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to assess the degree of liver disease continues to stimulate the development of novel
investigational procedures.
The exclusion of hereditary diseases (e.g., primary hemochromatosis, Wilson’s
disease, alpha-1-antitrypsin deciency) in a patient with an acquired disease (e.g.,
viral hepatitis) is part of a liver disease workup. By the same reasoning, a patient
with a hereditary or autoimmune disease in whom risk factors for viral hepatitides
have been identied should have these excluded.
In evaluating a patient with suspected liver disease, the author excludes treatable
causes, with a basic liver disease workup, as done in clinical trials of liver disease.
In addition to a hemogram, serum electrolytes, blood urea nitrogen, and creatinine,
and hepatic panel, including gamma-glutamyl transpeptidase, the basic workup
includes hepatitis B serology, i.e., surface antigen, anti-core, and anti-HBs, and IgG
hepatitis A antibodies, with IgM in cases of acute hepatitis, hepatitis C antibody
with reex to HCV RNA quantitation, iron studies, alpha-1 antitrypsin, and cerulo-
plasmin concentrations, autoantibodies (i.e., antinuclear antibodies and anti-smooth
muscle antibodies), and glycosylated hemoglobin, if appropriate, e.g., in patients at
risk for nonalcoholic fatty liver disease. If PBC is in the differential diagnosis, anti-
mitochondrial antibodies and IgM are added at the start. If primary sclerosing chol-
angitis is being considered, perinuclear anti-neutrophil cytoplasmic antibodies are
also requested. Specic tests to exclude specic diseases are discussed in the rele-
vant chapters.
Judicious but liberal use of noninvasive diagnostic tests guided by an inquisitive
mind will identify the etiology of liver disease in most patients.
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of Springer Nature 2022
N. V. Bergasa (ed.), Clinical Cases in Hepatology,
https://doi.org/10.1007/978-1-4471-4715-2_3
Chapter 3
Primary Biliary Cholangitis
NoraV.Bergasa
A 57-year-old woman was referred to the hepatology clinic because of increased
serum activity of alkaline phosphatase (AP). She felt well and did not report pruritus
or fatigue. On physical exam, she did not exhibit any ndings suggestive of liver
disease. Her liver disease workup was signicant for + antimitochondrial antibodies
(AMA), 1:160 titer, and high serum IgM.These ndings were consistent with pri-
mary biliary cholangitis (PBC). The patient opted to have a liver biopsy, which
revealed stage II PBC.She was started on ursodeoxycholic acid (UDCA) at a dose
of 13–15mg/kg of body weight in divided doses with meals. In association with
UDCA, the serum activity of AP normalized itself. She has remained asymptomatic
for 12years.
The salient features that suggest a diagnosis of PBC in this patient are female
gender and a liver prole suggestive of cholestasis. The presence of AMA in serum
and increased serum IgM concentration are classic ndings of PBC and substantiate
the diagnosis. At the time of her presentation, the patient met the criteria for the
diagnosis of probable PBC as previously dened [1, 2], i.e., increased serum activ-
ity of AP for at least 6months and presence of AMA in serum, with typical histo-
logical features, as a denitive diagnosis. As per current guidelines, a diagnosis of
PBC is based on meeting two of the following criteria: (1) biochemical evidence of
cholestasis with an elevation of AP activity, (2) the presence of AMA, and (3) histo-
pathologic evidence of nonsuppurative cholangitis and destruction of small or
medium-sized bile ducts [3].
N. V. Bergasa (*)
Department of Medicine, H+H/Metropolitan, New York, NY, USA
New York Medical College, Valhalla, NY, USA
Hepatology, H+H/Woodhull, Brooklyn, NY, USA
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28
The serological hallmark of PBC is the presence of AMA [4–7]. However, a
condition known as AMA-negative PBC exists; the clinical features and its natural
history are the same as that of classic PBC [8]. The 2 oxoacid dehydrogenase family
of enzymes is comprised of pyruvate dehydrogenase complex (PDC), 2 oxo-
glutarate dehydrogenase complex (OGDC), and the branched-chain 2 oxoacid
dehydrogenase complex (BCOADC) [9]. These complexes play a key role in the
oxidative metabolism in the mitochondria. AMA react with the E2 components of
PDC, OGDC, and BCOADC, and with protein X and with the E1a and E1b subunits
of PDC.The inner lipoyl domain is the dominant B cell autoepitope, with lipoic
acid, which plays a crucial role in these complexes’ enzymatic activity, as a cofactor
[6, 10–14]. A denitive diagnosis is considered when liver histology reveals the
classic bile duct injury of chronic nonsuppurative destructive cholangitis (CNSDC)
[2] (Fig.3.1).
PBC is a liver disease initially described in 1851 [15] and subsequently as a
series of cases in 1950 [16] when patients tended to present with hyperbilirubinemia
in advanced stages. The disease is characterized by chronic nonsuppurative destruc-
tive cholangitis that affects septal and interlobular intrahepatic bile ducts [17]
(Fig.3.1); it tends to progress and to lead to biliary cirrhosis and liver failure [18,
19]. A cure for PBC has not been identied; the administration of UDCA is approved
for the treatment of PBC [3, 20, 21], and it has been associated with a prolonged
period free of the need for liver transplantation [22], indicated for patients who
develop liver failure [23]. Obeticholic acid was approved for the treatment of PBC
in combination with UDCA for the use in patients whose AP activity has not
decreased to less than 1.67 times the upper limit of normal after 1year of treatment,
or alone for patients who do not tolerate UDCA. The drug is contraindicated in
patients with decompensated liver disease, i.e., Child’s B and C [3], witha history
of a decompensation event, and with portal hypertension in association with com-
pensated cirrhosis.
Fig. 3.1 The orid bile
duct lesion, i.e.
nonsuppurative destructive
cholangitis, in a patient
with primary biliary
cholangitis.
Theinammatory
inltrateis comprised of
mononuclear cells, some
plasma cells and,
characteristically,
eosinophils
N. V. Bergasa
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29
Etiology
The trigger of the inammatory destruction of the intrahepatic bile ducts is unknown.
PBC is considered an autoimmune disease, an idea supported by the immunological
alterations reported in association with this condition. Infectious agents, or infection
related processes, as a cause of the CNSDC of PBC have been proposed; in this
context, lipopolysaccharide, secreted by Gram negative organisms [24], and lipotei-
choic acid, a component of the cellular wall of Gram positive organisms including
Staphylococcus aureus [25, 26], have been reported to accumulate in the inamma-
tory inltrate of the CNSDC of PBC, and Propionibacterium acnes 16 ribosomal
RNA was extracted from granulomata from the liver of patients with PBC.These
proteins and organisms function as pathogen-associated molecular patterns
(PAMPS) [27]. PAMPS can elicit inammatory reactions, which, around bile ducts,
may contribute to the pathogenesis of the CNSDC of PBC. Biliary epithelial cells
(BECs), like other epithelial cells, exhibit pattern recognition receptors (PRRs)
[28], including Toll-like receptors (TLRs), the most prevalent type on this type of
cell. In human beings, responses to LPS, for example, are mediated by TLR4, which
culminates with the stimulation of nuclear factor kappa-B (NFkB) and production
of antimicrobial peptides and proinammatory cytokines [29, 30]. Accordingly, if
not causally related to the disease, a potential effect of PAMPS in the biliary epithe-
lial cell milieu has been interpreted to suggest a role of defense mechanisms against
infections, and hence, the innate immune system, in the pathogenesis of the CNSDC
of PBC [31]. Bacteriuria [32] and urinary tract infections [33] have been reported,
although inconsistently [34, 35], to be signicantly more prevalent in patients with
PBC than in disease control groups. In this context, AMA were reported in the
serum of subjects with recurrent urinary tract infections without a diagnosis of PBC
[36]. As mitochondrial antigens are well conserved among species, an antibody
response against bacterial mitochondrial antigens may trigger antibody formation
(i.e., AMA) against endogenous antigens in a susceptible individual, dening the
hypothetical process of molecular mimicry in the pathogenesis of autoimmune dis-
eases [37], potentially including PBC [36].
Novosphingobium aromaticivorans is an organism that metabolizes organic
compounds; some of its proteins have homology with the E2 component of the
pyruvate dehydrogenase complex, the lipoyl domain of which seems critical in the
production of AMA, the serological hallmark of PBC [4–7]. Novosphingobium aro-
maticivorans has been identied in the feces of human beings, including patients
with PBC.It was reported that serum samples that contained antibodies against vari-
ous components of the PDC-E2 group of enzymes from patients with PBC, and
some serum samples from patients with PBC without AMA, reacted against pro-
teins of Novosphingobium aromaticivorans, in contrast to the absence of reactivity
from the control serum samples. These results have been interpreted to suggest that
this organism may contribute to the induction of PBC [38].
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The cloning of a human betaretrovirus from isolates from perihepatic lymph
nodes from patients with PBC has been reported [39]. The viral sequence of the
isolated provirus is homologous to the mouse mammary tumor virus, and viral
sequences derived from human breast cancer tissue [40, 41] in 95–99% of its genetic
makeup. By the use of reversed transcriptase-polymerase chain reaction, viremia
has been reported in patients with PBC; immunohistochemistry studies indicate that
the human betaretrovirus can be detected in lymphoid tissue in an important per-
centage of patients with the disease [39]. These ndings have advanced further the
idea that PBC results, in part, from an infectious agent [39].
Estrogen containing medications, e.g., contraceptives, can be associated with
cholestasis [42, 43]. In this regard, the use of estrogen containing contraceptive
medications in women with PBC is not rare; this observation may be a reection of
the use of oral contraceptives by subjects who might have developed PBC anyway,
and not indicative of causation by estrogen, which interestingly, as an oral contra-
ceptive, was found to be associated with a decrease in the risk of developing PBC
[44]. However, the use of hormone replacement therapy was found in association
with the disease [45]. Other factors that have been identied in association with
PBC include smoking and certain cosmetic practices (e.g., use of hair dye and nail
polish) [44–46].
Environmental factors have also been considered as a cause of PBC, perhaps in
a genetically predisposed individual. In a study comprised of patients from
NewYork City, the prevalence ratio of patients with PBC who had been listed for
liver transplantation was signicantly higher in proximity to Superfund toxic waste
sites than in the control group composed of patients with primary sclerosing chol-
angitis [47]. Studies that used population-based data from northeast England from
1987 to 2003 have found space-time clustering [48]; space-time clustering is
observed when an increased number of cases of the disease are located within a
specic geographic area over a limited period, and it is usually associated with envi-
ronmental factors, especially infections, as potential causes of disease [48]. In addi-
tion, a seasonal pattern of diagnoses for PBC has been reported with the highest
number of diagnoses made in June, and a sinusoidal pattern in the rate of diagnoses
also peaking in June [49]. These ndings may suggest that a seasonal factor contrib-
utes to the cause of PBC [49].
Regarding environmental exposure, it has been suggested that xenobiotics
may contribute to the pathogenesis of PBC, as they are metabolized in the liver
and may form reactive metabolites that can induce changes in cellular proteins to
create neoantigens. Structures mimicking a lipoyl hapten as modied by xenobi-
otics were used to replace the lipoic acid of the E2 component of synthetic pyru-
vate dehydrogenase; some of these synthetic compounds reacted with AMA
containing serum from patients with PBC.It was reported that the presence of
halogenated compounds correlated with antibody binding. As halogenated prod-
ucts can result from the metabolism of chemicals to which human beings are
exposed, it was proposed that these compounds may function as mimeotopes for
a self antigen, thus identifying environmental exposure as a potential cause of
PBC [50].
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Interestingly, a study that explored the metabolomic signature of PBC in com-
parison with that of celiac disease, which has been reported in association with the
former [51], documented a unique metabolomic ngerprint, different from celiac
disease, that was interpreted as suggestive of impaired energy metabolism possibly
associated with altered gut microbiota, the study of which, as suggested by the
authors, may provide some insight into the pathogenesis of PBC [52].
Genetics
Susceptibility to the development of PBC is considered to be genetically deter-
mined, in part. This idea is supported by the high risk of developing PBC in rst
degree relatives of patients with the disease, reported to be 1–2% [53, 54] and by the
concordance, albeit incomplete, of the disease in monozygotic twins, reported at
63% [55]. The loss of one X chromosome is a process of aging of cells [56]; an
increase in the number of peripheral lymphocytes with only one X chromosome
(i.e., monosomy) has been reported to occur in PBC [57], suggesting that epigenetic
activities associated with gene silencing [58] may contribute to the susceptibility to
develop PBC.
The human leukocyte antigen genes, located in the major compatibility complex
(MHC) region in chromosome 6 21p, have been associated with diseases considered
to be of autoimmune origin [59, 60]. Ethnic and geographic groupings are likely to
dene the results of these types of studies. They have revealed a complex relation-
ship with alleles grouping towards protection from and vulnerability to develop
PBC.Various alleles within the HLA class II genes have been reported to be associ-
ated with PBC, including the HLA DRB1*08 allele in patients from Europe, North
America, Japan, and Italy [61–65]. Genome wide associated studies (GWAS) in
PBC have conrmed previously reported HLA II associations. They have identied
new gene loci of interest [66–69] including: (i) several single nucleotide polymor-
phisms (SNP) over the HLA region, and other SNP in non-HLA regions identied
as the IL12A locus and the IL12RB2 locus, which encode IL-12alpha and IL-12
receptor beta 2, respectively [66, 68], (ii) variants at IRF5-TNPO3, various genes in
chromosome17q12.21, and MMEL1 [67], and (iii) (a) the STAT4 gene, a down-
stream participant of the IL-12 signaling pathway, a process involved in the regula-
tion of innate resistance and adaptive immunity, (b) the NF-kB gene itself, and
genes that concern its activation including TAB1, TNFRSF1A, CD80, and
RPS6KA4, and (c) RPS6KA4, which suppresses the production of cytokines depen-
dent on the activation of TLRs, and genes in the signaling pathway of TNF-alpha
including TNFRSF1A, DENND1B, and TNFA1P2 [69]. In this regard, NK function
is related to the IL-12/STAT4 pathway. It was documented that peripheral NK cells
were constitutively activated, intensively expressing CD49a and the liver-homing
marker, CXCR6, in patients with PBC versus disease and healthy control subjects.
NK cells from patients with PBC were activated by minuscule amounts of IL-12,
which resulted in the upregulation of CXCR6 and signicantly increased the
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