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Primary biliary cirrhosis and primary sclerosing cholangitis are of infectious origin!
  1. T WADSTRÖM,
  2. Å LJUNGH
  1. Department of Medical Microbiology, Dermatology, and Infection
  2. Lund University, Lund, Sweden
  3. Department of Pathology, Gothenburg University
  4. Gothenburg, Sweden
  1. Professor T Wadström, Department of Medical Microbiology, Dermatology, and Infection, Sölvegatan 23, S-223 62 Lund, Sweden.torkel.wadstrom{at}mmb.lu.se
  1. R WILLÉN
  1. Department of Medical Microbiology, Dermatology, and Infection
  2. Lund University, Lund, Sweden
  3. Department of Pathology, Gothenburg University
  4. Gothenburg, Sweden
  1. Professor T Wadström, Department of Medical Microbiology, Dermatology, and Infection, Sölvegatan 23, S-223 62 Lund, Sweden.torkel.wadstrom{at}mmb.lu.se

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Editor,—Haydon and Neuberger (

) elegantly summarised the possibility that specific bacterial and viral pathogens may trigger early bile duct damage in the pathogenesis of primary biliary cirrhosis (PBC). It was concluded that a chronic infection, probably of viral origin, was driving an immune response with antimitochondrial and other autoantibodies enhancing the tissue damage in later stages of PBC. Besides detection of antibodies specific for mycobacterial antigens, such as the 55 kDa and 65–75 kDa antigens of M gordonae, in PBC the authors emphasised, based on studies by Mason and colleagues1 and others, that immune responses detected by immunoblotting to retroviral proteins with homology to HIV p24 and other retroviral antigens, such as HIAP, are common in PBC, in primary sclerosing cholangitis (PSC), and in Sjögren's disease.

Recent studies propose a possible role forHelicobacter pylori in Sjögren's disease.2 3 Contradictory data have appeared more recently based on a possible high relevance of anti-Helicobacter antibodies in saliva and sera of these patients.4 Most recently, Foxet al found that patients with chronic cholangitis in Chile were commonly infected by bile tolerant newHelicobacter species, previously only detected in chronic liver disease in mice and other rodents, such asH hepaticus and H bilis.5 6Nilsson et al first reported on bile and liver samples positive for Helicobacter DNA by polymerase chain reaction (PCR) in nearly half of 24 patients with PBC and PSC, and later immunoblot analyses of patients with these and other chronic liver diseases.7 8 Conflicting negative PCR results on bile were reported by Tanaka and colleagues9while studies in Taiwan and Korea regularly seem to detectHelicobacter in human bile in chronic cholestatic bile tract diseases.10 Recently, Bulajicet al reported on a strong correlation between bile duct malignancies and the presence ofH pylori DNA in bile.11 Since bile acids, intestinal acids, and highly charged mucin components are strong inhibitors of the PCR reaction, all of these studies have to be interpreted with caution until methods to safely remove or neutralise the effect of these inhibitors in bile, bile tract, and liver biopsies have been developed. We recently reported that PCR analyses of formalin fixed paraffin embedded liver, pancreas, and bile tree samples may be a safe way to produce reproducible PCR analyses ofHelicobacter and other potential bacterial invaders of the human bile tract.12 Interestingly, preliminary findings in our study on experimentally infected laboratory animals with various Helicobacter strains suggest that these may be translocated from the stomach and the intestine to the liver, and we speculate that this may involve uptake and intracellular survival in macrophages and other professional phagocytes activated in the stomach during mostHelicobacter infections (T Wadströmet al, unpublished observations). The pathogenesis may then be similar to infection of the bile tree with bile tolerant and bile adapted strains ofSalmonella typhi and other enteric organisms, known to invade the bile tree in chronic infections and in carriers, and to increase the risk of later development of primary biliary carcinoma, a disease associated with PSC in humans. Several laboratories are now focusing on development of a mouse model to study bile tract infections with these organisms. Interestingly, injection of porcine bile into the murine bile tree causes immune reactions with tissue damage, similar to PBC. It is tempting to speculate that variousHelicobacter species and possibly other “new” bile and liver pathogens in mice, other rodents, and dogs may also invade the human bile tree and liver.6 Further development of quantitative PCR (real time PCR and related methods) as well as immunoblot and immunohistochemistry staining methods for bile tree and liver biopsies will tell us if the report on approximately 50% Helicobacter infection in Swedish patients can be confirmed in studies using “backing up” diagnostic procedures. Recently, we have demonstrated morphologically intact spiral and coccoid-like forms of Helicobacter pylori by immunohistopathology and transmission electron microscopy (TEM) in a patient with PSC (fig 1A, B).

Figure 1

(A) Cluster of 3 μm Helicobacter species in primary sclerosing cholangitis damaged liver (arrows). Immunohistopathology with specific antibodies raised against H pylori.8Magnification ×1250. (B) Helicobacter species in liver tissue portal zone, demonstrating white energy spots, poly- P granulae (arrows). Transmission electron microscopy, magnification ×8800.

FUTURE PERSPECTIVES

The strong link between PSC and ulcerative colitis with associated malignancies in the colon and liver emphasises the importance of continuing analyses of Helicobacter and other new candidates which may trigger early development of the disease, and to consider antibiotic treatment studies in animal models. Isolation of a novel Helicobacter species from cotton top tamarins with a high incidence of ulcerative colitis-like disease supports this.13 The prominent early immune responses to Helicobacter antigens in severely ill PSC and PBC patients8 (T Wadströmet al, unpublished observations) may imply that they will not respond to antibiotic therapy forHelicobacter and other pathogens when these patients develop clinical disease. However, development of sensitive immunodiagnostic tests may serve as a screening tool and permit early diagnosis of Helicobacter associated bile tree and liver diseases in human patients as well as in laboratory animals.

We would certainly like to add PBC and PSC to the list of infectious diseases,14 and it seems likely that in a certain proportion of patients, H pylori and otherHelicobacter species may play a role in the pathogenesis.

Acknowledgments

Our own studies were supported by the Swedish Medical Research Council (16X-04723).

References

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