Immune-mediated drug-induced liver disease.

Drug-induced immune-mediated hepatic injury is an adverse immune response against the liver that results in a disease with hepatitic, cholestatic, or mixed clinical features. Drugs such as halothane, tienilic acid, dihydralazine, and anticonvulsants trigger a hepatitic reaction, and drugs such as chlorpromazine, erythromycins, amoxicillin-calvulanic acid, sulfonamides and sulindac trigger a cholestatic or mixed reaction. Unstable metabolites derived from the metabolism of the drug may bind to cellular proteins or macromolecules, leading to a direct toxic effect on hepatocytes. Protein adducts formed in the metabolism of the drug may be recognized by the immune system as neoantigens. Immunocyte activation may then generate autoantibodies and cell-mediated immune responses, which in turn damage the hepatocytes. Cytochromes 450 are the major oxidative catalysts in drug metabolism, and they can form a neoantigen by covalently binding with the drug metabolite that they produce. Autoantibodies that develop are selectively directed against the particular cytochrome isoenzyme that metabolized the parent drug. The hapten hypothesis proposes that the drug metabolite can act as a hapten and can modify the self of the individual by covalently binding to proteins. The danger hypothesis proposes that the immune system only responds to a foreign antigen if the antigen is associated with a danger signal, such as cell stress or cell death. Most clinically overt adverse hepatic events associated with drugs are unpredictable, and they have intermediate (1 to 8 weeks) or long latency (up to 12 months) periods characteristic of hypersensitivity reactions. Immune-mediated drug-induced liver disease nearly always disappears or becomes quiescent when the drug is removed. Methyldopa, minocycline, and nitrofurantoin can produce a chronic hepatitis resembling AIH if the drug is continued.

Drug-induced immunotoxicity.

Immune-related drug responses are one of the most common sources of idiosyncratic toxicity. A number of organs may be the target of such reactions; however, this review concentrates mostly on the liver. Drug-induced hepatitis is generally divided into two categories: acute hepatitis in which the drug or a metabolite destroys a vital target in the cell; immunoallergic hepatitis in which the drug triggers an adverse immune response directed against the liver. Their clinical features are: a) low frequency; b) dose independence; c) typical immune system manifestations such as fever, eosinophilia; d) delay between the initiation of treatment and onset of the disease; e) a shortened delay upon rechallenge; and f) occasional presence of autoantibodies in the serum of patients. Such signs have been found in cases of hepatitis triggered by drugs such as halothane, tienilic acid, dihydralazine and anticonvulsants. They will be taken as examples to demonstrate the recent progress made in determining the mechanisms responsible for the disease. The following mechanisms have been postulated: 1) the drug is first metabolized into a reactive metabolite which binds to the enzyme that generated it; 2) this produces a neoantigen which, once presented to the immune system, might trigger an immune response characterized by 3) the production of antibodies recognizing both the native and/or the modified protein; 4) rechallenge leads to increased neoantigen production, a situation in which the presence of antibodies may induce cytolysis. Toxicity is related to the nature and amount of neoantigen and also to other factors such as the individual immune system. An effort should be made to better understand the precise mechanisms underlying this kind of disease and thereby identify the drugs at risk; and also the neoantigen processes necessary for their introduction into the immune system. An animal model would be useful in this regard.

Immunotoxicology of the liver: adverse reactions to drugs.

Liver is a frequent target for drug-induced hepatitis. They can be classified in two categories: the hepatitis in which the drug or a metabolite reach a vital target in the cell and the hepatitis in which the drug triggers an adverse immune response directed against the liver. We will discuss essentially this second kind of disease. They have key clinical features such as the low frequency, the dose independence, the delay between the beginning of drug intake and the triggering of the disease, the shortening of the delay upon rechallenge and very often the presence of autoantibodies in the serum of the patients. Such signs were found in hepatitis triggered by drugs such as halothane, tienilic acid, dihydralazine, anticonvulsants. They will be taken as examples to show the recent progress in the understanding of the mechanisms leading to the disease. It has been postulated that the drug is metabolised into a reactive metabolite binding to the enzyme which generated it; therefore the neoantigen might trigger an immune response characterised by the production of antibodies recognising the native and or the modified protein. Most of these steps were proven in the cases of halothane, tienilic acid and dihydralazine. Several points seem important in the development of the disease; the equilibrium between toxication and detoxication pathways, the nature and amount of neoantigen, the individual immune response. However, many points remain unclear: for instance, the reason for the very low frequency of this kind of disease; the precise mechanism of the adverse immune response; the risk factors for developing such adverse reactions. Efforts should be made to better understand the mechanisms of this kind of disease: for instance, an animal model, tests to identify drugs at risk for such reactions, the role of these drugs in the processing of P450s and the processing of the neoantigens for their presentation to the immune system.

Anti-cytochrome P450 autoantibodies in drug-induced disease.

Drugs may induce hepatitis through immune mechanisms. In this review we have used the examples of 2 drugs to elucidate the first steps leading to the triggering of such disease, namely tienilic acid (TA) and dihydralazine (DH). These drugs are transformed into reactive metabolite(s) by cytochrome P450 (2C9 for TA and 1A2 for DH) (step 1). The reactive metabolites produced are very short-lived and bind directly to the enzymes which generated them (step 2). A neoantigen is thus formed which triggers an immune response (step 3), characterized by the presence of autoantibodies in the patient's serum (step 4). The autoantibodies are directed against the cytochrome P450 which generated the metabolite(s). Although the process by which TA and DH induce-hepatitis has been elucidated, further studies are necessary to generalize this mechanism. In addition, an animal model will also be useful to fully understand the immune mechanism of this type of disease.

Immune mechanisms in tienilic acid associated hepatotoxicity.

In order to investigate the mechanisms underlying the hepatotoxicity associated with tienilic acid (Ticrynafen) ingestion we have looked for evidence of sensitisation to drug altered liver cell determinants using an indirect antibody dependent, cell mediated cytotoxicity assay (ADCC). As targets, hepatocytes were isolated from rabbits pretreated with either tienilic acid or its isomer with or without previous enzyme induction with either phenobarbitone or B-naphthoflavone (BNF). Sera from 16 of 36 patients with presumed tienilic acid hepatotoxicity induced significant cytotoxicity to hepatocytes isolated from rabbits pretreated with BNF and subsequently tienilic acid. Three of 10 sera from patients receiving tienilic acid but without overt liver damage also induced significant cytotoxicity to these hepatocytes, however, although none of 20 normal controls or of 16 patients with other liver diseases did so. Non-organ specific autoantibodies, classified as anti-LKM2, were also detectable. These were present in association with tienilic acid associated antibodies: of the 36 patients with presumed tienilic acid hepatotoxicity, 38% had both antibodies, 18% had only anti-LKM2 antibodies and 9% only tienilic acid associated antibodies. These results suggest that this drug reaction is associated with sensitisation to drug altered liver cell antigens and autoantigens. If ticrynafen associated hepatotoxicity is immune mediated, then one possible mechanism is that the drug induced antigens break tolerance, leading to an immune attack on normal liver cell components.

Drug-induced hepatitis associated with anticytoplasmic organelle autoantibodies.

A study from five hepatology units documenting 157 cases of drug-induced hepatitis and a second study from a laboratory of immunology which tested more than 100,000 sera permitted us to establish the frequency of antiorganelle antibodies and their diagnostic value in drug-induced hepatitis. In drug-induced hepatitis caused by a heterogenous group of drugs consisting of ajmaline, aminopterine, isaxonine, isoniazid, perhexiline, phenylbutazone and troleandromycine, antiorganelle antibodies were absent or rare. In drug-induced hepatitis caused by another heterogenous group of drugs, including clometacin, fenofibrate, oxyphenisatin and papaverine, antismooth muscle, antinucleus and antimitochondria antibodies were found in isolation or in different combinations in 70% of cases. From the presence of antismooth muscle antibodies in sera, we could trace 30 cases of clometacin-induced hepatitis. The third group included drug-induced hepatitis with special antibody:iproniazid-induced hepatitis with antimitochondrial antibody 6 and tienilic acid (ticrynafen)-induced hepatitis with antiliver/kidney microsome antibody 2 (anti-LKM2). These two antibodies are rare in routine sera and were absent in patients who received the drug and had no liver damage. From the presence of corresponding antibodies, we detected six cases of iproniazid-induced hepatitis and 67 cases of tienilic acid-induced hepatitis. Antiorganelle antibodies found in high titers disappeared in 2 to 24 months following withdrawal of the offending drug. The fourth group was represented by halothane-induced hepatitis; antiliver/kidney microsome antibody 1 was weak and infrequent. Similarities between drug-induced hepatitis of the second group and lupoïd hepatitis suggest that drugs may reveal this spontaneous disorder.(ABSTRACT TRUNCATED AT 250 WORDS)

[Autoimmunity induced by drugs. Immunological characteristics and etiopathogenic hypotheses]. / Auto-immunité induite par les médicaments. Particularités immunologiques et hypothèses étiopathogéniques.

Drug-induced autoimmune diseases have two immunological peculiarities. Firstly, some autoantibodies are present, which are virtually never seen in spontaneous human diseases and may be regarded as specific. This applies to antimitochondria antibody type 3 (anti M3) in the lupus-like syndrome caused by Venocuran, to antimitochondria antibody type 6 (anti M6) in iproniazide-induced hepatitis, to anti-insulin antibody found after treatment with methimazole, and to anti liver/kidney microsome antibody type 2 (anti LKM2) associated with hepatitis induced by tielinic acid. Secondly, a search for other autoantibodies shows that the immune disorder is much more limited than in spontaneous autoimmune diseases. Thus, contrary to myasthenia and idiopathic autoimmune haemolytic anaemia, we never found autoantibodies specifically directed against the thyroid, the stomach or the adrenal gland during treatment with D-penicillamine and alpha-methyldopa. Only some hypotheses may account for these peculiarities. Cross-reaction between drug and autoantigen may occur, but the fact that the antigen-antibody reaction is not inhibited by the drug or its metabolites does not support this explanation. Much more attractive is the "T-cell bypass" theory, according to which autoreacting suppressor T-cells are circumvented by helper T-cells stimulated by the drug-modified autoantigen. In this case, the autoimmune reaction would indicate to which body substance the drug is bound, thus making it immunostimulant, and not a structural similarity between the drug and the autoantigen.

Vocal cord hematomas complicating anticoagulant therapy.

Described are the cases of two patients who presented with vocal cord hematomas consequent to poor control of anticoagulation. Both patients presented with hoarseness and cough. One required intubation due to respiratory obstruction. Vocal cord hematomas should be considered in patients who present with upper airway symptoms while anticoagulated.

Ticrynafen-associated hepatic injury: analysis of 340 cases.

Ticrynafen, a uricosuric diuretic, was withdrawn from clinical use in the United States in 1980 after having been implicated as the cause of a number of instances of serious hepatic injury. In this report, we analyze 340 cases of ticrynafen-associated hepatic disease reported to the manufacturer from the time of initial marketing until shortly after the drug had been recalled. Jaundice was recorded in 246 of 287 patients with sufficient clinical information, and 25 (10.2%) of these icteric patients died. The high levels of serum aminotransferase and the case fatality rate are consistent with the hepatocellular injury that was evident in all of the histologic material. In three-fourths of the cases available to us for histologic study, the lesion was that of acute hepatocellular injury. In the remaining cases there was evidence of chronic active hepatitis and/or cirrhosis. Comparison of demographic characteristics of the total population exposed to ticrynafen with the subset developing hepatic injury suggests a proportionately higher risk of injury for females over the age of 60 years. The variable and unusually prolonged latent period and lack of reported eosinophilia or rash generally suggest a mechanism other than hypersensitivity. However, the recurrence of hepatic injury in 15 of the 16 patients challenged with the drug and the prominence of eosinophils in hepatic tissue in some of the cases suggests that hypersensitivity may also play a pathogenetic role. Accordingly, there is reason to incriminate both metabolic idiosyncrasy and hypersensitivity in the mechanism of injury.

A new anti-liver-kidney microsome antibody (anti-LKM2) in tienilic acid-induced hepatitis.

The sera of 131 patients with anti-liver-kidney microsome antibodies (anti-LKM) detected between 1973 and 1979 in two different laboratories were re-examined. (1) Eighty-six anti-LKM corresponded to the description given by Rizzetto, Swana & Doniach (1973), with a pattern of fluorescence predominating on the 3rd portion of the proximal tubules (P3). This group comprised 45 cases of idiopathic chronic hepatitis or idiopathic cirrhosis and one case of halothane-induced hepatitis. (2) Forty-five anti-LKM gave a different pattern on male mouse liver and male rat kidney: (a) fluorescence was greater on centrolobular than on periportal hepatocytes; (b) the first and second portions of proximal tubules (P1 and P2) predominated over P3; (c) P1 fluorescence was equally intense as P2 and (d) P3 cells were heterogeneous with one cell out of 20 more positive than the rest. Absorption tests confirmed that the corresponding antigen was also present in the liver microsomal fraction. A retrospective clinical study discovered tienilic acid-induced hepatitis in all cases. We suggest naming this new antibody 'anti-LKM2'.

Multicentre controlled trial of tienilic acid in hyperuricaemic, hypertensive subjects, with intensive monitoring of liver function.

1 Tienilic acid, a diuretic with potent uricosuric properties, has been compared with conventional diuretic therapy, mainly thiazide, in a parallel group (random allocation) multicentre study in hyperuricaemic hypertensives (n = 96). 2 The study was designed to last 1 year but tienilic acid was withdrawn for suspected hepatotoxicity before the study was complete. Mean follow-up was 8.5 (range 1-12) months and the mean daily dose of tienilic acid was 278 (range 125-500 mg). 3 Blood pressure levels on tienilic acid and on conventional diuretics were similar. 4 Serum potassium and sodium levels were also similar in the two groups, but serum urea and creatinine rose somewhat more in the tienilic acid group. 5 Serum uric acid fell dramatically in the patients on tienilic acid from 0.56 to 0.32 mmol/l, but did not alter significantly in the control group. 6 There were no problems with renal failure or urate deposition probably because patients were instructed to drink plenty of fluid when tienilic acid was started, because initial dose was low and because all previous diuretics were stopped for 3 days before tienilic acid was started. 7 Mean liver function indices did not rise in either group. Mild elevation in liver enzymes occurred in one control patient and one patient on tienilic acid; the latter drug was stopped and the values returned to normal. 8 The general incidence of side-effects was low. 9 Our impression was that tienilic acid was a useful drug. Whether it could have been used safely with monitoring of liver function will not now be known.

Hepatotoxicity associated with ticrynafen--a uricosuric diuretic.

Herein, we describe a patient who had ticrynafen-associated acute hepatitis. This complication has been reported in 57 patients (52 to the manufacturer, four to the Food and Drug Administration, and the current patient) in this country. The mechanism of hepatocellular injury is not known, but from the data to date it seems most likely to result from a hypersensitivity reaction rather than a direct hepatotoxic effect. The histopathological findings are difficult to differentiate from acute viral hepatitis. Removal of this drug from the market resulted from the prompt action of physicians in reporting the complications to the manufacturer and the rapid response of the pharmaceutical firm once the risks became known.