notes by dr Claudio Italiano
The real clinical case. This is the case of a kind patient who, although
suffering from a severe jaundice, minimized his suffering to his wife, not to
alarm her. In his heart, however, he knew of the severity of the disease, since
the jaundice had become ingravescent. And, at a first ultrasound examination,
the bilious ways did not appear dilated. Having turned to my friend prof. Tonino
Borruto, of the Gastroenterology of P.O. of Taormina, he recommended an MRI
cholangium to clarify the clinical picture, before proceeding with any invasive
investigation. The radiologist, noticing an appearance of the bile ducts that
appeared fine and tortuous, without evidence of distal obstruction of the common
bile duct, suggesting other investigations of the case, posed the suspicion of a
primary biliary cirrhosis.
Biliary cirrhosis is the consequence of a prolonged lesion or obstruction of the
biliary or extrahepatic ways and is associated with reduced excretion of bile (cf.
cholestasis), with destruction of the hepatic parenchyma and progressive
fibrosis. Cirrhosis b.p. it is due to the presence of chronic inflammation and
fibrous obliteration of the intrahepatic bile ductules, while secondary biliary
cirrhosis is the consequence of a prolonged obstruction of the extrahepatic
major caliber ducts.
We confirm from now on that the two nosographic entities have many common features.
A trichrome stain highlights fibrosis around
a regenerative nodule
The etiology is unknown even if it is certain that it is frequently associated
with other autoimmune diseases such as CREST syndrome (calcinosis, Raynaud
phenomenon, esophageal dysmotility, sclerodactyly, telangiectasia), sicca
syndrome (dry eyes and mouth), thyroiditis autoimmune and renal tubular acidosis.
In order to diagnose the gastroenterologist, it seeks AMA antimegrading
circulating antibodies of the IgG class in over 90% of patients with c.b.p.
present; these antibodies turn, as a kind of missiles, (I apologize to my
colleagues but I must be understood by my navigators) against the proteins of
the energy critral of the cell, just the mitochondria, from 3 to 5 proteins,
which are part of the pyruvate dehydrogenase complex PDC, of the
branched-chain alpha-ketoacid dehydrogenase complex, BCKDC, and of the
alpha-ketoglutarate dehydrogenase complex. KGDC. The most relevant autoantigen
is the 74 kDA E2 complex of PDC, the dihydrolipoamide acetyltransferase. Thus,
the antibodies interact against a region essential for the binding of the lipoic
acid cofactor and inhibit the enzymatic activity of the PDC. Besides AMA there
are high levels of IgM and cryoproteins consisting of immune complexes that
activate complement. This results in inflammation with lymphocyte infiltrate in
the portal spaces surrounding the damaged bile ducts. These findings resemble
those encountered in transplant disease against the host, suggesting that
immunological mechanisms are at the root of this pathology, with alterations in
the cell line of suppressor lymphocytes.
PBC is initiated by an autoantigenic stimulus (upper, right) provided
either by a bacterial mimic of the autoepitope of PDC-E2, a xenobiotically
modified PDC-E2, or "spillage" of native mitochondrial autoantigens derived
perhaps from apoptotic cells. Hyper-responsiveness of innate immunity (top,
centre) can facilitate autoantigenicity; bacterial Cpg enhances IgM production
and cellular expression of TLR9. Genetic susceptibility is critical overall, and
depends particularly on multiple inherited deficits in immune tolerance, mostly
as yet undefined. APCs that become activated (lower, right) by stimulation
through TLRs present immunogenic self peptides (or mimics) via MHC Class II
molecules to autoreactive CD4+ T lymphocytes (centre) which in turn activate
CD8+ cytotoxic T lymphocytes and B lymphocytes that produce AMA. Treg
lymphocytes (lower, centre) that normally restrain activated autoreactive T
cells are deficient in PBC, thus further impeding T cell tolerance. Effector
mechanisms converge on the target cell in PBC, the BEC (lower left), which can
be damaged by injurious cytokines (IFN-γ) from CD4+ T cells, direct cytotoxicity
(Fas-L, perforin, granzyme B) from CD8+ T cells, or transcytosis of IgA-AMA.
The c.b.p. is divided into 4 stages.
- Chronic non-suppurative destructive cholangitis, ie necrotizing inflammation
of the portal spaces, with destruction of small and medium-sized bile ducts, by
the presence of a dense acute and chronic infiltrate of inflammatory cells, mild
fibrosis and biliary stasis.
- Subsequently the infiltrate is less evident and the number of bile ducts is
reduced while the smaller ductules proliferate.
- After months or years the progression of the disease leads to the reduction of
the interlobular ducts and the loss of hepatocytes and extension of the
periportal fibrosis.
Cirrhosis is determined, both micro and macronodular with total subversion of
the entire hepatic parenchymal structure.
Many patients are asymptomatic and, initially, only some signs are evident, such
as laboratory investigations, such as an increase in alkaline phosphatase, an
expression of cholestasis. Among the patients with symptomatic disease 90% are
female, aged between 35 and 60 years. They usually go to the doctor because
there is an unbearable itching, which extends to the palmar and plantar regions,
or because they feel asthenic; later, after a few months or a few years,
bilirubin levels also rise and jaundice appears. At this point, a whole series
of other signs affect the patient; since the bile salts in the digestive tract
are lacking, consequently the absorption of fats will be reduced or absent (malabsorption
syndrome) with the appearance of soft feces floating in the water of the water (steatorrhea)
and reflected in the stool investigations of a high amount of faecal fat. In
addition there is vitamin K deficiency due to lack of absorption of the same
and, therefore, defects in coagulation and ecchymosis in the body, bone pain,
lack of absorption of fat-soluble vitamin D and night blindness due to vitamin A
deficiency, with possible vitamin deficiency dermatitis E. Cholesterol increases
in tissues and settles in the eyes (xantelasms), joints and tendons (xanthomas).
Slowly, hepatic insufficiency, ascites and esophageal varices occur. In 75% of
patients c.b.p. is associated with sicca and CREST syndrome.
The laboratory meets the doctor and highlights the signs of cholestasis, ie the bile that locks, literally, which increases the value of alkaline phosphatase x 2 ox 5, and also the 5'-nucleotidase is high, while still within limits, in the initial phases are the values of transaminases and bilirubin. In this phase the positivity to AMA will be> 1:40. But when the pathology evolves, then the serum bilirubin rears until it reaches 30 mg / dl and the AST and ALT rise to values between 150 and 300 units. Hyperlipemia, hypercholesterolemia and lipoprotein X appear.
Poor results with care, perhaps only D-penicillamine can play a role in
chelating copper and controlling fibrogenesis. Cortisones can only worsen
calcium and bone metabolism. Perhaps colchicine plays some therapeutic role in
slowing down progression. Instead, it is excellent therapy with ursodeoxycholic
acid (bile salts dosed at 13-15mg / kg / day). For the itching, cholestyramine (questran)
orally sequences bile salts. Medium chain triglycerides are used in the diet to
reduce steatorrhea. Vitamin A and K media are also used parenterally as they are
fat-soluble. Osteomalacia contrasts with vitamin D or exactly 1-25
dihydroxyvitamin D3. The liver transplant remains, however, the only salvation
for these poor patients must always be attempted.
See also biliary cirrhosis secondary to sclerosing cholangitis or neoplastic
stenosis of the biliary tract or malignant bile ducts.