Hepatotoxicity of 6-mercaptopurine (6-MP) and Azathioprine (AZA) in adult IBD patients

OBJECTIVE: 6-Mercaptopurine (6-MP) and azathioprine (AZA) are effective in the treatment of IBD; however, drug-induced hepatotoxicity has been reported in 10-15% of pediatric patients and has been associated with the 6-MP metabolite 6-methylmercaptopurine ribonucleotide (6-MMPR) at levels >5,700 pmol/8 x 10(8) RBC. The aim of this study was to assess the prevalence of 6-MP/AZA hepatotoxicity and its correlation with serum 6-MMPR levels in adult IBD patients. METHODS: Aminotransferases, bilirubin, and 6-MP metabolite levels were measured in 173 adult IBD patients treated with 6-MP or AZA from November 2002 to December 2003. Hepatotoxicity was defined as AST and/or ALT >2x upper limit of normal or cholestasis. RESULTS: Eight patients (4.6%) met criteria for a diagnosis of 6-MP/AZA-induced hepatotoxicity. The mean 6-MMPR level in these 8 patients was 10,537 pmol/8 x 10(8) RBC versus 3,452 pmol/8 x 10(8) RBC in the nonhepatotoxic group (P < 0.001). Risk of hepatotoxicity above the third quartile (6-MMPR > 5,300) was 5 times that below the third quartile (11.4%vs 2.3%, P < 0.05); however, nearly 90% of all patients with 6-MMPR > 5,300 pmol/8 x 10(8) RBC had no hepatotoxicity, while almost 40% of subjects with hepatotoxicity had 6-MMPR levels below this cutoff. CONCLUSIONS: 6-MP/AZA-induced hepatotoxicity is uncommon in the adult population. Although hepatotoxicity is associated with higher mean 6-MMPR levels, the sensitivity and specificity of 6-MMPR for drug-induced hepatotoxicity was poor. Monitoring liver tests in patients on 6-MP/AZA is suggested, and dose reduction or cessation of 6-MP/AZA, even with high 6-MMPR levels, should be reserved for patients with elevated aminotransferases.     

Serum interleukin-6 (IL-6) and interleukin-4 (IL-4) in patients with multiple myeloma (MM)

In this study we determined, in patients with multiple myeloma (MM), serum levels of IL-4 and IL-6 at diagnosis and during the course of the disease, seeking a correlation with disease activity and prognosis. We studied 54 MM patients, 41 of whom responded to chemotherapy whilst 11 were resistant. At diagnosis, IL-6 was increased in 66% of patients (median 35.5 pg/ml) whereas IL-4 was low (median 4 pg/ml) in 75% of patients. In responding patients, IL-4 increased in remission (median 25 pg/ml), whereas IL-6 decreased (median 4 pg/ml). In chemotherapy-resistant patients, IL-6 and IL-4 values remained stable during the course of the disease.     

Fifth (human parvovirus) and sixth (herpesvirus 6) diseases

Fifth (erythema infectiosum) and sixth (roseola infantum) diseases are common rash illnesses of childhood that have long been recognized in clinical medicine. The discovery of the viruses that cause these illnesses has revealed relationships with other syndromes. Primary infection with the agent of erythema infectiosum, human parvovirus B19, is associated with transient aplastic crisis in hemolytic anemia, arthropathy in adults, chronic anemia in immunocompromised patients, and nonimmune fetal hydrops in pregnant women. The only documented illness associated with primary infection with human herpesvirus 6 is roseola or exanthema subitum in young children. However, reactivated infections in adults and immunocompromised patients may be associated with serious illness such as encephalitis/encephalopathy, and bone marrow suppression leading to transplant failure or graft-versus-host disease. Diagnostic studies for both viruses have been limited, although reliable serologic tests for human parvovirus B19 have recently become available. Diagnosis of human herpesvirus 6 remains problematic, because current tests cannot differentiate primary from reactivated disease. This is more of an issue for the putative relationship of these viruses to more chronic conditions, such as rheumatologic disease for human parvovirus B19 and multiple sclerosis for human herpesvirus 6. The relationship between the viruses and these conditions remains controversial, and better diagnostic tests and further information on viral pathogenesis for both viruses are required in order to make a reliable judgment in this regard.     

Robin Goodfellow (43-6)

As regular readers are aware, Robin is a great one for new things,so he was delighted to find that nerve roots are too. A letterhe dictated has been transformed to read that the medial sideof the calf is innovated by S1. However he is not so keen onpolitical innovation, particularly when it is done for expediency.The UK government's Patient Choice initiative has been developedto cut surgical waiting lists. The gist of the scheme is thatpatients whose wait may be long can be offered alternative venuesfor their operation. Apart from reducing surgeons to technicians(given the impracticality of sensible follow-up and the likelihoodthat someone distant may have to deal with complications withoutknowing details of what     

Robin Goodfellow (42-6)

It does, of course, take a time to know whether a transplantedshrub will take. Robin likes getting his hands dirty, but itis hard work. Every hole dug produces a pile of rocks; it isunderstandable that a restrictive covenant on the house forbidsquarrying, as Robin has so far dug up enough to build a smallchurch. It is quite relaxing to sit down and write a column... The osteoporosis industry might take a knock from a paper fromthe Oxford stable of Richard Doll (Trivedi, Doll and Khaw, Br Med J 2003;326:469–72).[Abstract/Free Full Text] Their 5-yr study of the over-65sshows that Vitamin     

Evaluation of inflammatory markers interleukin-6 (IL-6) and matrix metalloproteinase-9 (MMP-9) in asthma

Introduction: Even though IL-6 and MMP-9 are associated with airway inflammation in asthma, there is paucity of data in Indian population. Objective: To determine the levels of IL-6 and MMP-9 in the serum of patients suffering from asthma, and correlate with (a) disease severity, as per GINA guidelines; (b) clinical phenotypes; and (c) response to treatment. Methodology: The levels of IL-6 and MMP-9 were compared between moderate persistent asthma (n = 25), severe persistent asthma (n = 25) and normal controls (n = 30). IL-6 and MMP-9 were measured by ELISA (R&D Systems Inc., USA and Canada) and compared between controls and asthmatics and between groups of different asthma severity, clinical variables, spirometry, and allergen sensitization. Spirometry was repeated after 2 months of ICS+LABA to assess response to treatment in relation to baseline IL-6 and MMP-9 levels. Results: We observed a significant difference in both IL-6 and MMP-9 levels among asthmatics versus controls (p < 0.001), moderate versus severe persistent asthma (p < 0.001). A significant negative correlation was observed between MMP-9 and pre-bronchodilator FEV₁ and FVC, but not with IL-6. There was no association between IL-6 and MMP-9 with asthma duration, total IgE, AEC, number of allergens sensitized and degree of sensitization. No significant correlation (p > 0.5) was observed with IL-6 and MMP-9 levels and FEV₁ improvement after 2 months of ICS+LABA. Conclusion: Higher levels of IL-6 and MMP-9 were observed in asthmatics as compared to controls and in severe persistent asthma as compared to moderate persistent asthma, higher levels of MMP-9 was associated with lower lung functions.