Case reports

Case 1—A 23 year old female student complained of nausea, malaise, and jaundice one month after starting pyritinol 600 mg a day for “memory improvement.” She had also been taking paracetamol with codeine sporadically for some years because of headache. Discontinuation of pyritinol led to rapid clinical improvement and to normalisation of liver function five months later.

Case 2—An 18 year old female student was prescribed nitrofurantoin 400 mg a day for cystitis and pyritinol 600 mg a day for “memory improvement.” Five days later she was admitted to hospital with pruritus and jaundice of the skin and sclera. One year earlier she had been taking pyritinol at the same dose for 20 days with no known adverse effects. Improvement of her condition was observed after she stopped taking pyritinol, and liver function returned to normal five months later.

Case 3—A 27 year old woman presented at the out-patient clinic with jaundice and abnormal liver function tests. She had been taking oral contraceptives for three years and had started taking pyritinol 400 mg a day 25 days before presenting at the clinic. Liver function returned to normal more than six months after she stopped taking pyritinol.

Case 4—A 21 year old woman was admitted to hospital with malaise, vomiting, and fever of three days' duration and abnormal results for liver function tests. She had been taking pyritinol 600 mg a day for a month and was also taking nimesulide (one or two pills a month) for dysmenorrhoea. After she stopped taking pyritinol, liver function improved but did not return to normal for nine months.

Case 5—Ten days after starting to take pyritinol 600 mg a day, a 41 year old man was admitted to hospital with nausea, vomiting, jaundice, and abnormal liver function. Complete clinical and biochemical normalisation was seen two months after he stopped taking the drug.

Case 6—A 24 year old woman had nausea, vomiting, abdominal pain, fever, and jaundice 14 days after starting to take pyritinol 400 mg a day for “memory improvement.” She had also been taking erythromycin 500 mg every six hours during the previous eight days for a sore throat. Liver function returned to normal within a month. When she inadvertently took pyritinol again six months later, she developed the same symptoms and blood tests gave similar results.

Investigations

The table summarises the main features in these six patients, who were referred to our unit in the past 10 years. The pattern of the liver injury was clearly cholestatic, with concentrations of bilirubin exceeding 342 μmol/l in four out of the six patients. The kinetics of the enzymatic changes showed that the highest level of transaminases occurred within the first two weeks, while peaks in alkaline phosphatase and γ-glutamyl transpeptidase were observed two to three months later in most cases. The time taken for normalisation of liver enzymes exceeded three months in four cases, and admission to hospital was required in four. Extrahepatic obstruction of the biliary tree was excluded by liver ultrasonography, and viral hepatitis (A, B, and C) by serology. Liver biopsy was performed in four cases and showed mild inflammatory infiltrate of polymorphonuclear cells, lymphocytes, and sometimes eosinophils with important canalicular and parenchymal cholestasis and mild focal hepatocellular necrosis.

Table 1

Clinical and epidemiological features of the six patients

	Case 1	Case 2	Case 3	Case 4	Case 5	Case 6
Sex	Female	Female	Female	Female	Male	Female
Age (years)	23	18	27	21	41	24
Duration of pyritinol use before first symptoms (days)	28	5	25	34	10	14
Previously used pyritinol (and how long ago)	No	12 months	No	No	Not known	No
Clinical symptoms:
Nausea or vomiting, or both	Yes	No	Yes	Yes	Yes	Yes
Jaundice	Yes	Yes	Yes	Yes	Yes	Yes
Pruritus	No	Yes	Yes	Yes	Yes	No
Fever	No	No	Yes	Yes	No	Yes
Admitted to hospital	Yes	Yes	No	Yes	Yes	No
Time between stopping pyritinol and normalisation of liver function (days)	157	156	193	270	64	19
Other drugs taken at same time	Paracetamol	Nitrofurantoin	Desogestrel, ethynilestradiol	Nimesulide	None	Piracetam, halazepam, erythromycin
Score on clinical diagnostic scale (positive diagnosis)8	14 (probable)	14 (probable)	14 (probable)	12 (possible)	14 (probable)	19 (definite)*
Laboratory features† :
Aspartate aminotransferase	2	4	16	4	9	5
Alanine aminotransferase	4	12	43	6	20	7
Alkaline phosphatase	4	5	7	12	2	2
γ-glutamyl transpeptidase	11	7	8	22	11	3
Total bilirubin	12	6	10	30	23	5
Pattern of liver injury‡	Cholestatic	Cholestatic	Cholestatic	Cholestatic	Mixed	Cholestatic
Liver ultrasonography	Normal	Normal	Hepatomegaly	Normal	Hepatomegaly	Hepatomegaly
Liver biopsy	Yes	No	Yes	Yes	Yes	No
Autoantibodies	Negative	Mitochondrial	Negative	Negative	Negative	Not done

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^*Non-intentional positive rechallenge.

^†Values are expressed in multiples of the upper limits of normal.

^‡Liver injury defined according to the ratio of maximum transaminase to alkaline phosphatase (Council for International Organizations of Medical Sciences).

The mechanism for this putative hepatotoxicity of pyritinol is a non-dose dependent one involving metabolic idiosyncrasy or immunological hypersensitivity.² To investigate this latter possibility we performed in vitro lymphocyte proliferation assays to the suspected drugs as previously described.³ Lymphocyte reactivity to pyritinol was shown in all cases investigated (cases 1-5) (fig 1). Maximum stimulation indices were much higher than those previously reported in a large series of patients with drug allergic hepatitis associated with a variety of drugs investigated in our laboratory.³ Importantly, six healthy controls and three other controls (a female patient who had previously taken pyritinol without adverse effects, a male patient with alcoholic hepatitis with cirrhosis, and a patient with chronic hepatitis B) all showed no lymphocyte responses to pyritinol. In three of our cases, we did sequential studies at 36 months (case 3), 24 and 27 months (case 4), and 3 and 12 months (case 5). A progressive decline in the stimulation index was observed in all cases, although the indices remained clearly above the level considered to be normal (that is, 2). In three cases, we also did proliferation assays to drugs other than pyritinol (nitrofurantoin, erythromycin, and paracetamol with codeine). No reactivity to these drugs was observed either in the patients or the controls.

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Fig 1

Lymphocyte proliferative responses to pyritinol. Drug stimulation indices in five patients and nine controls assessed by ³H thymidine incorporation after a pulse of 1 microcurie in the previous six hours of the culture and counted in a gaseous scintillation β counter. Values ≤2 are considered to be normal

Figure 2 shows the characterisation of the T cell subsets contributing to the proliferative response, as described in previous work.⁴

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Fig 2

Characterisation of the T cell subsets contributing to the proliferative response in a patient and in a healthy control. Cells were intracellularly stained with antibromodeoxyuridine (BrdU) monoclonal antibody after incubation with BrdU during the previous 24 hours of the culture. Numbers in the upper right quadrant represent the percentage of T cells that are CD4+ and BrdU+, and those in the lower right quadrant represent the percentage of T cells that are CD4- (CD8+) and BrdU+

Discussion

Although pyritinol has been used in Europe for more than 20 years, only a few cases of drug induced hepatitis have been published.^2,5-7 Interestingly, the doctors who referred the patients to our unit did not consider pyritinol to be a likely cause of hepatitis, so it is possible that this non-dose dependent drug hepatotoxicity may have been substantially under-reported during these years.

These six cases fulfil the usual criteria for diagnosis of drug induced liver injury, namely a temporal relation and the exclusion of alternative causes. Moreover, when we used a semiquantitative diagnostic scale, the results showed high levels of probability for drug induced liver injury.⁸ In four patients, immunological investigation showed a marked drug specific in vitro lymphocyte proliferative response, and CD4+ T lymphocytes were identified as the predominant drug specific lymphocytes. What is more striking is that the degree of T lymphocyte reactivity to the drug is much higher than the one usually observed in drug hypersensitivity hepatitis.³ Noteworthy, in addition to its putative effect on the memory and intellectual concentration, pyritinol has been shown to have favourable effects on rheumatoid arthritis¹ similar to the ones described for penicillamine, which is also a drug with an active sulfhydryl group.² Interestingly, penicillamine is typically responsible for several adverse reactions of immunological nature, such as immune complex nephropathy, autoimmune-like skin disorders, leucopoenia, and thrombocytopoenia.²

Clinically, the most striking feature in these patients was the severe and prolonged nature of the cholestasis that required admission to hospital in four previously healthy young individuals. The seriousness of this adverse reaction contrasts with the relatively small clinical importance of the problem that led to its prescription. Therefore, the cases reported here justify a reassessment of the risk and benefit of pyritinol.

Notes

References