Immune allergic drug reactions

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Drug-induced hepatitis is rare during therapeutic dosage regimens. Although of unknown aetiology, several features suggest an immunological basis including: (i) frequent symptoms of hypersensitivity, with fever, rash and eosinophilia; (ii) the presence of specific autoantibodies; (iii) liver parenchymal lesions, usually including a mixed cellular infiltrate; and (iv) a more rapid and more severe response following rechallenge. Several hundred commonly prescribed drugs are associated with liver toxicity. Berson et al. [7], reviewing 71 patients treated with 41 different agents, identified no single unifying HLA association. Although none of the individual study groups was of sufficient size for HLA association studies (the maximum was seven patients), a number of interesting observations were reported for individual drugs (Table 16.1), including associations of reactions to tricyclic antidepressants with HLA A11, diclofenac with A11 and chlorpromazine with DR6. In addition, patients with B17 seemed to be more likely to develop severe and prolonged cholestasis. Earlier studies also suffered from small numbers, but associations have been reported for HLA A11 with halothane hepatitis [8], DR6 and DR2 with nitrofurantoin [9], and B8 with clometacin toxicity [10] (Table 16.2). Collectively, these data represent interesting preliminary observations on which to base future hypotheses.

There have been two recent independent studies of HLA associations in co-amoxiclav-associated cholestasis [11, 12]. Co-amoxiclav (amoxicillin-clavulanate potassium) extended the antibacterial spectrum of amoxicillin when introduced in the UK in 1981 and has become one of the most frequently prescribed antibiotics. Hepatotoxicity is uncommon, is mostly cholestatic and rarely fatal. It is associated with infiltration of the biliary epithelium by various immunocytes including neutrophils, eosinophils and macrophages and with focal injury to interlobular bile ducts. Both reports cite an elevated frequency of the DRB1*1501-DQB1*0602 hap-lotype. In the first study from Belgium [11], 57% of the 35 patients tested had this haplotype and, in the second study from Scotland [12], 70% of 20 compared with 11% and 20% (respectively) of matched 'healthy' controls. The findings suggest a highly significant, 6.5-fold increased likelihood of cholestasis in patients with DRB1*1501-DQB1*0602 treated with co-amoxiclav. The second study also reported an increased frequency of patients (35%) who were homozygous for this haplotype (odds ratio [OR] = 8.7).

The same extended DRB1*1501-DQB1*0602 haplotype has been associated with halothane hepatitis in Japan [15], with liver disease in cystic fibrosis [13] (see below), with primary sclerosing cholangitis, an autoimmune cholestatic liver disease [16] and with a high incidence of allergies, particularly ragweed pollen hypersensitivity [17]. Interestingly, this haplotype may encode resistance to type 1

Table 16.1. Summary of the principal HLA associations with drug-induced idiosyncratic hepatitis

Drug

n

Antigen % patients % controls

Reference

Tricyclic antidepressants

12

A11 50

12

7

Diclofenac

4

A11 75

12

7

29

Class II negative -

-

Halothane

17

A11 29

11

8

DR2 n/a

n/a

Chloropromazine

5

DR6 80

22

7

Nitrofurantoin

9

DR6 56

29

9

DR2 56

29

Clometacin

10

B8 70

16

10

Co-amoxiclav

35

DRB1*1501 57

10

11

20

DRB1*1501 70

20

12

Table 16.2. Role of HLA in determining susceptibility to liver disease in the single gene

disorders cystic fibrosis (F) and a-1-antitrypsin deficiency (

a-1-AU)

Percentage

CF

n B7

DR15

DQ6

With liver disease

175 33

44

67a>b

No liver disease

76 21

26

33

Controls

141 23

29

29

a-1-ATi

n DR3

DR4

With liver disease

75 47c

39

No liver disease

28 18

61d

Controls

100 23

36

In CF, a p<0.001, OR = 5.0 for liver disease versus controls and b p<0.005, OR = 4.1 for liver disease versus no liver disease.

In a-1-ATi, cp<0.001, OR = 2.92 for liver disease versus controls and dp<0.02, OR = 2.75 for no liver disease versus controls.

Source: Based on Duthie et al. [13] and Doherty et al. [14].

autoimmune hepatitis [18]. The debate continues as to whether the susceptibility allele is DRB1*1501 itself or a linked gene such as HLA A3, HLA B7, MICA*008, TNFA*2 or the distantly linked gene mutation C282Y (responsible for the iron storage disease, haemochromatosis [19]). Finally, there is some evidence that T-cell recognition of amoxicillin is DR restricted but may not require antigen processing [20].

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