Primary Biliary cholangitis, lecture class for MBBS

Pratap Sagar Tiwari, MD, DM, Hepatology
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Biliary Cirrhosis
• Old term for liver damage from Biliary obstruction.
• Secondary biliary cirrhosis: This results from prolonged bile duct obstruction
or narrowing or closure of the bile duct for other reasons, such as a tumor,
extrahepatic bile duct obstruction due to gallstone, stricture, Ca head of
pancreas
2

Introduction: Primary biliary cholangitis
• PBC; is a autoimmune cholestatic liver disease with several characteristics, including:
cholestasis, presence of antimitochondrial antibodies (AMA), with accompanying
histologic evidence of chronic non-suppurative, granulomatous, lymphocytic small
bile duct cholangitis and without extra hepatic obstruction.
•T cell attack on small intralobular bile ducts
•Granulomatous inflammation
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Note: The granulomatous inflammatory response is a special type of chronic inflammation
characterised by often focal collections of macrophages, epithelioid cells and multinucleated giant
cells.

Background
• It was first described in 1851 by Addison and Gull [1] and later by Hanot
[2] .
• The association with high serum cholesterol levels and skin xanthomas
led to the term ‘ xanthomatous biliary cirrhosis ’ .
• Ahrens et al. [3] termed the condition ‘ primary biliary cirrhosis ’ .
• The term primary biliary cholangitis better reflects the most current
natural history of the disease, in which fewer than a third of pts have
cirrhosis at the time of presentation [4] and removes the stigma a/with
such terminology.
1. Addison T , Gull W . On a certain affection of the skin —vitiligoidea — alpha plana, beta tuberosa . Guy ’ s Hosp. Rep.1851 ; 7 : 265 .
2. Hanot V. Etude sur une Forme de Cirrhose Hypertrophique de Foie (Cirrhose Hypertrophique avec Ict è re Chronique) . Paris : Bailli è re , 1876 .
3. Ahrens EH Jr , Payne MA , Kunkel HG et al. Primary biliary cirrhosis . Medicine 1950 ; 29 : 299 – 364 .
4. Baldursdottir TR, Bergmann OM, Jonasson JG, Ludviksson BR, Axelsson TA, Bjornsson ES. The epidemiology and natural history of primary biliary cirrhosis: a nationwide population-based study. Eur J
Gastroenterol Hepatol 2012;24(7):824–30. 4

Epidemiology
• Data from multiple studies indicate that globally, an estimated 1 in 1,000
women over the age of 40 live with PBC. [1]
• The disease is far more common in women, with a female : male ratio of
approximately 9 : 1 and a mean age: 52 years.[2]
1. Jepsen P, Gronbaek L, Vilstrup H. Worldwide incidence of autoimmune liver disease. Dig Dis 2015;33:2–12.
2. Kim WR, et al: Epidemiology and natural history of primary biliary cirrhosis in a US community. Gastroenterology 119:1631–1636, 2000.
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Risk factors
• Predisposition to developing PBC is influenced by both genetic background and
environmental exposures.
• The strongest risk factor is a family HX of PBC or other autoimmune disease.
• The prevalence of PBC in first-degree relatives is approx 4%, .
• Increased rates of PBC have been noted with exposures to cigarette smoke, hair dye,
hormonal replacement therapy, etc
SCHIFF 6

Aetiology
• The precise aetiology of PBC remains uncertain.
• is an autoimmune disorder that leads to the gradual destruction of intrahepatic bile
ducts, resulting in periportal inflammation and cholestasis. Prolonged hepatic
cholestasis subsequently causes cirrhosis and portal hypertension.
• This autoimmune process is thought to be triggered in ‘ susceptible ’ individuals by
exposure to one or more environmental triggers which initiate and/or perpetuate
the disease process.
• The loss of tolerance to mitochondrial autoantigens is an early event in this
progressive disease.
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Natural History of Untreated Patients
• PBC has a long protracted clinical course, and the following four distinct clinical phases
are recognized:
1. Preclinical or silent
2. Asymptomatic
3. Symptomatic
4. Preterminal or liver failure
• The rate of progression is highly variable and pts do not necessarily pass through all
four phases . They may first start at any of these phases and may skip phases as they
progress.
ZAKIM
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Symptomatic disease
• The typical patient with symptomatic disease is a middle-aged woman
with a complaint of fatigue or pruritus. Other symptoms include right
upper quadrant abdominal pain, and jaundice.
Sleisenger 9

Symptomatic presentation: Fatigue
• Fatigue has been reported in up to 80% of pts with PBC at the time of DX
and is typically a/with excessive daytime somnolence and severely
impaired quality of life.
• The exact mechanism responsible for this symptom remains unclear and
there appears to be no correlation between its severity and the degree of
cholestasis, hepatocellular dysfunction, or histological stages of PBC.
• Some reports have also proposed that fatigue in PBC may be secondary,
to mitochondrial dysfunction .
• Other nonhepatic causes of chronic fatigue, such as depression, anemia,
hypoadrenalism, and sleep apnea, should also be excluded.
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Symptomatic presentation: Pruritus
• Defined as an unpleasant sensation that triggers the need to scratch (Itching is
an act of scratching).
• It is reported by up to 80% of pts followed up for 10 yrs after establishing the
DX of PBC but is only present in 19-55% of pts at the time of initial DX.
• Pruritus is characteristically generalized and intermittent.
• More severe in the limbs, particularly in soles of feet and palms of hands, and
is exacerbated by heat or contact to wool.
• Diurnal variation, with worsening of this symptom in the late evenings and at
night.
• Importantly, some experience significant exacerbations during pregnancy, thus potentially
leading to misdiagnosis of intrahepatic cholestasis of pregnancy. Note: in IHCOP pruritus is
resolved following delivery.
• Similar to fatigue, the severity of pruritus does not correlate with histological progression of PBC and
may actually improve during later stages in certain pts.
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Systemic Conditions Associated With PBC
ZAKIM
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Note: Primary Sclerosing cholangitis

Bone Disease
• Osteoporosis is present in 20%-40% of pts with PBC. In contrast,
osteomalacia is only rarely seen .
• Although the pathogenesis of hepatic osteodystrophy in PBC is still
disputed, it appears to be characterized by a combination of decreased
bone formation and increased bone resorption.
13

Fat-Soluble Vitamin Deficiency
• As PBC progresses and cholestasis worsens, the lack of an available pool
of bile salts required for absorption of fat-soluble vitamins may lead to
malabsorption of vitamins A, D, E, and K.
14
Hyperlipidemia
• Up to 85% of pts with PBC will have hyperlipidemia at presentation.
• Xanthelasmas, yellowish subcutaneous cholesterol deposits found around
the eyes, and xanthomas, cholesterol deposits around the tendons, bony
prominences, and peripheral nerves, are commonly seen in pts with PBC.

Other
• Hepatomegaly is found in approximately 70% of pts with PBC, including
asymptomatic pts, and becomes even more common as the disease
progresses.
• Splenomegaly
• Features of PHTN
• HCC
15

Diagnosis
• The diagnosis of PBC may be established in the presence of two of the
following three criteria:
(i) biochemical evidence of chronic cholestasis denoted by an otherwise
unexplained elevation of serum ALP (in the absence of a cholestatic drug
reaction or biliary obstruction)
(ii) presence of AMAs
(iii) histological findings of nonsuppurative destructive cholangitis SCHIFF
A definite diagnosis requires the presence of all three criteria and a probable
diagnosis requires two of these three. Source: Sherlock
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• Additional biochemical abnormalities in pts with PBC include
hypergammaglobulinemia with a selective elevation of IgM.
Note: Histology finding
Autoimmune hepatitis: Interface hepatitis
Primary biliary Cholangitis: Florid Duct lesion
Primary Sclerosing Cholangitis: “onion skin” periductal fibrosis
In addition, in the presence of one of the previously-mentioned associated autoimmune diseases, the
Corresponding autoantibody is likely to be detected as well: anti-SSA/Ro in sicca syndrome, anti-Scl70 in systemic
scleroderma, and anticentromere antibody with CREST syndrome, for example.
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Extended imaging
• MRCP in cholestatic pts is a safe and accurate imaging method for the
intra- and extrahepatic biliary tree, when performed by experienced
practitioners.
• Detection of intra- and/or extrahepatic bile duct stenoses and dilatation
is essential for the diagnosis of primary or secondary sclerosing
cholangitis .
Imaging: Absence of biliary obstruction
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Transient Elastography
• Transient elastography (Fibroscan; Echosens, Paris, France) is a new
noninvasive tool to evaluate the degree of liver fibrosis, which has been
studied in pts with PBC [1].
1. Corpechot C, El Naggar A, Poujol-Robert A, Ziol M, Wendum D, Chazouilleres O, et al. Assessment of biliary fibrosis by transient elastography in patients with PBC and PSC. HEPATOLOGY 2006;43:1118-
1124.
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Ludwig’s histological staging classification for PBC
SCHIFF
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Treatment: Therapies to slow disease progression
• Ursodeoxycholic acid
• Obeticholic Acid
• Budesonide & others
• Fibric acid derivatives: Bezafibrate
• Immunomodulators: Rituximab
• Liver Transplantation
21

Ursodeoxycholic acid
• Recommended for all pts with PBC and is usually continued for life .
• Data suggest that the optimum dose is 13–15 mg/kg per day.
• Reductions in biochemistries may be noticed in the first 1–2 weeks of therapy.
• UDCA is very safe, with minimal side effects when administered to pts at its
recommended dose (AE: weight gain, hair thinning, diarrhea and flatulence).
• There are no data to suggest that UDCA is teratogenic.
• Evidence-based advice over use in pregnancy and breast feeding is lacking, but it is
considered safe to use before and during the first trimester and beyond, as well
during breast feeding[1,2].
1. Kondrackiene J, Beuers U, Kupcinskas L. Efficacy and safety of ursodeoxycholic acid vs. cholestyramine in intrahepatic cholestasis of pregnancy. Gastroenterology 2005;129:894–901.
2. [126] Bacq Y, Sentilhes L, Reyes HB, Glantz A, Kondrackiene J, Binder T, et al. Efficacy of ursodeoxycholic acid in treating intrahepatic cholestasis of pregnancy: a meta-analysis. Gastroenterology
2012;143:1492–1501.
22

UDCA: Mechanism of Action
• The 7β isomer of chenodeoxycholic acid.
• The MOA of UDCA in PBC are multiple [1,2].
• 1ST, UDCA is a hydrophilic bile acid and, as such, lacks the cytotoxic
effect on cell membranes that is so characteristic of more
hydrophobic bile acids, such as lithocholic acid. Thus, bile
enrichment with UDCA protects the cholangiocytes against
membrane damage.
• 2ND, UDCA has a known choleretic effect . This stimulation of biliary
secretion is achieved mainly through up-regulation of synthesis and
activation of the bile salt export pump (BSEP) and the conjugate
export pump (Mrp2).
• Third, UDCA can stabilize the mitochondrial membrane and reducing production of reactive oxygen
species and preventing apoptosis. Hydrophobic bile acids, on the other hand, are known to ↑
mitochondrial permeability, leading to mitochondrial swelling and activation of caspase-9, thereby
triggering a cascade of events that culminate with cell apoptosis.
• Finally, UDCA has immunomodulatory effects .It is possible that these effects are mediated through
activation of the glucocorticoid receptor.
1. Paumgartner G, Beuers U: Ursodeoxycholic acid in cholestatic liver disease: mechanisms of action and therapeutic use revisited. Hepatology 36:525–531, 2002.
2. Beuers U: Drug insight: mechanisms and sites of action of ursodeoxycholic acid in cholestasis. Nat Clin Pract Gastroenterol Hepatol 3:318–328, 2006. 23

Treatment of PBC symptoms and consequences
• Pruritus
• Fatigue
• Sicca complex
• Metabolic Bone Disease: Osteoporosis
• Fat-Soluble Vitamin Deficiency
• Hyperlipidaemia
• Varices
• HCC
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Pruritus: management: Bile sequestrants
Bile sequestrants/bile acid binding resins are widely used as first-line
therapy, with side effects including bloating and constipation [1]. If they are
taken 1–4 times daily, the pruritus will usually start to improve in 4–11 days.
Bile sequestrants must be given 2–4 h before or after other medications
(including UDCA or OCA) as they interfere with intestinal absorption [2].
• Cholestyramine; Starting dose is 4 g/day, which can be increased up to
four times daily.
• Colesevelam is a newer, often better tolerated, bile sequestrant.
1. Datta DV, Sherlock S. Cholestyramine for long term relief of the priritus complicating intrahepatic cholestasis. Gastroenterology 1966;50:323–332.
2. Rust C, Sauter GH, Oswald M, Buttner J, Kullak-Ublick GA, Paumgartner G, et al. Effect of cholestyramine on bile acid patterns and synthesis during administration of ursodeoxycholic acid in man. Eur J Clin
Invest 2000;30:135–139.
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Pruritus: management
• LT for cholestatic pruritus that is ‘persistent and
intractable’ after therapeutic trials, is highly
effective in terms of rapid reduction in pruritus
severity (frequently within the first 24h of LT) [1].
1. Gross CR, Malinchoc M, Kim WR, Evans RW, Wiesner RH, Petz JL, et al. Quality of life before and after liver transplantation for cholestatic liver disease. Hepatology
1999;29:356–364.
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There is no evidence to suggest that UDCA has any effect on pruritus
[1,2], whilst OCA at higher doses can exacerbate it.

Fatigue: Management
• Fatigue is not related to severity of liver disease [1], and it is not
responsive to UDCA or OCA [2,3].
1. Carbone M, Bufton S, Monaco A, Griffiths L, Jones DE, Neuberger JM. The effect of liver transplantation on fatigue in patients with primary biliary cirrhosis: a prospective study. J Hepatol 2013;59:490–494.
2. Carbone M, Mells GF, Pells G, Dawwas MF, Newton JL, Heneghan MA, et al. Sex and age are determinants of the clinical phenotype of primary biliary cirrhosis and response to ursodeoxycholic Acid.
Gastroenterology 2013;144:560–569.
3. Nevens F, Andreone P, Mazzella G, Strasser SI, Bowlus C, Invernizzi P, et al. A placebo-controlled trial of obeticholic acid in primary biliary cholangitis. N Engl J Med 2016;375:631–643.
27

Sicca complex
• Most patients have sicca symptoms (xerophthalmia:
dry eyes, xerostomia: dry mouth) rather than
primary Sjögren’s syndrome. Artificial tears and
saliva are often helpful.
• Pilocarpine or cevimeline (muscarinic receptor
agonists) can be used if symptoms are refractory
[1,2].
1. Bacq Y, Sentilhes L, Reyes HB, Glantz A, Kondrackiene J, Binder T, et al. Efficacy of ursodeoxycholic acid in treating intrahepatic cholestasis of pregnancy: a meta-analysis. Gastroenterology 2012;143:1492–
1501.
2. Gong Y, Huang Z, Christensen E, Gluud C. Ursodeoxycholic acid for patients with primary biliary cirrhosis: an updated systematic review and metaanalysis of randomized clinical trials using Bayesian approach
as sensitivity analyses. Am J Gastroenterol 2007;102:1799–1807.
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Metabolic Bone Disease:Osteoporosis
• Supplements of calcium [1000-1500 mg/d] (if
there is no history of renal stones) and
vitamin D can be considered.
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Fat-Soluble Vitamin Deficiency
• The cholestasis that affects pts with PBC and the
subsequent reduced bile acid secretion, may
result in increased risk of lipid malabsorption.
However, deficiencies in the fat-soluble vitamins
A, D, E, and K are uncommon in PBC [1,2,3].
1. Kaplan MM, Elta GH, Furie B, Sadowski JA, Russell RM. Fat-soluble vitamin nutriture in primary biliary cirrhosis. Gastroenterology 1988;95:787–792.
2. Phillips JR, Angulo P, Petterson T, Lindor KD. Fat-soluble vitamin levels in patients with primary biliary cirrhosis. Am J Gastroenterol 2001;96:2745–2750.
3. Maillette de Buy Wenniger L, Beuers U. Bile salts and cholestasis. Dig Liver Dis 2010;42:409–418.
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Primary Biliary cholangitis, lecture class for MBBS

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Primary Biliary cholangitis, lecture class for MBBS