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See article on page 435
In this issue Lenzi et al (see page435) provide convincing evidence that non-organ specific autoantibodies (NOSA) are highly prevalent in subjects exposed to hepatitis C virus (HCV), and their presence is associated with clinical and biochemical signs of liver disease. The observation that autoimmunity and HCV infection are associated is not new: several hundred hits are returned when Medline is interrogated using HCV and autoimmune, including autoantibodies, as coordinates. Invariably, however, the infected individuals are patients referred to hospital and who have undergone some form of selection, primarily dictated by the severity of their underlying disease. The population studied by Lenziet al makes their paper unique.
During the screening of an unselected population of 7000 (the Dionysos study1) for indicators of liver disease, 226 were positive for HCV markers. Lenzi and colleagues found NOSA in 25% of these subjects, a prevalence much higher than that of the 226 demographically matched uninfected individuals and of the 78 HBsAg positive subjects from the Dionysos study. Within the HCV positive group, the presence of NOSA was significantly associated with clinical and biochemical evidence of liver disease.
The already high NOSA prevalence of 25% is certainly an underestimate as the serum samples were tested at a dilution of 1 in 40, and not at the conventional screening dilution of 1 in 10. Thus in a study investigating NOSA in a nosocomial paediatric HCV series, Gregorio and colleagues2 found that the autoantibody prevalence more than doubled (from 27 to 65%) if the samples were tested at a 1 in 10 dilution instead of 1 in 20. What does the presence of NOSA in HCV infection mean? Do they carry a pathogenic or a clinical message?
The fact that in an unselected HCV positive population the presence of NOSA is associated with clinical manifestations of chronic liver disease and with high activities of alanine aminotransferase indicates incontrovertibly that there is a connection between autoantibodies and liver damage. Are NOSA also the cause of the damage? I concur with Lenzi et al that currently there are insufficient data to provide an answer. Does measurement of NOSA add anything to the information obtained through the conventional assessment of liver function? The number of reports describing adverse reactions to interferon treatment in autoantibody positive HCV patients is increasing steadily2-4 and invariably the autoantibody associated with these reactions is liver/kidney microsomal antibody type 1 (LKM-1). In addition to being the hallmark of the eponymous form of autoimmune hepatitis, LKM-1 is also present in up to 10% of chronically infected HCV patients. HCV/LKM-1 positive patients on interferon experience increases in aminotransferase activities,2-4 occasionally of such magnitude to warrant suspension of treatment,2 4 or may even, rarely, progress to LKM-1 positive autoimmune hepatitis. The amino acid sequence similarities between cytochrome P4502D6, the molecular target of LKM-1, and HCV polyprotein suggests that a process of molecular mimicry and crossreactive immunity is the link between viral and autoimmune condition. Whether, and at what stage, interferon treatment should be replaced by immunosuppression in LKM-1/HCV positive patients5 is still a matter of conjecture.
From the recent literature it is clear that LKM-1 should be measured in all patients with HCV, especially those undergoing interferon treatment, and this should be done at a dilution of 1 in 10. In the study by Gregorio and colleagues2 treatment with interferon had to be suspended in four patients because of a notable rise in aminotransferse activities: three were LKM-1 positive, two at a titre of 1/10. In that series the only other LKM-1 positive patient taking interferon had normal aminotransferases. LKM-1 seems to act as a danger signal whatever its titre. Interestingly, Cassani and colleagues6 have shown that the presence of LKM-1 in HCV infection is associated with a greater histological severity of liver disease and the recent localisation of CYP2D6 to the liver cell membrane—an ideal target for an autoantibody mediated attack—may explain why LKM-1 is associated with liver damage.
Methodologically, it should be noted that LKM-1 is notoriously difficult to identify and is frequently mistaken for antimitochondrial antibody in view of their similar immunofluorescence patterns on rodent renal tubules.7 This problem should hopefully be overcome in the near future when objective assays based on molecularly defined targets (i.e. CYP2D6) will replace the subjective immunofluorescence testing. Such assays are already available for research purposes,7-9 and commercial ones are being marketed and their performance assessed.
Autoimmunity in HCV infection is not limited to autoantibody seropositivity but embraces the full spectrum of textbook autoimmune disorders,10 ranging from the non-organ specific cryoglobulinaemia to the exquisitely organ specific autoimmune thyroiditis and includes such conditions as rheumatoid arthritis, Sjögren’s syndrome, glomerulonephritis, lichen planus, periarteritis nodosa, and type 1 diabetes. At the opposite extreme of HCV associated autoimmune disease, the pathogenic mechanisms differ. Thus in cryoglobulinaemia and HCV associated glomerulonephritis it is the formation of immune complexes that causes pathology. Hepatitis C viral constituents are integral components of the immune complex and interferon induced control of the viral infection is associated with an improvement in cryoglobulinaemia and glomerulonephritis. Interferon is also involved at the other end of the spectrum, but this time in unmasking subclinical or inducing de novo autoimmune thyroiditis. Appropriately, it is further work by Lenzi et al, only published in abstract form, that shows, firstly, the much more frequent appearance of thyroiditis in HCV patients who receive interferon if they also are positive for LKM-1 and, secondly, that the possession of the “autoimmune” haplotype HLA B8, DR3 is key to the autoimmune manifestations of HCV infection.
See article on page 435
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