explanation of specificity; and tuberculin, mallein, and typhoidin reactions are to a considerable degree specific. If such reaction bodies cannot be produced by precisely the same methods of administration as to time and quantity which are successful in calling forth protein antibodies, this should not astonish us, since, after all, the substances that we are dealing with are simpler in chemical structure than are the proteins, and physically are probably of relatively greater diffusibility. It may be that the greater diffusibility of the proteose-like substances transfers much of the actual reaction phenomena to an intracellular location, and that this to some extent influences the presence of circulating antibodies. It may also be that these more diffusible non-protein antigens are more rapidly eliminated from the animal body than are the proteins. Indeed, the above mentioned observations of Avery and Dochez, and the recent work of Wildbolz (23), Lanz (24), Imhof (25), and Gibson and Carroll (26), who demonstrated tuberculin active antigens in the urine of active cases, would corroborate such a view. The evidence available at the present time, however, concerning antibody formation to these non-protein substances is, we recognize, largely indirect, at least as far as our own work is concerned, and we present it in the present connection purely as a working hypothesis. Finally, perhaps the most important theoretical consideration indicated by our experiments is the following. We have in the tuberculin reaction a form of hypersensitiveness which seems to be (in guinea pigs, at least) analogous entirely to the typhoidin reaction, the mallein reaction, and the abortin reaction. Whenever reactions of this type have been carefully studied, whatever the bacteria involved, they have been associated with infection as in tuberculosis, and have been followed by analogous clinical manifestations. It would seem perhaps that we are dealing with a law applicable to bacterial infection in general. It would appear that certain non-coagulable substances of uncertain chemical constitution are being constantly elaborated in the course of bacterial growth, and passed into the circulation of infected animals. As a result of this, infected animals become sensitized to these heat-and acid-resistant materials, in tuberculosis in the course of I to 2 weeks, in the case of more rapidly growing bacteria perhaps sooner. Early in the course of infection, the animal becomes sensitized and subsequently the further elaboration and distribution of these materials from the bacterial focus plays a fundamental part in the injury of the animal. These proteose-like substances, like tuberculin, possessing but slight toxicity for the normal animal, become highly toxic to the sensitized one. Thus, these substances, while not being true exotoxins in the ordinary sense, would still represent a highly toxic bacterial product comparable in its injurious effect to toxins when produced in the body of an animal thus sensitized. If there is any value in these deductions the attention of bacteriologists should be turned to the non-protein constituents of bacterial cells in their further immunological studies, as well as to the protein materials. It is obvious that the next step in our investigations must consist in producing the non-coagulable material from bacterial extracts in considerable quantity, to determine their antibody-forming properties in detail, and elucidate, if possible, the laws which govern sensitization with them. This work has been begun, but it has seemed advisable to publish this as far as we have gone because it will take a long time before it can be completed.

From the foregoing description of the histological changes in the leptomeninx it is quite evident that we are dealing with a chronic, stationary, healing form of tuberculous inflammation. This statement is substantiated, in the first place, by the clinical history. The only reasonable interpretation of the symptoms would establish the duration of the process as four months. The imaginable contingency that there existed first a meningeal syphilitic lesion that was dispersed by the iodide of potassium only to be followed by a tuberculous infection is so remote and unlikely that it need not be discussed. At all events the tuberculous leptomeningitis, which presented a typical distribution, began insidiously, existed at times in a latent condition, and pursued a very anomalous course, marked by a relative mildness of all the symptoms, and thus it came about that when an apparent or real improvement followed the administration of iodide of potassium able observers were induced to make an erroneous diagnosis. Death occurred as a result of an intercurrent infection. The long duration of the process is also shown, anatomically, by the thick layer of firm, translucent and gelatinous material that matted together the structures at the base, and also by the evident adhesions between the pia and the brain. The histological examination furnishes proof positive of the correctness of the conclusion in regard to the peculiar character of this process because it shows:(1) That the tuberculous proliferation is uniform in development and has reached nearly the same stage of evolution throughout the entire extent of the leptomeninx involved; it is not a process that has advanced by exacerbations and irregular extensions; the lesions are, generally speaking, of nearly the same age everywhere and must have begun at about the same time.(2) That only a very limited degree of caseous degeneration is present, pointing to an early arrest of the activity of the tubercle bacillus or to a very decided diminution or attenuation of its virulence.(3) That the subendothelial intimal proliferations of epithelioid cells, so generally found in acute tuberculous leptomeningitis,* have in this case become more or less completely changed into distinct fibrous tissue in which but very slight, if any, direct evidence of its tuberculous origin can be found. It is only by recognizing that the chronic endarteritis is most marked in correspondence with the most advanced adventitial tuberculous changes, and by finding an imperfect, much altered giant cell in one district of intimal thickening, that we were able to establish the direct kinship of the endovascular changes with those of the pia in general.(4) That acute inflammatory changes, in the form of emigration of polymorphonuclear leucocytes and of fibrinous exudation, are entirely absent in all parts of the district involved. The presence of a turbid serous fluid is of course not at all inconsistent with the view that the anatomical changes are of long duration.(5) That the granulation tissue present is, in general, undergoing fibrillation and contains a rich supply of enabryonal capillary vessels as well as of larger blood-vessels of evidently new formation. The absence of any considerable extent of polymorphonuclear leucocytic infiltration in this tissue has already been referred to. The cells in the granulation tissue correspond to the cells of embryonal or formative connective tissue. Vacuolation is rarely present.(6) That the unusually large number of giant cells present are remarkably free from evidences of necrosis and degeneration of the character ordinarily observed in tuberculous proliferations, that they do not contain in demonstrable form tubercle bacilli, and that the majority of the giant cells seem to be separating into individual cells and smaller masses often with, but sometimes also without, evidences of nuclear disintegration. The possibility that these phenomena may signify fusion instead of the sundering of cells will be discussed below. For these reasons there can be no doubt that the general claim that we are dealing with an instance of chronic, healing tuberculous meningitis must be regarded as established beyond dispute. The growth of tubercle bacilli in the glycerine-agar tubes, inoculated with the fluid from the pial meshes, and the demonstration of tubercle bacilli, though in very small numbers, between the cells of the embryonal tissue, furnish the positive evidence that we are actually dealing with a tuberculous process due to living and not to dead bacilli. The degree of virulence of the cultures of tubercle bacilli was, unfortunately perhaps, not studied. The presence of living tubercle bacilli in a tissue free from active and acute changes characteristic of tuberculosis demonstrates that, whatever the actual degree of virulence of the bacilli may have been, the tissue in which they were found was at this time relatively immune from their action. The manner in which this immunity was produced, and in which the process of healing was initiated, need not be discussed at this time any further than to again direct attention to the fact that the bacilli lost their virulency as regards the cells in this leptomeninx before these cells underwent any marked degree of degeneration. The cells of the tuberculous proliferations survived the further action of the bacilli whose original effect it was to initiate cell accumulation or proliferation; the cells also retained sufficient vitality to develop, in some instances at any rate, into formative cells according as their origin would dictate, e. g. into fibroblasts. That fibroblasts are formed only by embryonal connective tissue cells, and not by wandering cells, such as the large mononuclear leucocytes, we are well aware, is possibly still a disputable assumption, and we do not consider it pertinent to discuss the question any further in connection with this study, but would only emphasize the point that some of the cells of tuberculous proliferations may, under favorable circumstances, become formative cells, and, furthermore, that the amount of formative tissue produced may be far in excess of what is actually needed for purposes of repair only. Surely the appearances here noted indicate that the bacillus of tuberculosis has the power to stimulate fixed cells to multiply, unless one assumes that all, or almost all, the formative cells here seen are derived from wandering cells attracted by the presence of the bacillus and its products. As to the ultimate fate of the formative and other cells in this healing tuberculous tissue no final statements can be made. It must be remembered that it is only one stage in the process of healing that is dealt with. The well marked evidences of fibrillation, the quite extensive formation of new vessels, the absence of evidences of degenerative changes in the uninuclear cells, all point to the production of new fibrous tissue as sure to occur, but it seems quite probable that occasional epithelioid cells may undergo or have undergone dropsical or other forms of degeneration, although it is certainly apparent that so far as the small cells are concerned the involution of the tuberculous tissue is not occurring through disintegration. Perhaps the most interesting feature in this case is the opportunity it affords to study the changes in the giant cells of healing, non-degenerated tuberculous tissue. In the first place, the large number of giant cells is quite remarkable. The general characters of the tissue in which they are found recall the fact that giant cells are regarded as quite constant elements in chronic mild tuberculosis; often the giant cells are the only cells that contain bacilli (Koch). In this instance the giant cells do not contain bacilli that are demonstrable by the usual methods; neither do they contain bodies that can be definitely interpreted as degenerate forms of bacilli such as those found by Metchnikoff, Stchastny, Weicker, and others, in the giant cells of Spermophilus guttatus, in avian and in human tuberculosis. Metchnikoff states, however, that he knows of the occurrence of such degenerate forms only in the Spermophilus guttatus under the circumstances mentioned, and in the rabbit and guinea-pig in mammalian tuberculosis, but not in man; consequently, the manner in which the giant cells rid themselves of the bacilli undoubtedly present in their interior at some time during their existence, must as yet remain without any explanation. In the description of the histological changes the various appearances presented by the giant cells are described somewhat minutely. The essential observations made concern, in my opinion, the further fate of giant cells which are still found to persist in healing nondegenerated tuberculous tissue. It was, I believe, quite conclusively shown that the consecutive changes appear to consist in the breaking up of the nuclei, the removal of the detritus by phagocytes, and the formation of a few apparently viable uninuclear cells in the case of more degenerated, exhausted giant cells, while other, and, as it would seem, better preserved or younger giant cells, separate into a number of individual, uninuclear cells with but little or no nuclear disintegration. Objection might be raised to this interpretation of the appearances in the giant cells. While no one could very well dispute the view that part of the giant cells are undergoing retrogressive and absorptive changes with the production of some viable cells, a question might well be raised concerning the nature of the process taking place in those giant cells that have been spoken of as splitting up or dividing into uninuclear cells and smaller multinucleated masses without much evidence of nuclear disintegration. It might be claimed that the process is one of fusion of many cells to form giant cells, and not one of division of fully formed giant cells into small cells. But a broad view of the processes described speaks against fusion. In the first place we are not dealing with a stage of tuberculous proliferation (Baumgarten), or cell accumulation (Metchnikoff), in which one would look for the production of giant cells, no matter which view concerning the histogenesis of tubercle be assumed as the correct one, because it has been demonstrated that, from whichever point of view the lesions are examined, the same positive conclusion that they are in the process of healing is reached; there is, therefore, no occasion for the formation of new giant cells in such wide-spread degree throughout the district involved. It might he claimed that the cells became arrested and, as it were, fixed in the act of fusion which was taking place in the early stage of the meningitis, but it would be difficult to understand the nature of the stimulus that could hold the cells together in such a peculiar manner for such a long time. It must be remembered that bacilli or bacillary detritus could not be found among the incomplete or in the complete giant cells. In the second place the difference between the cells that are undergoing disintegration and those regarded as dividing is essentially, to a certain extent at any rate, one of degree, because in the first instance there is not much, if any, doubt but that viable smaller cells are also formed, and in the second instance some, though often very slight, evidence of nuclear fragmentation is nearly always present; it would also be correct to infer that in advanced subdivision of a giant cell much, and perhaps all, of the nuclear detritus produced might have been removed up to the last trace; finally, the two extremes of these changes in the giant cells are connected by transition stages passing by gradation from the one to the other. Hence it is justifiable to conclude, for the time being, that in healing non-degenerated tuberculous tissue, the multinucleated giant cells may in part disintegrate and undergo absorption, in part form viable small cells; that both these changes may, and usually do, affect the same cell, but that in one class of cells-presumably the older or the more exhausted-the retrogressive process is predominant, while in a second class of cells-presumably the young and vigorous-the progressive changes are the more marked. In this connection it may be pointed out that while there cannot very well be any question but that we are dealing only with dividing and not coalescing cells, yet if this conclusion should be disputed and found incorrect, then the only remaining alternative would be to infer that this tissue furnished a unique and striking example of the formation of plasmodial masses by fusion in human tuberculosis, a conclusion to which many pathologists would refuse to subscribe, if for no other reason than because it is not in accordance with the almost universally accepted teachings of Baumgarten and Weigert in regard to the mode of formation of the giant cells in tuberculosis. Believing as I do that the giant cells under consideration are in the act of division and not at all of fusion, there remain to be discussed some of the histological and other features presented by the dividing cells. Many of the giant cells, perhaps the majority, contain larger and smaller vacuoles in the protoplasm. The exact significance of this vacuolation is not always clear. When the vacuolation accompanies an evident solution of the nucleus (karyolysis), there cannot be any doubt but that we are in the presence of a distinctly retrogressive process. Vacuoles are also most numerous in the giant cells that present other evidences of degeneration, such as coarseness of the granules in the protoplasm and extensive nuclear disintegration, but they occur as well around nuclei that stain deeply, around cells that seem to be separating from the giant cell, and even about nuclei that present mitoses. The formation of vacuoles seems to be responsible, to a certain extent at any rate, for the diminution in the volume of disintegrating and dividing giant cells, as shown by the clear spaces that form about them; these spaces are too large and occur too uniformly to be attributed solely to artificial shrinking produced by the hardening in alcohol. Further undoubted evidence of retrogression in certain giant cells is the occurrence of nuclear disintegration, or karyorhexis, which sets free larger and smaller chromatin masses that are recognized in the giant cell as well as in the interior of the phagocytes usually found around such cells. Almost all the polymorphonuclear leucocytes found in this tissue are met with around giant cells with broken-up nuclei. In many nuclei of disintegrating giant cells can be noted appearances that correspond well to certain stages in the complicated karyorhexis observed in anaemic necrosis by Schmaus and Albrecht; some of the nuclei with budding processes correspond particularly well with those in certain of their drawings; the interior of giant cells of tuberculous tissue may, it would seem, present conditions favorable to the development of this series of postnecrotic nuclear change. Vacuolation, karyolysis and karyorhexis are the essential steps that lead to destruction of the whole or parts of some of the giant cells; associated with these processes there is usually observed a splitting up of the body of the giant cell into irregular fragments with as well as without nuclei; and, as described, more or less phagocytosis of the resulting remnants of various kinds is seen. But evident degenerative and necrotic processes in a giant cell may be associated with progressive changes. While some nuclei undergo vacuolation or break up, others seem to become richer in chromatin and to stain more deeply at the same time that they seem to acquire cell bodies quite distinct from the protoplasm of the giant cells: this hyperchromatosis does not, therefore, seem to be a stage in karyorhexis. A very few but undoubted karyokinetic figures were found, together with evidences of division of the cell body formed in the giant cell protoplasm. Precisely similar changes are described by Klebs in healing pulmonary tuberculosis of the guinea-pig; the nuclei of the giant cells became rich in chromatin and karyokinetic figures occurred. Krückmann among others has found occasional mitoses in giant cells around foreign bodies, as well as elsewhere, but it would seem that such mitoses have always been interpreted as indicating the probable mode of formation of the giant cells rather than of their involution. The question of mitosis in existing multinucleated cells has recently been studied by Krompecher, who concludes that the individual nuclei of such cells may undoubtedly divide by mitosis, either simultaneously or at separate times. Division by amitosis can also occur, but mitosis is the only progressive form of division, amitosis being a retrogressive, disintegrating process that must be looked upon as an evidence of degeneration of the nucleus. Ziegler states that in division of giant cells whose nuclei have multiplied by mitosis it may happen that the separating cell remains enclosed in the protoplasm of the mother cell. A singular phase in the involution of the giant cells in this pia is to be found in the existence of progressive changes side by side with nuclear necrosis and with degeneration; this finding indicates that giant cells may contain many independent elements which, though apparently fused into one large cell, may preserve their individuality so that while some nuclei die, others proliferate and perhaps feed on the remnants of their dead brethren and form new, viable small cells. The nuclei in giant cells may be looked upon as representing independent centres, capable at times of existing even though the cell protoplasm is disintegrated. Many of the giant cells separate into individual cells, unaccompanied or unassociated with much evidence of necrosis. These cells may be regarded as the more vigorous forms. Here also are observed occasional mitoses-but on the whole extremely few-and very constantly an evident increase in the amount of chromatin in the nuclei of the new cells as compared with the amount ordinarily found in the nuclei of giant cells. These deductions concerning the persistence of the vitality of some of the nuclei, even in the presence of molecular and morphological changes in the cytoplasm and in other nuclei of the giant cell that lead to disintegration, are not entirely without the support of previous observations on cells, which, although made under different conditions, are nevertheless, it would seem, applicable to cells in general. Thus the brilliant investigations of Loeb upon the effects of various unfavorable surroundings, such as absence of oxygen or reduction of the amount of water, upon the cleavage of eggs of many kinds, show that the conditions which arrest development are qualitatively alike for nucleus and protoplasm, but quantitatively less for the protoplasm; when the irritability of the protoplasm is suspended the nucleus may segment without segmentation of the protoplasm, but upon re-establishment of favorable conditions the protoplasm may divide into about as many spheres as there are nuclei preformed-the nucleus persists, preserves the irritability of the cell and stimulates the protoplasm to segmentation. From the appearances of the giant cells here described it would seem, then, that some nuclei are able to maintain their vitality longer than others in the same cell, and under certain conditions to stimulate parts of the protoplasm to segment; in other cells all the nuclei have, as a rule, preserved their irritability. The groups of cells formed by the dividing of the giant cells can be traced by studying the process at the different stages in the different parts of the tissue. They assume an oval or spindle-shaped form, becoming more and more like the formative and endothelioid cells of young connective tissue, but their ultimate fate cannot be determined because it concerns essentially only one limited period in the involution of the tissue. It may be said with reasonable certainty, however, that the new cells do not form blood-vessels, but as regards their forming lymph-vessels nothing definite can be concluded. It would not be safe to draw any definite conclusions, from the appearances described, with regard to the origin and the mode of formation of the giant cells. The resulting small cells in general resemble very much endothelial and formative cells, but some of them are, at certain stages at any rate, not unlike large mononuclear leucocytes; their final fully developed or mature condition being unknown, no positive inference can be drawn as to their pre-giant-cell origin. The evidence points to the fact that the most probable origin of the giant cells, as indicated by their form and the apparent future career of their descendants, would be the fixed mesoblastic cells of the pia. In regard to the mode of formation of the giant cells it is quite clear that it must involve some process which is not incompatible with the viability of the small cells which may spring from the giant cells. Whether this would speak more in favor of formation by fusion than by karyokinesis of a single cell without division of the cell body cannot be well determined, and as long as authors are not agreed upon the question of the production of living, procreative cells by amitosis (direct segmentation, direct and indirect fragmentation) it would not be profitable to discuss the compatibility or incompatibility of the views of those investigators who trace the origin of giant cells to amitotic division, with the progressive changes that giant cells have been shown to be capable of. The fact that giant cells in tuberculous tissue, under certain conditions, undergo progressive changes and separate into small, living cells proves that they are not, as claimed by Baumgarten, Weigert and others, necrobiotic elements that are doomed to destruction from their very inception. On the other hand it lends more strength, if that were necessary, to the teleological view urged by Metchnikoff that they are living, defensive cells (whatever their origin may be), formed for the distinct purpose, like plasmodial masses in general, of isolating and removing foreign, harmful bodies, in this case the tubercle bacillus, and, having accomplished their object without being destroyed or exhausted, or the cause of their formation being removed or neutralized in some way, they, or their nuclei, may retain enough irritability to form a larger or smaller number of living, small, uninuclear cells.

The case of a 64 year old female patient is presented who has treated herself for 9 months with various Indian Ayurvedic herbal products for her vitiligo and experienced a causally related severe hepatotoxicity (ALT, 601 U/L; AST, 663 U/L; Bilirubin, 5.0 mg/dL). After discontinuation, a rapid improvement was observed. Causality assessment with the updated CIOMS (Council for International Organizations of Medical Sciences) scale showed a probable causality (+8 points) for Bakuchi tablets containing extracts from Psoralea corylifolia leaves with psoralens as ingredients, as the primary candidate causing the hepatotoxic reaction. The degree of probability was lower with +6 points for other used herbs: Khadin tablets containing extracts from Acacia catechu leaves; Brahmi tablets containing Eclipta alba or Bacopa monnieri; and Usheer tea prepared from Vetivexia zizaniodis. The case is the first report of Indian Ayurvedic herbal products being potentially hepatotoxic in analogy to some other herbs.<br />

Hepatotoxicity by drugs and dietary supplements (DDS) is a rare and unpredictable event but with the risk of a life-threatening clinical course when it occurs. It may emerge despite intensive chemical, toxicological and observational studies that indicate no hepatotoxic signals. This suggests major clinical and regulatory issues that must be addressed in the area of accurate testing, reporting, and accessibility of reliable n data. Consequently, in a clinical setting, safety concerns are key elements in the treatment of patients, and require that the diagnosis of DDS hepatotoxicity clearly be established. Causality of DDS hepatotoxicity may be pursued using a diagnostic algorithm consisting of a pre-test, a main-test as the scale of the updated CIOMS (Council for International Organizations of Medical Sciences), and a post-test. The results of these tests are then sent item by item to the National Health Agency, where the case will undergo further evaluation for pharmacovigilance, strategic aspects and safety issues. After this analysis, all items of the tests are included in the regulatory database freely accessible to the health and scientific community. With this diagnostic and regulatory algorithm the risk of misdiagnoses and inappropriate regulatory measures may be minimized and the safety improved. In conclusion,DDS hepatotoxicity is a rare but is a potentially life-threatening entity requiring a reliable diagnosis with the aid of a diagnostic algorithm, and a thorough pharmacovigilance evaluation by national and international health agencies. Safety aspects in DDS hepatotoxicity represent a major clinical and regulatory issue and should consequently be addressed.<br />

OBJECTIVE: To report a case of acute hepatitis related to atenolol administration in a liver transplant (LT) recipient. CASE SUMMARY: A 57-year-old woman was evaluated for LT because of liver failure due to cirrhosis of unknown origin. LT was performed in November 2006. In March 2007, results of liver function tests (LFTs) were within the reference ranges. She had received atenolol for hypertension for 3 years prior to surgery and it was reintroduced at a dose of 100 mg/day because of recurrence of hypertension. One month later, she presented with acute hepatitis. The first post-LT liver biopsy was performed. Histologic examination disclosed a combination of portal and centrilobular inflammatory lesions. The diagnosis of acute rejection was accepted and 3 bolus doses of prednisone 500 mg/day were administered. Evolution was not favorable and a second liver biopsy was obtained. Histologic examination showed the complete disappearance of portal inflammatory lesions but an increase of centrilobular lesions. Toxic hepatitis was suspected and atenolol was stopped. No other therapeutic modification was done and resolution of the toxicity was good. An objective causality assessment revealed that the adverse drug event was probable. DISCUSSION: This case report represents a very rare severe hepatotoxicity due to atenolol and illustrates the diagnostic difficulties raised by such clinical situations in the context of LT. It is noteworthy that the initial diagnosis considered in this patient was acute rejection. This diagnosis had to be reconsidered because of the unfavorable outcome, despite specific treatment of rejection. Moreover, the patient had been treated with atenolol for 3 years before LT: in the absence of any other etiology, the possibility that she had drug-induced cirrhosis may therefore be considered. The mechanism of beta-blocker-related hepatotoxicity is debatable. In our case, the composition of the inflammatory infiltrates observed in the liver biopsy specimens suggests an immune-mediated mechanism. CONCLUSIONS: Despite the fact that beta-blocker-induced hepatotoxicity is probably extremely rare, it must be suspected and the drug therefore discontinued.

OBJECTIVES: Black cohosh (BC) is a herbal drug or herbal dietary supplement used for treatment of menopausal symptoms. Recently, however, reports have appeared about the occurrence of rare toxic liver disease in an assumed relationship with the use of BC. METHODS: We have analyzed and reviewed the data of all 69 reported cases with suspected BC hepatotoxicity. Causality for BC was assessed utilizing the scale of the original structured quantitative Council for International Organizations of Medical Sciences (CIOMS), or the main-test as its updated form. RESULTS: With the hepatotoxicity specific causality assessment methods, there was an excluded, unlikely, unrelated or unassessable causality for BC in 68 of 69 cases with liver disease. One patient had a possible causality for BC and a symptomatic cholelithiasis with confounding variables of fatty liver of unknown etiology; unknown BC brand including possible herbal mixture; unknown daily BC dosage; and an unassessable duration of BC usage. In general, the cases of the 69 patients were poorly documented. Confounding variables were: failure to identify the BC product; use of herbal mixtures with multiple ingredients in addition to BC; co-medication with synthetic drugs and dietary supplements including herbal ones; missing temporal association between BC use and development of liver disease; not specified modalities of BC treatment; failure of dechallenge after BC discontinuation; pre-existing liver diseases; insufficiently excluded other liver diseases; presence of alternative liver diseases. CONCLUSIONS: The analysis of 69 cases shows little, if any, supportive evidence for a significant hepatotoxic risk of BC.

ETHNOPHARMACOLOGICAL RELEVANCE: Ethanolic and acetonic kava extracts have previously been causally related to rare hepatotoxicity observed in patients from Germany and Switzerland, but causality assessment was not performed in cases of patients having taken the traditional aqueous kava extracts of South Pacific islands or kava-herbs mixtures. AIM OF THE STUDY: To study the possible hepatotoxicity of aqueous kava extracts of the South Pacific Islands. MATERIALS AND METHODS: Causality of hepatotoxicity by aqueous kava extracts and kava-herbs mixtures was assessed, using the updated score of the quantitative CIOMS (Council for the International Organizations of Medical Sciences). RESULTS: Causality was established in five patients from New Caledonia, Australia, the United States and Germany for aqueous kava extracts and kava-herbs mixtures. A comparison with 9 patients from Germany and Switzerland with established causality of hepatotoxicity by ethanolic and acetonic kava extracts reveals that the clinical picture in all 14 patients is similar, independently whether aqueous, ethanolic and acetonic kava extracts or kava-herbs mixtures were used. CONCLUSIONS: Kava hepatotoxicity occurs also with traditional aqueous kava extracts of the South Pacific islands and thereby independently from ethanol or acetone as chemical solvents, suggesting that the toxicity is linked to the kava plant itself with a possibly low quality of the used kava cultivar or kava plant part rather than to chemical solvents.

BACKGROUND: Kava hepatotoxicity in 20 patients from Germany has been debated worldwide following a regulatory ad hoc causality assessment and ban of kava, an anxiolytic herbal remedy obtained from the rhizome of Piper methysticum Forster. AIMS: We assessed causality with a quantitative structured causality analysis in all 20 cases of patients with liver disease, presented by the German regulatory agency that assumed a causal relationship with the use of kava extracts. METHODS: The quantitative scale of CIOMS (Council for International Organizations of Medical Sciences) in its updated form was employed for causality assessment and quality evaluation of the regulatory data presentation. RESULTS: The regulatory information is scattered and selective, and items essential for causality assessment, such as exclusion of kava independent causes, were not, or only marginally, considered by the regulator. Quantitative causality assessment for kava was possible (n=2), unlikely (n=12), or excluded (n=6), showing no concordance with the regulatory ad hoc causality evaluation. CONCLUSION: The regulatory data regarding kava hepatotoxicity is selective and of low quality, not supportive of the regulatory proposed causality; but instead, is an explanation of the overall causality discussions of kava hepatotoxicity. We are proposing that the regulatory agency reports data in full length and reevaluates causality.