Page 1061 - Clinical Immunology_ Principles and Practice ( PDFDrive )

1024 Part seven Organ-Specific Inflammatory Disease

PRIMARY BILIARY CHOLANGITIS more frequent in PBC than in controls, with E. coli being the
main etiological agent. The mechanisms linking infections and
Nomenclature autoimmune biliary tract damage are suspected to involve
Recently the nomenclature for primary biliary cirrhosis has been molecular mimicry. Besides E. coli, a number of other bacteria
shifted toward primary biliary cholangitis (PBC) to correct the have been examined as cross-reactive agents in PBC, including
inaccurate description and remove the cirrhosis stigma as well Proteus mirabilis, Klebsiella pneumoniae, Staphylococcus aureus,
as all the misunderstandings, disadvantages, and discriminations Neisseria meningitidis, Salmonella minnesota, Mycobacterium
emanating from this misnomer. This change was necessary after gordonae, and Trypanosoma brucei. Novosphingobium aromaticiv-
the dramatic improvement in PBC diagnosis, prognosis, and orans, a ubiquitous xenobiotic-metabolizing gram-negative
treatment. Currently, an early diagnosis of PBC can be established bacterium, has been proposed to be the ideal candidate for PBC
with the more accurate measurements of markers of cholestasis development because it contains proteins with the highest degree
and with improvement in the detection of the classic serological of homology with the major epitope of PDC-E2 while having
hallmark, antimitochondrial antibodies (AMAs). In parallel, the ability to metabolize organic compounds and estrogens.
treatment was improved with the introduction of orthotopic Moreover, N. aromaticivorans can elicit antibody reactivity in
liver transplantation and ursodeoxycholic acid (UDCA, 13–15 mg/ PBC patients but not in controls. Regarding viral infections, a
kg daily) therapy. At present, two of three patients diagnosed novel human beta-retrovirus was found in perihepatic lymph
with primary biliary cirrhosis and treated with UDCA have an nodes and other biological samples from patients with PBC;
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expected survival equal to that of the general population, and however, the data have remained inconclusive. Xenobiotics are
only a minority will ever develop cirrhosis. 16 foreign compounds that may trigger an autoimmune response
to self-proteins, which may modify their molecular structures
Epidemiology or complex to self or nonself proteins to generate neoantigens.
PBC is a chronic autoimmune cholestatic disease characterized In this view, it was shown that 2-nonynoic acid, an organic
by high-titer serum AMA and immune-mediated destruction compound found in nail polish, was able to elicit AMA production
1
of the small- and medium-sized intrahepatic bile ducts. It affects in patients with PBC once they were attached to the major
women more frequently, with a female:male ratio of 9 : 1; the mitochondrial epitope backbone. 25
average age at diagnosis is within the fifth and sixth decades of The complex pathogenesis of PBC, however, is not fully
life. Geographically, it presents with widely variable prevalence; explained by genetics and environmental factors; as suggested
the highest rate has been described in Minnesota, with a point for most other autoimmune diseases, epigenetic modifications
prevalence of 402 per million in the general population. 17,18 could represent the link between genetic and environmental
factors influencing the onset and evolution of PBC. Epigenetic
Pathogenesis dysregulation results in the overexpression of certain genes in
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As with essentially every autoimmune disease, genetics and several key immune cells. However, conclusive data implicating
environmental factors interact to lead to PBC. Genetic factors epigenetic modifications in the pathogenesis of PBC are not yet
play a significant role in PBC susceptibility, as suggested by the available.
fact that it is more frequent in relatives of affected individuals;
the term “familial PBC” has been coined to indicate families that Clinical Features and Diagnosis
have more than one case. In our experience, 6% of cases have a In the early phase of disease, symptoms of PBC are mainly
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first-degree relative that is also affected, while AMA may be fatigue and pruritus, while physical findings may include skin
positive in first-degree relatives and offspring of patients with hyperpigmentation, hepatosplenomegaly, and (rarely) xanthe-
PBC without any sign of disease, thus indirectly suggesting the lasmas. End-stage symptoms are indistinguishable from those
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existence of a strong genetic predisposition. More importantly, of other types of liver cirrhosis and include ascites, jaundice,
the concordance rate observed among monozygotic twins for hepatic encephalopathy, and upper digestive bleeding. Fatigue is a
PBC is 63%, among the highest reported in autoimmunity, nonspecific symptom present in 70% of PBC patients and is often
reinforcing the idea that genetic risk factors play an important overlooked, particularly in middle-aged women. The severity of
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role. As for other autoimmune disorders, genetic factors are fatigue is independent of the stage of PBC or its other features
not limited to a single gene but to a complex multigene trait. (pruritus or severe cholestasis), and it appears not to depend on
The relevance of the multifactorial genetic basis in PBC has been psychiatric factors. Pruritus is similarly frequent, being present
reinforced by recent observations including the high concordance in 70% of patients with PBC and jaundice. Pruritus might long
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rate among monozygotic (identical) twins as well as by reports precede jaundice onset and typically worsens at night, after contact
that lymphocytes from women with PBC preferentially use one with wool, or in warm climates. Portal hypertension is frequently
of their X chromosomes, rather than the usual random X chromo- found in patients with PBC and, importantly, does not imply
some inactivation observed in healthy women. 22,23 PBC has been the presence of liver cirrhosis. Over half of untreated patients
associated with the HLA-DRB1*08 allele but also with two eventually develop portal hypertension over a 4-year period.
protective alleles, HLA-DRB1*11 and -DRB1*13. Polymorphisms Prevention and treatment for PBC-associated portal hypertension
in HLA class II loci were confirmed to play a key role by GWAS. are the same as for other chronic liver diseases. Metabolic bone
Notably, this study demonstrated that genes coding for disease is present in PBC when comparing sex- and age-matched
interleukin-12 and its receptor also confer risk for PBC. 24 healthy individuals. Hyperlipidemia is common in up to 85% of
However, it can be hypothesized that other factors may patients with PBC; both elevated serum cholesterol and triglyceride
contribute to genetics as complementary modes of pathogenetic levels are encountered. Interestingly, however, such alterations
import, including epigenetics, exposure to environmental factors, are not accompanied by a proportionally increased incidence
etc. Infections and xenobiotics play a key role in increasing the of cardiovascular events or atherosclerosis and do not correlate
susceptibility to PBC. Urinary tract and vaginal infections are with disease stage. Autoimmune diseases may overlap with PBC,