Primary Biliary cholangitis, lecture class for MBBS

Primary Biliary cholangitis

1. Pratap Sagar Tiwari, MD, DM, Hepatology Primary Biliary Cholangitis For MBBS 1

2. 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

3. 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 3 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 .

4. 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. Addison T , Gull W . On a certain affection of the skin — vitiligoidea — alpha plana , beta tuberosa . Guy ’ s Hosp. Rep.1851 ; 7 : 265 . Hanot V. Etude sur une Forme de Cirrhose Hypertrophique de Foie ( Cirrhose Hypertrophique avec Ict è re Chronique ) . Paris : Bailli è re , 1876 . Ahrens EH Jr , Payne MA , Kunkel HG et al. Primary biliary cirrhosis . Medicine 1950 ; 29 : 299 – 364 . 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

5. 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] Jepsen P, Gronbaek L, Vilstrup H. Worldwide incidence of autoimmune liver disease. Dig Dis 2015;33:2–12. Kim WR, et al: Epidemiology and natural history of primary biliary cirrhosis in a US community. Gastroenterology 119:1631–1636, 2000. 5

6. 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

7. 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. 7

8. Natural History of Untreated Patients PBC has a long protracted clinical course, and the following four distinct clinical phases are recognized: Preclinical or silent Asymptomatic Symptomatic 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 8

9. 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

10. 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 . 10

11. 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. 11

12. Systemic Conditions Associated With PBC ZAKIM 12 Note: Primary Sclerosing cholangitis

13. 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

14. 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.

15. 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

16. 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 16

17. 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. 17

18. 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 18

19. 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]. 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. 19

20. Ludwig’s histological staging classification for PBC SCHIFF 20

21. Treatment: Therapies to slow disease progression Ursodeoxycholic acid Obeticholic Acid Budesonide & others Fibric acid derivatives: Bezafibrate Immunomodulators: Rituximab Liver Transplantation 21

22. 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]. Kondrackiene J, Beuers U, Kupcinskas L. Efficacy and safety of ursodeoxycholic acid vs. cholestyramine in intrahepatic cholestasis of pregnancy. Gastroenterology 2005;129:894–901. [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

23. UDCA: Mechanism of Action T he 7β isomer of chenodeoxycholic acid. The MOA of UDCA in PBC are multiple [1,2]. 1 ST , 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. 2 ND , 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. Paumgartner G, Beuers U: Ursodeoxycholic acid in cholestatic liver disease: mechanisms of action and therapeutic use revisited. Hepatology 36:525–531, 2002. Beuers U: Drug insight: mechanisms and sites of action of ursodeoxycholic acid in cholestasis. Nat Clin Pract Gastroenterol Hepatol 3:318–328, 2006. 23

24. Treatment of PBC symptoms and consequences Pruritus Fatigue Sicca complex Metabolic Bone Disease : Osteoporosis Fat-Soluble Vitamin Deficiency Hyperlipidaemia Varices HCC 24

25. 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. Datta DV, Sherlock S. Cholestyramine for long term relief of the priritus complicating intrahepatic cholestasis. Gastroenterology 1966;50:323–332. 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. 25

26. 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]. 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. 26 There is no evidence to suggest that UDCA has any effect on pruritus [1,2], whilst OCA at higher doses can exacerbate it .

27. Fatigue: Management Fatigue is not related to severity of liver disease [1], and it is not responsive to UDCA or OCA [2,3]. 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. 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. 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

28. 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]. 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. 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. 28

29. 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. 29

30. 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]. Kaplan MM, Elta GH, Furie B, Sadowski JA, Russell RM. Fat-soluble vitamin nutriture in primary biliary cirrhosis. Gastroenterology 1988;95:787–792. 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. Maillette de Buy Wenniger L, Beuers U. Bile salts and cholestasis. Dig Liver Dis 2010;42:409–418. SCHIFF 30

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