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Primary Biliary Cholangitis

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A complete guide to Primary biliary cholangitis / Primary biliary cirrhosis/ PBC

Publicada em: Saúde e medicina
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Primary Biliary Cholangitis

  1. 1. Pratap Sagar Tiwari, MD, DM Resident, Hepatology NAMS, Bir Hospital , Nepal 1
  2. 2. Content • Introduction & Background • Epidemiology ,Risk factors and aetiology • Natural History of disease & Presentation • Diagnosis, Workup & differentials • Management • Liver transplantation & Recurrence • Special situations: Pregnancy and Overlap syndrome 2
  3. 3. Introduction: Primary biliary cholangitis • PBC; formerly known as primary biliary cirrhosis, is a globally recognised autoimmune cholestatic liver disease with several characteristics, including: cholestasis, serologic reactivity to antimitochondrial antibodies (AMA) or specific antinuclear antibody (ANA) reactivity, with accompanying histologic evidence of chronic non-suppurative, granulomatous, lymphocytic small bile duct cholangitis. EASL 2017 3
  4. 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 ’ . • With increased awareness and better diagnostic tools, most pts are diagnosed at early disease stages. This has led to a strong global effort to remove the word cirrhosis from the name of this disease. • 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
  5. 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] • Historically, PBC is known to affect predominantly Caucasians, although it is reported in all races and ethnicities. • The disease is far more common in women, with a female : male ratio of approximately 10 : 1 (9:1 ;Sleseinger) and a mean age at diagnosis of 52 years.[2] • The diagnosis of PBC usually is made between the ages of 30-60 yrs, with a range of 21-93 yrs. The disease has been documented in even younger pts—2 teenagers 15 and 16 years of age, respectively.[3] 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. 3. Dahlan Y, Smith L, Simmonds D, et al. Pediatric-onset primary biliary cirrhosis. Gastroenterology 2003; 125:1476-9. 4. Carbone M, et al: Sex and age are determinants of the clinical phenotype of primary biliary cirrhosis and response to ursodeoxycholic acid. Gastroenterology 560–569, 2013. According to data from the UK PBC cohort, it appears that men are diagnosed at an older age than women, have more advanced disease, and a lower response rate to therapy. [4] Among female pts, those presenting at a younger age also have a lower response rate to RX. For example, the response rate to UDCA was >90% in pts ≥70 yrs and below 50% in pts presenting aged ≤30 yrs.[4] 5
  6. 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%, and the in monozygotic twins is approx 66%. • PBC appears to be a multigene disease; the identified ones are HLA gene DQB1 and genes in the IL12 inflammatory pathway to be significantly a/with the development of PBC. • Increased rates of PBC have been noted in persons with exposures to cigarette smoke, hair dye, hormonal replacement therapy, atomic bomb explosions, and toxic Superfund sites. SCHIFF 6
  7. 7. Proposed Risk Factors and Associations for PBC ZAKIM 7
  8. 8. Aetiology • The precise aetiology of PBC remains uncertain [1] . • The balance of evidence supports an autoimmune process in which autoreactive effector mechanisms are directed at self - epitopes expressed on small - duct biliary epithelial cells [2] . • 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. 1. Hohenester S , Oude - Elferink RP , Beuers U. Primary biliary cirrhosis . Sem. Immunopathol. 2009 ; 31 : 283 – 307 . 2. 34 Jones DE. Pathogenesis of primary biliary cirrhosis . Gut 2007 ; 56 : 1615 – 24 . 8
  9. 9. 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 9
  10. 10. Natural History of Untreated Patients • The so-called silent phase is characterized by an incidentally found positive AMA, but with normal serum liver biochemistry measurements. • Without RX it can take up to 22 yrs for a pt to progress from an isolated positive AMA to death. • Metcalf et al. have been following a small cohort of 29 pts initially found to have an isolated positive AMA and normal liver chemistries. At DX, most had LB findings S/O PBC. After up to 18 yrs of FU, 76% developed symptoms and 83% proceeded to show abnormal liver tests in a cholestatic pattern S/O PBC.[1] 1. Metcalf JV, et al: Natural history of early primary biliary cirrhosis. Lancet 348:1399–1402, 1996. 10
  11. 11. Natural History of Untreated Patients • Most pts today present in the asymptomatic phase, which can last several years. Eventually, however, symptoms will develop; thus this phase is regarded as temporary. • In a study from England, half of 469 pts who were asymptomatic at presentation developed symptoms at 5 ys of FU, and it was estimated that only 5% remained asymptomatic after 20 yrs.[1] • Liver related mortality is decreased in asymptomatic pts compared with symptomatic pts, with median survival of 24.1 years versus 14.6 years, respectively.[2] • Huet et al. confirmed this by demonstrating a clear correlation between higher hepatic vein gradients and worse survival among pts with PBC.[3] • Once fluid retention ensues, survival is significantly decreased, with approximately half of the pts deceased at 3 yrs.[4] • Similarly, 3-year survival after the 1ST episode of VB is slightly less than 50%.[5] 1. Prince MI, et al: Asymptomatic primary biliary cirrhosis: clinical features, prognosis, and symptom progression in a large population based cohort. Gut 53:865–870, 2004. 2. Springer J, et al: Asymptomatic primary biliary cirrhosis: a study of its natural history and prognosis. Am J Gastroenterol 94:47–53,1999. 3. Huet PM, et al: Portal hypertension and primary biliary cirrhosis: effect of long-term ursodeoxycholic acid treatment. Gastroenterology 135:1552–1560, 2008. 4. Chan CW, et al: Survival following the development of ascites and/ or peripheral oedema in primary biliary cirrhosis: a staged prognostic model. Scand J Gastroenterol 40:1081–1089, 2005. 5. Gores GJ, et al: Prospective evaluation of esophageal varices in primary biliary cirrhosis: development, natural history, and influence on survival. Gastroenterology 96:1552–1559, 1989. 11
  12. 12. Natural History of Untreated Patients P1 P2 P3 P4 DEATH 20-22 yr 76 % in 18 yr Metcalf et al (24pt) [3] 50% in 5 yr 83 % in 18 yr Median survival : 24.1 yrs Median Survival 9-10 yrs Springer J, et al(91pt)[5] 95% in 20 yr Prince MI, et al (469)[4] Median survival : 14.6 yrs Sherlock S[1]Median Survival 7-8 yrs Long RG (20 pt)[2] 1. Sherlock S. Primary biliary cirrhosis (chronic intrahepatic obstructive jaundice) . Gastroenterology 1959 ; 31 : 574 . 2. Long RG , Scheuer PJ , Sherlock S . Presentation and course of asymptomatic primary biliary cirrhosis . Gastroenterology 1977 ; 72 : 1204 – 1207 . 3. Metcalf JV, Mitchison HC, Palmer JM, Jones DE, Bassendine MF, James OF. Natural history of early primary biliary cirrhosis. Lancet 1996;348(9039):1399–402. 4. Prince MI, et al: Asymptomatic primary biliary cirrhosis: clinical features, prognosis, and symptom progression in a large population based cohort. Gut 53:865–870, 2004. 5. Springer J, et al: Asymptomatic primary biliary cirrhosis: a study of its natural history and prognosis. Am J Gastroenterol 94:47–53,1999. 12
  13. 13. Natural history of AMA-negative PBC • The natural history of AMA-negative PBC has been classically considered similar to that of AMA-positive PBC, including histological progression, response to pharmacotherapy with UDCA, and clinical outcomes [1,2,3]. • However, data from a recent retrospective study evaluating 96 pts with AMA-negative PBC suggest that pts with AMA-negative PBC have diminished survival free of liver-related complications as well as increased need for LT and mortality compared to pts with AMA-positive PBC [4]. 1. Lacerda MA, Ludwig J, Dickson ER, Jorgensen RA, Lindor KD. Antimitochondrial antibody-negative primary biliary cirrhosis. Am J Gastroenterol 1995;90(2):247–9. 2. Invernizzi P, Crosignani A, Battezzati PM, et al. Comparison of the clinical features and clinical course of antimitochondrial antibody-positive and-negative primary biliary cirrhosis. Hepatology 1997;25(5):1090– 5. 3. Kim WR, Poterucha JJ, Jorgensen RA, et al. Does antimitochondrial antibody status affect response to treatment in patients with primary biliary cirrhosis? Outcomes of ursodeoxycholic acid therapy and liver transplantation. Hepatology 1997;26(1):22–6. 4. JuliussonG, Imam M, Bjornsson ES, Talwalkar JA, Lindor KD. Longterm outcomes in antimitochondrial antibody negative primary biliary cirrhosis. Scand J Gastroenterol 2016;51(6):745–52. 13
  14. 14. PBC: Presentation • Asymptomatic disease • Symptomatic disease Fatigue Pruritus Other symptoms 14
  15. 15. Presentation: Asymptomatic disease • Most pts DX with PBC are asymptomatic (60%) and physical examination at the time of dx generally unveils nonspecific clinical findings. • Unfortunately, the definitions of “asymptomatic disease” vary among the published studies, but frequently indicate pts who do not have specific liver-related symptoms or complications. • The proportion of pts presenting in the asymptomatic stage appears to be higher in Western countries and Japan, accounting for up to 85% of all pts. In India, Lithuania, Singapore, and Hong Kong the rate of asymptomatic disease at presentation ranges between 20% and 47%.[1] • Abnormalities in routine liver biochemistries, particularly elevations in ALP and GGT and less commonly hyperbilirubinemia are the main diagnostic clues for PBC in otherwise asymptomatic pts. 1. Kumagi T, Onji M: Presentation and diagnosis of primary biliary cirrhosis in the 21st century. Clin Liver Dis 12:243–259, vii, 2008. 15
  16. 16. 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 16
  17. 17. Symptomatic presentation: Fatigue • Fatigue has been reported in up to 81% 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 resulting in increased muscle fatigability following exercise with excessive acidosis. 17
  18. 18. Symptomatic presentation: Fatigue • Recently, an autonomic neuropathy has been described in a/with fatigue in pts with PBC.[1] • It is conceivable that the autonomic dysregulation affects blood supply to peripheral muscles and the function of lactate transporters involved in adaptation to the anaerobic metabolism, thus leading to muscle fatigue. • Fatigue does not improve with RX of depression, is often constant over time,[2] is frequently a/with excessive daytime somnolence, and may be a manifestation of untreated hypothyroidism which occurs in about 20% of pts with PBC.[3] • Restless leg syndrome is more common in pts with PBC compared to the general population (29% vs. 5–10%,) and data support a positive correlation between the severity of this syndrome and poor sleep quality as well as excessive daytime sleepiness and fatigue . • Other nonhepatic causes of chronic fatigue, such as depression, anemia, hypoadrenalism, and sleep apnea, should also be excluded. 1. Bergasa NV, Mason A, Floreani A, Heathcote J, Swain MG, Jones DEJ, et al. Primary biliary cirrhosis: Report of a focus group. HEPATOLOGY 2004;40:1013-1020. 2. van Os E, van den Broek WW, Mulcer PGH, ter Borg PC, Bruijn JA, van Buuren HR. Depression in patients with primary biliary cirrhosis and primary sclerosing cholangitis. J Hepatol 2007;46:1099-1103. 3. Elta GH, Sepersky RA, Goldberg MJ, Connors CM, Miller KB, Kaplan MM. Increased incidence of hypothyroidism in primary biliary cirrhosis. Dig Dis Sci 1983;28:971-975. 18
  19. 19. Symptomatic presentation: Pruritus • Defined as an unpleasant sensation that triggers the need to scratch (Itching is an act of scratching), pruritus is a common complaint among pts with PBC. • 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, but in some it may be persistent and debilitating. • It is usually 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. 19
  20. 20. Symptomatic presentation: Pruritus • Prince et al.[1] followed 770 pts with PBC for symptom progression and found that 18.9% reported pruritus at the time of DX; the cumulative risk of having pruritus was 45% at 5 years and 57% at 10 years. • Later, the natural history of pruritus in PBC was evaluated in pts participating in clinical trials at the Mayo Clinic. • The annual risk of developing pruritus among pts(n=180) who did not have this complaint at entry was 27%, whereas the annual risk of reporting resolution or improvement of pruritus was 23%.[2] 1. Prince M, Chetwynd A, Newman W, et al. Survival and symptom progression in a geographically based cohort of patients with primary biliary cirrhosis: Follow-up for up to 28 years. Gastroenterology 2002; 123:1044-51. 2. Talwalkar JA, et al: Natural history of pruritus in primary biliary cirrhosis. Clin Gastroenterol Hepatol 1:297–302, 2003. Pathogenesis of Pruritus Pruritogenic bile acids ↑ opioidergic tone Autotoxin(ATX) mediated 20
  21. 21. Pruritus: Pruritogenic bile acids • The pathophysiology of pruritus in PBC has not been completely elucidated but several hypotheses have been formulated. • One of the initial theories was founded on the basis of elevated plasma levels of pruritogenic bile acids and their accumulation in the skin; however, some pts have no pruritus despite elevated levels of bile acids. • Additionally, the lack of correlation between concentrations of bile acids and the severity of pruritus, and commonly reported improvement of pruritus during late stages of PBC also dispute this theory. 21
  22. 22. Pruritus: ↑ opioidergic tone • Several lines of evidence support a role for an ↑ opioidergic tone in the pathogenesis of pruritus in PBC. • First, as opposed to healthy volunteers, pts with PBC develop withdrawal- like symptoms after taking an opioid antagonist. • Second, central administration of opioids induces pruritus, which is then improved by an opioid antagonist. • Third, pts with cholestatic liver disease have increased serum levels of the endogenous opioid peptides methionine-enkephalin and leucineenkephalin, with down-regulation of μ-opioid receptors. • Fourth, clinical trials show that opioid antagonists improve pruritus in the setting of cholestasis. • Taken together, the data suggest that there is increased central opioidergic neurotransmission leading to pruritus . 22
  23. 23. Pruritus: Autotoxin(ATX) • Pruritus in cholestatic liver disease may be mediated in part by lysophosphatidic acid and the enzyme autotoxin(ATX), which leads to the production of lysophosphatidic acid from lysophosphatidylcholine. • Serum levels of lysophosphatidic acid and activity of autotaxin have been shown to correlate with the severity of pruritus.[1] • Furthermore, rifampin, a drug with strong antipruritic effects, was found to inhibit ATX expression. 1. Kremer AE, Martens JJ, Kulik W, et al. Lysophosphatidic acid is a potential mediator of cholestatic pruritus. Gastroenterology 2010; 139:1008-18, 1018 e1. 23
  24. 24. Presentation: Other symptoms • Abdominal pain or discomfort localized in the RUQ is reported by up to 17% of pts(10 % :ZAKIM) but usually resolves spontaneously. • Importantly, additional reasons for pain should be actively investigated and excluded, particularly symptomatic cholelithiasis, erosive gastropathy and duodenopathy, or even PUD. • Jaundice is typically a marker of late stages of the disease, thus it is infrequent (3%) at the time of diagnosis. • Symptoms related to extrahepatic disorders such as sicca or Sjogren syndrome (xerostomia and xerophtalmia), Hashimoto thyroiditis, Graves disease, CREST syndrome (calcinosis cutis, Raynaud phenomenon, esophageal dysmotility, sclerodactyly, and telangiectasia), and RA may be present in up to 40% of pts with PBC. 24
  25. 25. Systemic Conditions Associated With PBC ZAKIM25
  26. 26. Frequency of extrahepatic AI disorders in pts with PBC Other rarely reported associations include IBD, sarcoidosis, ITP, autoimmune hemolytic anemia, polymyositis, pulmonary fibrosis, and pulmonary hypertension. The risk for lymphoma in pts with PBC is less than 1%. SLEISENGER 26
  27. 27. Bone Disease • Osteoporosis is present in 20%-40% of pts with PBC. In contrast, osteomalacia is only rarely seen . • Such increased prevalence of osteoporosis actually translates into a measurable 2X increase in fracture risk, especially at the spine, forearm, and hip. RF for osteoporosis include advanced age, low BMI (≤ 24 kg/m2), and advanced histologic disease stage. • The severity of cholestasis, the PBC Mayo risk score, postmenopausal state, and intestinal calcium malabsorption have all been inconsistently reported as predictive of osteoporosis. • 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. 27
  28. 28. 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. • As such, data derived from a clinical trial involving 180 pts with PBC indicated that the proportion of pts with vitamin A, D, E, or K deficiency was 33.5%, 13.2%, 1.9%, or 7.8%, respectively. • In general, the risk of a fat-soluble vitamin deficiency is higher with more advanced disease and lower cholesterol or albumin levels. 28
  29. 29. Hyperlipidemia • Up to 85% of pts with PBC will have hyperlipidemia at presentation. • Hypercholesterolemia is typical in early and intermediate stages, with marked elevation of HDLs and modest elevations of LDLs and VLDLs, respectively. • As the disease advances, we observe that HDL levels decrease significantly, whereas LDL levels remain elevated because of a progressive decrease in LDL receptors in injured hepatocytes and subsequent decrease in LDL clearance. • Also, the composition of LDL changes during this stage: the concentration of lipoprotein X, a particle of LDL that is believed to have antiatherogenic properties, is elevated as well. • Triglyceride levels are normal or mildly elevated in the advanced stages. • A clear correlation between hyperlipidemia and cardiovascular disease has not been demonstrated in pts with PBC. 29
  30. 30. Hyperlipidemia • 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. • Xanthomas, but not xanthelasmas, directly correlate with the plasma cholesterol levels and are usually seen with cholesterol levels >600 mg/ dL. • Xanthelasmata are a classic feature of late PBC but only present in 5–10% of pts, and besides the negative aesthetic aspect, they rarely cause any significant functional impairment. • In contrast, xanthomata are uncommon in PBC but may impair normal function when localized in hands or feet, thus adversely affecting quality of life. 30
  31. 31. Other • Hepatomegaly is found in approximately 70% of pts with PBC, including asymptomatic pts, and becomes even more common as the disease progresses. • Although the frequency of splenomegaly in PBC has not been established, particularly in asymptomatic pts and during early stages of the disease, it is a characteristic finding secondary to portal HTN during late states. 31
  32. 32. Portal Hypertension • Only a minority of pts with PBC will have signs and symptoms consistent with PHTN at the time of their diagnosis. • In one of the largest population-based studies(n=770), 3% of pts had ascites, 1.3% had bleeding EV, and 1.4% had HE at presentation. It was estimated that 10 years later 20% would have ascites, 10% would have bleeding EV, and 12.6% would have HE. [1] • Interestingly, complications of PHTN can precede the histologic development of cirrhosis in 10% to 20% of pts, due to portal venous compression, perisinusoidal fibrosis, and NRH. [1] • Clinical features of PHTN in PBC are similar to those in pts with other forms of CLD. 321. Prince M, et al: Survival and symptom progression in a geographically based cohort of patients with primary biliary cirrhosis: follow-up for up to 28 years. Gastroenterology 123:1044–1051, 2002.
  33. 33. Hepatocellular carcinoma • As with almost any form of cirrhosis, pts with PBC may develop complications due to the chronicity of their disease. One of the most serious is the development of HCC. • The incidence of HCC among pts with diagnosed PBC is estimated at 0.36 per 100 person years. Higher histological stage on LB denotes an ↑ risk for HCC [1]. • A recent multicentre study from North America and Europe, based on prolonged observation of 4,565 pts with PBC, showed an incidence rate of 3.4 HCC cases for every 1,000 patient-years [2]. • Male sex was a confirmed risk factor, as well as inadequate response to UDCA; indeed, men without advanced disease who are UDCA non-responders are at a higher risk of developing HCC than women with cirrhosis who respond to UDCA. [2]. 1. Jones DE, Metcalf JV, Collier JD, Bassendine MF, James OF. Hepatocellular carcinoma in primary biliary cirrhosis and its impact on outcomes. Hepatology 1997;26:1138–1142. 2. Trivedi PJ, Lammers WJ, van Buuren HR, Pares A, Floreani A, Janssen HL, et al. Stratification of hepatocellular carcinoma risk in primary biliary cirrhosis: a multicentre international study. Gut 2016;65:321–329. 33
  34. 34. 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 or PBC-specific antinuclear antibodies (ANAs) (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 34
  35. 35. LAB • Increased serum ALP is the hallmark biochemical manifestation of cholestasis. • Initial evaluation of cholestasis should include a detailed history that may elucidate recent or current use of drugs potentially responsible for elevations of ALP (cholestatic drug-induced liver injury). • It is also critical to exclude intra- or extrahepatic biliary obstruction as a cause of cholestasis, thus USG is recommended as part of the initial work-up and MRCP may be considered in selected cases. • Mild elevations of the AST and ALT are common in PBC; however, levels >3–5 times the ULN are unusual and should prompt evaluation for overlap with AIH or other diseases. • Bilirubin levels typically remain under normal limits, particularly during early stages of PBC. • Similar to other CLD, advanced stages of PBC are characterized by progressive hepatic dysfunction and hyperbilirubinemia. 35
  36. 36. The diagnostic approach to cholestasis: A • Cholestasis is the impairment of bile formation and/or bile flow which can be asymptomatic, or manifest with fatigue, pruritus, RUQ abdominal discomfort and jaundice. • Early biochemical markers include increased serum ALP and GGT, followed by conjugated hyperbilirubinemia at more advanced stages. • Cholestasis is considered chronic if it lasts>6 months, is classified as intrahepatic or extrahepatic, and includes hepatocellular and cholangiocellular forms of impaired bile formation. • Jaundice (icterus) is the yellow discoloration of skin, sclera and mucous membranes due to hyperbilirubinemia, which can be a sign of severe cholestasis, but also has a broader diagnosis including pre-, intra- and posthepatic causes . 36
  37. 37. The diagnostic approach to cholestasis: B • Chronic cholestatic liver diseases often have an asymptomatic course over months or years, and can be identified by elevated serum ALP. • Serum ALP can have different sources (e.g. liver, intestine, bone, placenta). Therefore, its elevation can be caused not only by cholestatic liver disease, but also rapid bone growth in children, extrahepatic diseases (e.g. bone diseases such as Paget’s disease), vitamin D deficiency or pregnancy. • In clinical practice, the hepatic origin of elevated serum ALP is usually supported by simultaneous elevation of serum GGT (or 5’ nucleotidase) • Differentiation of ALP isoforms from different organs is possible, but not commonly used. 37
  38. 38. The diagnostic approach to cholestasis: C • About 30% of pts with DILI show a cholestatic serum enzyme pattern. • Antibiotics such as amoxicillin/clavulanic acid and trimethoprim/sulfamethoxazole, anabolic steroids or azathioprine can be relevant potential injurious agents. • When administered within 90 days of development of cholestasis, these medications should be stopped (if they have not been stopped already), and intensity of cholestasis should be followed. • Previous surgery and blood transfusions should be listed. 38
  39. 39. DD of intra- and extrahepatic cholestasis in adults. 39
  40. 40. DD of intra- and extrahepatic cholestasis in adults IgG4-associated cholangitis: Typically, elderly male patients present with abdominal discomfort, weight loss, jaundice, and itch. At present, no accurate diagnostic test for IAC and IgG4-RD is at hand, often causing significant diagnostic delay. Serum IgG4 is only diagnostic when markedly raised (>4× ULN). Imaging in IAC discloses mass-forming lesions and/or strictures in the biliary tract. Histology may show tissue infiltration of IgG4-expressing plasma cells. Diagnostic criteria for histologic and imaging findings, serum tests, organ manifestation pattern, and response to immunosuppressive therapy (HISORt) criteria are used for the diagnosis of IgG4-RD. 40
  41. 41. • Vanishing bile duct syndrome refers to a group of acquired disorders resulting in progressive destruction and disappearance of the intrahepatic bile ducts and ultimately cholestasis. Ductopenia (a pathologic description) refers to the associated reduction in the number of intrahepatic bile ducts, a process that ultimately leads to cholestasis. The diagnosis is made pathologically, although it can be suggested on imaging tests such as ERCP MRCP when disease is advanced. • Graft versus host disease (GVHD) is an immune-mediated disease resulting from a complex interaction between donor and recipient adaptive immunity. Acute GVHD describes a distinctive syndrome of dermatitis, hepatitis, and enteritis developing within 100 days after allogeneic hematopoietic-cell transplantation (HCT). Chronic GVHD describes a more diverse syndrome developing after day 100. In addition to allogeneic HCT, procedures associated with high risk of GVHD include transplantation of solid organs containing lymphoid tissue and transfusion of unirradiated blood products. 41
  42. 42. DD 42
  43. 43. COMMON DRUGS CAUSING VARIOUS DRUG INDUCED CHOLESTATIC SYNDROMES Cholestasis without Hepatitis Cholestasis with Hepatitis Cholestasis with Bile Duct Injury Vanishing Bile Duct Syndrome (Ductopenia) Sclerosing Cholangitis like cholestasis steroids Estrogens Tamoxifen Azathioprine Cyclosporine Nevirapine Glimepiride Metolazone Infliximab Cetirizine Isoniazid Methyldopa Macrolide TCA Amoxicillin-clav Azathioprine NSAID's Celecoxib Carbamazepine Fenofibrate Hydrochlorothiazides Metformin Glimepiride Orlistat Gabapentin Proplthiouracil Itraconazole Atorvastatin Flucoxacillin Amoxicillin-clav Amitriptyline Amoxicillin/clavulani Ampicillin Azathioprine Ciprofloxicin Clindamycin Co-trimoxazole Diazepam Erythromycin Estradiol Flucloxacillin Phenytoin Hypertonic saline, iodine solution, formaldehyde, absolute alcohol 43
  44. 44. Antibodies • Antimitochondrial Antibodies :AMA and its subtypes • PBC-specific types of Antinuclear Antibodies:ANA Anti gp120 Anti sp100 P62 (Nucleoporin 62 ) Anti-centromere • HK1 • KLHL12 44
  45. 45. Antimitochondrial Antibodies: AMA • AMAs are the hallmark autoantibodies of PBC and are directed against various proteins confined to the inner mitochondrial membrane, especially target the E2-subunit of the pyruvate dehydrogenase complex (PDC-E2). • AMA positivity is observed in >90-95% of pts with PBC ; is highly specific to the disease . • There are 9 subtypes of AMA (M1–M9), four of which are associated with PBC: M2, M4, M8, and M9. • The M2 subtype was considered the most specific AMA for PBC. • AMA titers of at least 1 : 40 ,greater or >0.1 unit are considered significant for DX of PBC; however, the magnitude of titers does not correlate with severity of the disease. 45
  46. 46. Antimitochondrial Antibodies: AMA • In approximately 5–10% of pts with PBC, AMA antibodies are absent or present only in low titer <1/80), when immunofluorescent techniques are used (AMA-negative PBC), in which case histology demonstrating histological features of PBC is mandatory to establish the diagnosis. [AASLD] • In this scenario, testing for PBC-specific autoantibodies such as anti- gp210, anti-sp100, and/or anti-p62 may be helpful to corroborate the diagnosis. • For pts with AMA-negative PBC, particularly males, it is critical to obtain detailed imaging studies of the intrahepatic bile ducts (i.e., MRCP) to rule out the possibility of sclerosing cholangitis. 46
  47. 47. Antimitochondrial Antibodies: AMA • Asymptomatic pts with AMA titers ≥ 1 : 40 or AMA >0.1 unit and N liver biochemistry values have been followed for up to 30 yrs and the likelihood that these individuals will eventually develop clinically evident PBC is very high: at the end of follow-up, 80% of these pts will have definite PBC, and an additional 14% will have probable PBC. • Nevertheless, in the general population, in which up to 0.5% of individuals can test positive for AMA. • Perhaps healthy individuals found to have AMA positivity should undergo annual evaluation of serum liver biochemistry values, although no specific guidelines currently exist. 47
  48. 48. 48
  49. 49. Antinuclear antibodies: ANA • In addition to AMAs, approx 30–50% of pts with PBC have detectable ANAs in serum. • Indirect immunofluorescence patterns of PBC-specific types of ANA include: 1. Nuclear rim for autoantibodies targeting the nuclear-pore membrane glycoprotein 210 (gp210) 2. Multiple nuclear dots for autoantibodies targeting the nuclear body speckled 100 kDa protein (sp100) 3. Nucleoporin 62 (p62) 49
  50. 50. Antinuclear antibodies: ANA • Anti-gp210 antibodies are only detected in 20–40% of pts with PBC depending on the stage of the disease (increased SN in late stages), but are highly specific. • Serum titers of these antibodies may change from negative to positive and vice versa depending on disease activity and histological stage. • Autoantibodies directed against centromeric proteins (anti-centromere), commonly noted in pts with CREST syndrome, are found in 10–30% of pts with PBC. • Anti-gp210, anti-sp100, and anti-centromere antibodies have been a/with poorer outcomes in pts with PBC. 50
  51. 51. Antinuclear antibodies: ANA • Additional AA recently identified in pts with PBC include the nuclear protein kelch-like 12 (KLHL12) and the mitochondrial enzyme hexokinase 1 (HK1). • The SN and SP of these autoantibodies are 40% and 96.1% for anti- KLHL12, respectively, and 45% and 96.9%, for anti-HK1, respectively. • The sensitivity of either anti-KLHL12 or anti-HK1 is higher than that of anti-gp210 or anti-sp100 but still modest at best. • Using a combination of these two autoantibodies along with AMAs and PBC-specific types of ANA markedly improves sensitivity in all PBC pts (95%) as well as pts with AMA-negative PBC (75%). 51
  52. 52. • Additional biochemical abnormalities in pts with PBC include hypergammaglobulinemia with a selective elevation of IgM. 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. 52
  53. 53. PBC-Specific ANAs and Clinical Correlation ZAKIM 53
  54. 54. Imaging • PBC does not cause any abnormality to liver morphology that may be detected by imaging. However, pts with suspected PBC should have an abdominal ultrasound to rule out extrahepatic causes of cholestasis or liver neoplasms. • Liver imaging is also useful to identify signs of advanced PBC, which are similar to other CLD, and include: PHTN, splenomegaly or ascites. • The presence of hilar lymphadenopathy is frequent in pts with PBC. • Lymphadenopathy has been reported in 62% to 88% with PBC, mainly in the periportal region. Frequently, portocaval, cardiophrenic, gastroduodenal, periaortic, and peripancreatic adenopathy is also reported. • Although the risk of lymphoma is reportedly <1%, bulky lymphadenopathy may need further investigation to exclude malignancy. 54
  55. 55. Imaging • Abdominal ultrasound is the first recommended imaging technique for all patients to exclude mechanical bile duct obstruction, mass lesions (in and outside the liver) and abnormalities of the gallbladder. It is sensitive, non- invasive, portable and relatively inexpensive. • Its findings, however, are operator dependent and abnormalities of bile ducts may be missed. • In the context of a normal abdominal ultrasound, a diagnosis of intrahepatic cholestasis is most likely. 55
  56. 56. 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 . • Endoscopic ultrasound (EUS) is clinically equivalent to MRCP in the detection of bile duct stones and lesions causing extrahepatic obstruction, particularly of the distal bile duct. 56
  57. 57. MRI • Liver morphology studies show that hypertrophy of the left lobe or caudate is frequently seen. Investigators have reported a lacelike pattern of fibrosis, with thin or thick bands of low attenuation surrounding regenerating nodules, by T2-weighted MRI and CT in advanced PBC. • This finding, however, is not specific for PBC. The “halo sign” by MRI— hypointense areas encircling small portal vein branches, which would represent areas of fibrous deposition around the portal triads—is thought to have some specificity to PBC. • Finally, MRI with MRCP can also be used to differentiate the pruning of small intrahepatic bile ducts seen with advanced-stage PBC from the typical beading pattern of stricturing and dilatations characteristic of PSC. 57
  58. 58. 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. 58
  59. 59. Histology • With increased awareness of the disease among healthcare providers and improved sensitivity of newer-generation AMA tests, liver biopsy is no longer considered a requirement to make the diagnosis of PBC. • Moreover, prognostic information can be obtained through well-validated mathematical models that do not require input regarding histologic results. • Liver biopsy is required in following situations: Overlap with autoimmune hepatitis An alternative diagnosis, such as small-duct PSC Serum alkaline phosphatase level <1.5 times the ULN plus a serum AST level >5 times the ULN. AMA Negative PBC 59
  60. 60. Histology • One of the earliest histologic changes may be a loss of the canals of Hering, which can be demonstrated by biliary cytokeratin 19 staining. • Damage to the epithelial cells of the small bile ducts can also be appreciated early in the disease course. • The most important and only diagnostic clue in many cases is ductopenia, defined as the absence of interlobular bile ducts in >50% of portal tracts. • The florid duct lesion, in which the epithelium of the interlobular and segmental bile ducts degenerates segmentally, with formation of poorly defined, noncaseating epithelioid granulomas, is nearly diagnostic of PBC, mainly in early stages. • In PBC only bile ducts that are <100 μm in diameter are involved. 60
  61. 61. Histology: Ludwig and Scheuer systems • Two staging systems have been used to describe the histologic progression of PBC—Ludwig and Scheuer systems, which are both similar. • In Stage I disease there is inflammation and nonsuppurative destruction of the bile ducts; the infiltrates contain lymphocytes, plasma cells, eosinophils, and mast cells, and the process is restricted to the portal tracts. Epithelioid noncaseating granulomas form very close to the injured bile duct, forming the so-called florid duct lesion. They can occasionally be seen in the lobule as well. • Florid duct lesion which is pathognomonic of PBC but only present in approximately 36–55% of pts with PBC, with an inverse correlation between its prevalence and staging of the disease (53% in early stages and 21% in late stages) [1,2]. • As the disease progresses, these damaged bile ducts disappear, causing ductopenia, a very important diagnostic hint. 1. Degott C, Zafrani ES, Callard P, Balkau B, Poupon RE, Poupon R. Histopathological study of primary biliary cirrhosis and the effect of ursodeoxycholic acid treatment on histology progression. Hepatology 1999;29(4):1007–12. 2. Combes B, Markin RS, Wheeler DE, et al. The effect of ursodeoxycholic acid on the florid duct lesion of primary biliary cirrhosis. Hepatology 1999;30(3):602–5. 61
  62. 62. Histology: stage 2 disease • In stage 2 disease, the inflammation extends from the portal tract into the hepatic parenchyma; this lesion is called interface hepatitis or (formerly) piecemeal necrosis. • There are two main types of interface hepatitis. • The first is lymphocytic piecemeal necrosis, the association of hepatocellular necrosis or apoptosis with lymphohistiocytic cells. This is similar to the lesion found in autoimmune hepatitis (AIH). • Second is biliary piecemeal necrosis, which is marked by a striking ductular reaction, sometimes referred to as ductular proliferation, and accompanied by edema, neutrophil infiltration, periductular fibrosis, and necrotic hepatocytes, the latter associated with cholestasis. • The French have shown that severity of interface hepatitis is highly predictive of development of extensive fibrosis.[1,2] • Both Stage I and Stage II are considered “early.” 1. Corpechot C, Carrat F, Poupon R, Poupon RE. Primary biliary cirrhosis: incidence and predictive factors of cirrhosis development in ursodiol treated patients. Gastroenterology 2002;122:652-658. 2. Degott C, Zafrani ES, Callard P, Balkau B, Poupon RE, Poupon R. Histopathological study of primary biliary cirrhosis and the effect of ursodeoxycholic acid treatment on histology progression. HEPATOLOGY 1999;29:1007-1012. 62
  63. 63. Histology: stage 3 & 4 disease • Stage III is characterized by a distortion of the hepatic architecture with numerous fibrous septa. • Cirrhosis with the existence of regenerative nodules defines stage IV. • Nodular regenerative hyperplasia is a known complication of PBC and should be differentiated from cirrhosis. • Interestingly, features of all stages can overlap. For instance, a florid duct lesion can be seen in a biopsy specimen with septal fibrosis and interface hepatitis. • These classification systems have been criticized for not allowing more detailed staging, especially with respect to the degree of fibrosis. 63
  64. 64. Schematic representation of the staging system of PBC (Ludwig) Stage I is inflammation within the portal space, focused on the bile duct. Stage II occurs when the inflammation extends into the hepatic parenchyma (interface hepatitis or piecemeal necrosis). Stage III is fibrosis. Stage IV is cirrhosis with regenerative nodules. ZAKIM 64
  65. 65. Liver histologic abnormalities in PBC (A) Stage 1: a damaged bile duct is surrounded by chronic inflammatory cells. (B) Stage 2: proliferation of abnormal bile ductules and chronic inflammation of portal tract. (C)Stage 3: portal fibrosis. (D)Stage 4: cirrhosis SCHIFF 65
  66. 66. Histology: Florid duct lesion in PBC .A, H & E stain (magnification approximately ×200) demonstrating a classic florid duct lesion in a patient with PBC. (From Sclair SN, Little E, Levy C.Current Concepts in PBC and PSC. Clinical and Translational Gastroenterology. 2015; 6, e109.) B, Immunostaining of the portal tract in A with anticytokeratin-7 highlighting the bile duct that is infiltrated with lymphocytes. (Courtesy of Nilesh Kashikar MD, PhD, University of Miami.) 66
  67. 67. Ludwig’s histological staging classification for PBC SCHIFF67
  68. 68. Histology: Other staging systems • Two new histologic scores have been devised for use in PBC: the Japanese staging system (Nakanuma) and the French staging system, also called FBI (fibrosis, bile duct ratio, interface hepatitis). • These systems appear reproducible, but are not yet used routinely in clinical practice. Specifically, the Japanese system may correlate with clinical outcome as well. 68
  69. 69. Nakanuma’s histological grading and staging system for PBC 69
  70. 70. Nakanuma’s histological grading and staging system for PBC 70
  71. 71. Treatment: Therapies to slow disease progression • Ursodeoxycholic acid • Obeticholic Acid • Budesonide & others • Fibric acid derivatives • Immunomodulators • Stem Cell Transplantation SCHIFF 71
  72. 72. Ursodeoxycholic acid • Recommended for all pts with PBC by AASLD/EASL and is usually continued for life . • Data suggest that the optimum dose is 13–15 mg/kg per day, which can be given as a single oral daily dose or divided doses. In PBC, a dose of 13–15 mg/kg/day has been reported to be superior to 5–7 mg/kg/day or 23–25 mg/kg/day. • Reductions in biochemistries may be noticed in the first 1–2 weeks of therapy, and will continue over the next 3–6 months. • UDCA is very safe, with minimal side effects when administered to pts at its recommended dose (AE: weight gain of 3 kg in the first 12 months, hair thinning, and, rarely, diarrhea and flatulence are reported). • 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. 72
  73. 73. UDCA: Mechanism of Action • 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. 73
  74. 74. Review of studies on UDCA • Of the 16 randomised clinical trials evaluating UDCA against placebo[1], the administration of UDCA was a/with an improvement of serum liver tests. • An updated Cochrane meta-analysis showed that overt ascites and jaundice are less frequent in pts randomised to UDCA, but there was no difference in the number of pts with bleeding varices or HE [2]. • The protective effect of UDCA on the development of EV has also been addressed prospectively, and in a study of 180 pts with PBC, the 4-year probability was significantly lower in treated vs. untreated pts (16% vs. 58%; p<0.001) [3]. 1. 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. 2. Rudic JS, Poropat G, Krstic MN, Bjelakovic G, Gluud C. Ursodeoxycholic acid for primary biliary cirrhosis. Cochrane Database Syst Rev 2012;12: CD000551. 3. Invernizzi P, Alessio MG, Smyk DS, Lleo A, Sonzogni A, Fabris L, et al. Autoimmune hepatitis type 2 associated with an unexpected and transient presence of primary biliary cirrhosis-specific antimitochondrial antibodies: a case study and review of the literature. BMC Gastroenterol 2012;12:92. 74
  75. 75. Review of studies on UDCA • A Canadian study[1] measured the portohepatic gradient in 132 pts with PBC at baseline and every 2 years thereafter. • The investigators noticed that after 2 years of RX with UDCA the gradient was either stabilized or decreased, and such response predicted better survival on analysis. • Another independent predictor was normalization of the serum AST level at 2 years. • Pts who achieved both goals were considered “responders,” and they had the same 15-year survival as the control population. 1. Huet PM, et al: Portal hypertension and primary biliary cirrhosis: effect of long-term ursodeoxycholic acid treatment. Gastroenterology 135:1552–1560, 2008. 75
  76. 76. Review of studies • The definition of response to therapy has been the subject of debate, and defining who is a biochemical responder is important in identifying pts who could benefit from additional therapies. • Pares et al. showed that pts with PBC who had normalization or at least a 40% ↓ from baseline values toward the ULN in the ALP level after 1 yr of RX with UDCA had similar survival times as the age and gender-matched control population and significantly better outcomes than predicted by the Mayo risk score after up to 16 yrs of follow-up.[1] • These predictors came to be known as the Barcelona criteria. 1. Pares A, et al: Excellent long-term survival in patients with primary biliary cirrhosis and biochemical response to ursodeoxycholic acid. Gastroenterology 130:715–720, 2006. 76
  77. 77. Review of studies: Paris criteria • Corpechot et al. developed a new set of goals, known as the Paris criteria, to define biochemical responders to UDCA. • In this study involving 292 pts with PBC, investigators demonstrated that the combination of a bilirubin ≤1 mg/dL, ALP ≤3X ULN, and AST ≤ 2X ULN after 1 yr of therapy could accurately discriminate pts at lower risk of death or LT.[1] • Indeed, pts who did not meet those criteria had a 2.5X ↑ in the risk of death or LT. • Yet another conclusion of the study was that long-term RX with UDCA over a 7-yr period was a/with a 40% ↓in the risk of death or LT when compared with survival estimated by the Mayo risk score. 1. Corpechot C, et al: Biochemical response to ursodeoxycholic acid and long-term prognosis in primary biliary cirrhosis. Hepatology 48:871–877, 2008. 77
  78. 78. Review of studies: Rotterdam criteria • A subsequent Dutch study (Rotterdam criteria)[1] assessing the usefulness of serum albumin and bilirubin in determining long-term prognosis. The investigators reached the following conclusions: 1. Pts with normal baseline values for S. albumin and bilirubin have survival similar to the general population. 2. Normalization of S. albumin and/or bilirubin levels after 1 yr of RX with UDCA when one or both of these parameters was (were) abnormal at baseline is a/with ↑ survival free of LT, compared with pts who do not normalize. The Paris criteria performed well in discriminating pts at higher mortality risk, but the Rotterdam criteria only worked well for individuals with early-stage disease (defined as normal baseline serum albumin and bilirubin concentrations).[1] 1. Kuiper EM, et al: Improved prognosis of patients with primary biliary cirrhosis that have a biochemical response to ursodeoxycholic acid. Gastroenterology 136:1281–1287, 2009. 78
  79. 79. The Mayo Natural History Model for PBC • It is the most validated mathematical model for predicting survival for individuals with PBC and utilizes readily available biochemical data and clinical findings, without the need for liver biopsy [1]. • The variables included in this model include age, bilirubin, albumin, prothrombin time, presence of peripheral edema, and use of diuretics. • A Mayo PBC score >4.1 is used as a threshold to advocate initiation of screening and surveillance protocols for GEV and HCC [2]. 1. Dickson ER, Grambsch PM, Fleming TR, Fisher LD, Langworthy A. Prognosis in primary biliary cirrhosis: model for decision making. Hepatology 1989;10(1):1–7. 2. Lindor KD,GershwinME, Poupon R, et al. Primary biliary cirrhosis. Hepatology 2009;50(1):291–308. 79
  80. 80. Sample: Mayo model Source: https://www.mayoclinic.org 80
  81. 81. Review of studies: PBC Globe Score[1] • Regardless of the stage of disease, all studies show a longterm benefit of UDCA therapy in PBC in pts who have a biochemical response as defined by any of the previously mentioned criteria. • Recently, the Global PBC Study Group[1], an international consortium of 15 North American and European centers, reported that serum levels of ALP and bilirubin followed annually correlated with important clinical outcomes. • The Global PBC Study Group [4] (n = 4,845), revealed a significantly improved liver transplant-free survival in treated vs. untreated (at 5 years, 10 years and 15 years: 90%, 78%, and 66% vs. 79%, 59%, and 32% for UDCA-treated and non-treated group, respectively; p<0.001). • A PBC GLOBE score of >0.3 predicts decreased survival. Conversely, a PBC GLOBE score of 0.3 or less is associated with normal survival [94]. • Calculator available at http://www.globalpbc.com/globe 1. Lammers WJ, van Buuren HR, Hirschfield GM, Janssen HL, Invernizzi P, Mason AL, et al. Levels of alkaline phosphatase and bilirubin are surrogate end points of outcomes of patients with primary biliary cirrhosis: an international follow-up study. Gastroenterology 2014;147:1338–1349. 2. Lammers WJ, Hirschfield GM, Corpechot C, et al. Development and validation of a scoring system to predict outcomes of patients with primary biliary cirrhosis receiving ursodeoxycholic acid therapy. Gastroenterology 2015;149(7):1804–12.e4. 81
  82. 82. UK-PBC Score • Another prognostic scoring system recently developed and validated by the UK-PBC consortium includes baseline albumin level and platelet count, as well as levels of bilirubin, aminotransferases, and ALP after 12 mnths of therapy with UDCA (available online at: www.ukpbc.com). [1] • It estimate the risk (expressed in percentage) that a PBC pt established on RX with UDCA will develop liver failure requiring LT within 5, 10 or 15 years from diagnosis. • The score may be used to identify high-risk pts for closer monitoring and second-line therapies, as well as low-risk pts who could potentially be followed-up in primary care. 1. CarboneM, Sharp SJ, Flack S, et al. The UK-PBC risk scores: Derivation and validation of a scoring system for long-term prediction of end-stage liver disease in primary biliary cholangitis. Hepatology 2016;63(3):930–50. 82
  83. 83. Prognostic scores for PBC: SUMMARY 83
  84. 84. References to the previous slide 94.Lammers WJ, Hirschfield GM, Corpechot C, et al. Development and validation of a scoring system to predict outcomes of patients with primary biliary cirrhosis receiving ursodeoxycholic acid therapy. Gastroenterology 2015;149(7):1804–12.e4. 95. Pares A, Caballeria L, Rodes J. Excellent long-term survival in patients with primary biliary cirrhosis and biochemical response to ursodeoxycholic acid. Gastroenterology 2006;130(3):715–20. 96. Corpechot C, Abenavoli L, Rabahi N, et al. Biochemical response to ursodeoxycholic acid and long-term prognosis in primary biliary cirrhosis. Hepatology 2008;48(3):871–7. 97. Corpechot C, Chazouilleres O, Poupon R. Early primary biliary cirrhosis: biochemical response to treatment and prediction of longterm outcome. J Hepatol 2011;55(6):1361–7. 98.Kumagi T, Guindi M, Fischer SE, et al. Baseline ductopenia and treatment response predict long-term histological progression in primary biliary cirrhosis. Am J Gastroenterol 2010;105(10):2186–94. 99. CarboneM, Sharp SJ, Flack S, et al. The UK-PBC risk scores: Derivation and validation of a scoring system for long- term prediction of end-stage liver disease in primary biliary cholangitis. Hepatology 2016;63(3):930–50. 100. Kuiper EM, Hansen BE, de Vries RA, et al. Improved prognosis of patients with primary biliary cirrhosis that have a biochemical response to ursodeoxycholic acid. Gastroenterology 2009;136(4):1281–7. 101. Dickson ER, Grambsch PM, Fleming TR, Fisher LD, Langworthy A. Prognosis in primary biliary cirrhosis: model for decision making. Hepatology 1989;10(1):1–7. 102. Freeman RB, Jr., Wiesner RH, Harper A, et al. The new liver allocation system: moving toward evidence-based transplantation policy. Liver Transpl 2002;8(9):851–8. 84
  85. 85. Obeticholic acid • In 2016, the US and European Union approved the first adjunctive therapy to UDCA for PBC, obeticholic acid (OCA). • OCA is a bile acid derivative, 6-ethyl chenodeoxycholic acid, which is a potent agonist of the FXR . Stimulating FXR leads to increased excretion of bile acids into the bile, decreased ileal uptake of bile acids, and decreased synthesis of new bile acids. • OCA also has anti-inflammatory and antifibrotic properties. 1. Beuers U, Trauner M, Jansen P, Poupon R. New paradigms in the treatment of hepatic cholestasis: from UDCA to FXR, PXR and beyond. J Hepatol 2015;62:S25–S37. 2. Trauner M, Fuchs CD, Halilbasic E, Paumgartner G. New therapeutic concepts in bile acid transport and signalling for management of cholestasis. Hepatology 2017;65:1393–1404. 3. Schaap FG, Trauner M, Jansen PL. Bile acid receptors as targets for drug development. Nat Rev Gastroenterol Hepatol 2014;11:55–67. 4. Gomez-Ospina N, Potter CJ, Xiao R, Manickam K, Kim MS, Kim KH, et al. Mutations in the nuclear bile acid receptor FXR cause progressive familial intrahepatic cholestasis. Nat Commun 2016;7 10713.85
  86. 86. Review of studies on OCA • The first randomised, double-blind controlled trial of OCA in PBC evaluated the therapeutic efficacy of three doses (10, 25, and 50 mg/day) as an add-on therapy to UDCA in a multicenter study restricted to pts(N=165) with persistent elevations in serum ALP (>1.5X ULN) [1]. • In this study, the primary endpoint was a significant reduction in serum ALP from baseline, and was met across all three doses of OCA vs. placebo. • Moreover, 87%, 69% and 7% of all OCA-treated pts who completed therapy achieved a decline in serum ALP of at least 10%, 20% or complete normalisation (vs. 14%, 8% and 0% with placebo). Note: end of study day 85. • In the extension study, levels of ALP continued to decrease to a mean level of 202 ± 11 U/L after 12 mnths vs 285 ± 15 U/L at baseline. 1. Hirschfield GM, Mason A, Luketic V, Lindor K, Gordon SC, Mayo M, et al. Efficacy of obeticholic acid in patients with primary biliary cirrhosis and inadequate response to ursodeoxycholic acid. Gastroenterology 2015;148:751–761. CONCLUSIONS: 1. Daily doses of OCA, ranging from 10 to 50 mg, significantly reduced levels of ALP, GGT, and ALT, compared with placebo, in pts with PBC who had inadequate responses to UDCA. 2. The incidence and severity of pruritus were lowest among pts who received 10 mg/d OCA. 3. Biochemical responses to OCA were maintained in a 12-month open-label extension trial. 86
  87. 87. POISE STUDY • Data from the PBC OCA International Study of Efficacy phase III clinical trial (POISE) have been published [1]. • The POISE study recruited pts(n=217) with PBC and a persistent elevation in serum ALP (prior biochemical non-responders according to modified Toronto criterion; ALP >1.67X ULN and/or elevated total bilirubin <2X ULN). • The primary endpoint during the 12-mnth period was attainment of both an ALP value <1.67X ULN (with a ≥15% reduction from baseline) and a normal serum bilirubin level. • Biochemical response was met in 10% of the placebo group relative to 47% and 46% in the 10 mg and 5–10 mg dose-titrated OCA groups, respectively (p<0.0001 for both). Note: 93% received UDCA. Both OCA groups met predefined end-points). 1. 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. CONCLUSIONS: OCA acid administered with ursodiol or as monotherapy for 12 mnths in pts with PBC resulted in ↓ from baseline in alkPO4 and total bilirubin levels that differed significantly from the changes observed with placebo. However, there were more adverse events with obeticholic acid. 87
  88. 88. Obeticholic acid • Treatment with OCA is a/with a dose dependent exacerbation in pruritus, leading to treatment discontinuation in 1–10% of pts [1,2]. • OCA-treated pts may also exhibit (reversible) alterations in serum lipid levels [1,2]; specifically, a decrease in HDL and total cholesterol. It is not yet known whether these consequences impact long-term cardiovascular risk. 1. Hirschfield GM, Mason A, Luketic V, Lindor K, Gordon SC, Mayo M, et al. Efficacy of obeticholic acid in patients with primary biliary cirrhosis and inadequate response to ursodeoxycholic acid. Gastroenterology 2015;148:751–761. 2. 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. EASL Recommendation: Oral OCA has been conditionally approved for pts with PBC in combination with UDCA for those with an inadequate response to UDCA, or as monotherapy in those intolerant to UDCA. EASL suggests considering its use in such pts (initial dose 5 mg; dose titration to 10 mg according to tolerability at 6 mnths). 88
  89. 89. Other drugs in older studies • A variety of older drugs have been tested without major success in pts with PBC, including immunosuppressants (prednisolone, azathioprine, cyclosporine, chlorambucil, MTX, budesonide, and mycophenolate mofetil), antifibrotic agents (D-penicillamine and colchicine), and thalidomide. • As a result of the immune nature of PBC, corticosteroids and other immunosuppressants received early attention. • However, despite a marginal effect noticed with some of these drugs given alone or in combination with UDCA, treatment-related irreversible side effects preclude their clinical use. 89
  90. 90. Budesonide • Budesonide is a synthetic corticosteroid resulting in minimal systemic side effects when compared to prednisolone [1]. • Nevertheless, the pharmacokinetics of budesonide become augmented as liver disease progresses, and can result in deleterious outcomes in pts with cirrhosis and PHTN [1]. • A 1999 randomised placebo-controlled trial (n = 39) was the first to study budesonide (9 mg/d) as addon therapy to UDCA in pts with early-stage PBC [2]. • Over the 2-year study period, pts receiving combination therapy exhibited a significant reduction in serum ALP as well as improvement in liver histology according to the Ludwig classification system. 1. Hempfling W, Grunhage F, Dilger K, Reichel C, Beuers U, Sauerbruch T. Pharmacokinetics and pharmacodynamic action of budesonide in earlyand late-stage primary biliary cirrhosis. Hepatology 2003;38:196–202. 2. Leuschner M, Maier KP, Schlichting J, Strahl S, Herrmann G, Dahm HH, et al. Oral budesonide and ursodeoxycholic acid for treatment of primary biliary cirrhosis: results of a prospective double-blind trial. Gastroenterology 1999;117:918–925 90
  91. 91. • Moreover, in a subsequent 3-year randomised, non-blinded study performed in non-cirrhotic PBC pts (n = 77), budesonide 6 mg/day + UDCA (n = 46) was a/with a 25% regression in liver fibrosis [1]. • However, despite encouraging results, there was overall high rate of fibrosis progression (an increase of 70%) in pts. • A US based open-label study [2] of 22 biochemical non-responders (ALP persistently >2XULN) reported only a very minimal additional benefit of budesonide to UDCA, with a significant ↑ in the Mayo PBC score prognostic index, and significant deterioration in bone mineral density. 1. . 2. Rautiainen H, Karkkainen P, Karvonen AL, Nurmi H, Pikkarainen P, Nuutinen H, et al. Budesonide combined with UDCA to improve liver histology in primary biliary cirrhosis: a three-year randomized trial. Hepatology 2005;41:747–752. 3. Angulo P, Jorgensen RA, Keach JC, Dickson ER, Smith C, Lindor KD. Oral budesonide in the treatment of patients with primary biliary cirrhosis with a suboptimal response to ursodeoxycholic acid. Hepatology 2000;31:318–323. Data from phase III randomised trials for budesonide (in non-cirrhotic patients), and bezafibrate, both in combination with UDCA, are not yet published; EASL suggests currently a recommendation for therapy cannot be made. 91
  92. 92. Methotrexate • Methotrexate is still used by some experts for pts who fail to respond to UDCA. • However, a large randomized control study of combination UDCA/methotrexate versus UDCA/ placebo administration for a median follow-up time of 7.6 yrs did not demonstrate any additional benefit of methotrexate on progression of disease, development of EV, need for LT, or ↓ mortality in comparison with the use of UDCA alone.[1] 1. Combes B, et al: Methotrexate (MTX) plus ursodeoxycholic acid (UDCA) in the treatment of primary biliary cirrhosis. Hepatology 42:1184–1193, 2005. 92
  93. 93. Fibric acid derivatives • Early studies have evaluated the use of bezafibrate (400 mg per day) as an adjunctive therapy to UDCA, in which normalization of serum ALP was reported in 45% of pts who did not respond to UDCA vs. 18% taking placebo [1]. • More recently, a non-blinded prospective randomised-controlled study (n = 27; 100–120 mnths of RX) reported that pts’ serum ALP levels were significantly lower following combination therapy (UDCA + bezafibrate), and were a/with a trend towards improved overall survival (p = 0.057) [2]. • Data from an open-label study (n = 28) also showed a significant improvement in itch severity in pts treated with bezafibrate, wherein all 12 pts who reported itch prior to starting treatment achieved complete or partial symptom resolution [3]. Moreover, 20 and 24 pts who did not respond to UDCA attained a serum ALP reduction >40% within 6 and 12 months, respectively, with combination bezafibrate therapy. 1. Kanda T, Yokosuka O, Imazeki F, Saisho H. Bezafibrate treatment: a new medical approach for PBC patients? J Gastroenterol 2003;38:573–578. 2. Hosonuma K, Sato K, Yamazaki Y, Yanagisawa M, Hashizume H, Horiguchi N, et al. A prospective randomized controlled study of long-term combination therapy using ursodeoxycholic acid and bezafibrate in patients with primary biliary cirrhosis and dyslipidemia. Am J Gastroenterol 2015;110:423–431. 3. Lens S, Leoz M, Nazal L, Bruguera M, Pares A. Bezafibrate normalizes alkaline phosphatase in primary biliary cirrhosis patients with incomplete response to ursodeoxycholic acid. Liver Int 2014;34:197– 203. 93
  94. 94. Fibric acid derivatives • Fibrates exert potent anti-cholestatic effects through the variable activation of peroxisome proliferator-activated receptors (PPAR), in addition to downregulation of several pathways leading to bile acid synthesis [1]. • Whilst there is long-standing interest regarding these agents in cholestatic liver disease [2,3], in some jurisdictions, drug labelling has documented contraindication to their use in PBC because of concerns over reported hepatotoxicity. 1. Ghonem NS, Assis DN, Boyer JL. Fibrates and cholestasis. Hepatology 2015;62:635–643. 2. Yin Q, Li J, Xia Y, Zhang R, Wang J, Lu W, et al. Systematic review and metaanalysis: bezafibrate in patients with primary biliary cirrhosis. Drug Des Devel Ther 2015;9:5407–5419. 3. Tanaka A, Hirohara J, Nakanuma Y, Tsubouchi H, Takikawa H. Biochemical responses to bezafibrate improve long-term outcome in asymptomatic patients with primary biliary cirrhosis refractory to UDCA. J Gastroenterol 2015;50:675–682. EASL suggests currently a recommendation for therapy cannot be made 94
  95. 95. Immunomodulators • Novel therapies targeting the immune response have also been studied. Rituximab, a monoclonal antibody against CD20, was evaluated as proof of concept in two small pilot studies.[1,2] • Use of rituximab was a/with only a modest improvement in serum ALP levels but a significant decrease in autoantibody production. • Studies with ustekinumab, an antibody directed at the common IL12/IL23 p40 chain, and NI-08091, an anti-CXCL10 monoclonal antibody, yielded negative results. • Other immunomodulatory drugs are currently under evaluation in PBC, including abatacept, a T cell inhibitor. 1. Tsuda M, et al: Biochemical and immunologic effects of rituximab in patients with primary biliary cirrhosis and an incomplete response to ursodeoxycholic acid. Hepatology 55:512–521, 2012. 2. Myers RP, et al: B-cell depletion with rituximab in patients with primary biliary cirrhosis refractory to ursodeoxycholic acid. Am J Gastroenterol 108:933–941, 2013. 95
  96. 96. Stem Cell Transplantation • Umbilical cord–derived mesenchymal stem-cell transplantation was attempted in 10 pts. Although a significant improvement was noted in serum ALP levels, other liver biochemistries, IgM, and Mayo Risk Score were unchanged. • Long-term effects of stemcell transplantation in PBC are not known. ZAKIM 96
  97. 97. Treatment of PBC symptoms and consequences • Pruritus • Fatigue • Sicca complex • Metabolic Bone Disease:Osteoporosis • Fat-Soluble Vitamin Deficiency • Hyperlipidaemia • Varices • HCC • Liver transplantation • Recurrent PBC Special settings: • Pregnancy • Overlap Syndrome 97
  98. 98. Pruritus: general measures • Practical advice must also be given to pts and should encompass aspects of care including: 1. Use of emollients and oat meal extract to improve dry and inflamed skin. 2. Use of cold water for baths to provide some symptom relief of pruritus triggered or exacerbated by heat/warmth (at night). There is no evidence to suggest that UDCA has any effect on pruritus [1,2], whilst OCA at higher doses can exacerbate it. 1. 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. 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. 98
  99. 99. 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(non-absorbable resin); Starting dose is 4 g/day, which can be increased up to four times daily. • Colesevelam is a newer, often better tolerated, bile sequestrant, however, despite clinicians describing benefit and significant decreases in serum bile acid levels, a recent placebo-controlled trial failed to demonstrate effectiveness [3]. 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. 3. Kuiper EM, van Erpecum KJ, Beuers U, Hansen BE, Thio HB, de Man RA, et al. The potent bile acid sequestrant colesevelam is not effective in cholestatic pruritus: results of a double-blind, randomized, placebo-controlled trial. Hepatology 2010;52:1334–1340. 99
  100. 100. Pruritus: management: Rifampicin • Rifampicin is a second-line agent, which probably acts through its function as a pregnane X receptor agonist [1]. • Randomised, placebo-controlled trials have shown rifampicin to be effective in the MX of cholestatic pruritus [2-5]. This effect has been confirmed in meta- analyses [6,7]. • Given a 10% to 15% risk of hepatitis, start at only 150 mg/day and titrate up to a maximum of 300 mg twice a day.[8] (NOTE: EASL: 150-300 mg od) • Importantly, rifampicin also affects vit K metabolism and can lead to an ↑in INR[9]. 1. Kremer AE, van Dijk R, Leckie P, Schaap FG, Kuiper EMM, Mettang T, et al. Serum autotaxin is increased in pruritus of cholestasis, but not of other origin and responds to therapeutic interventions. Hepatology 2012;56:1391–1400. 2. Ghent CN, Carruthers SG. Treatment of pruritus in primary biliary cirrhosis with rifampicin. Results of a double-blind, crossover, randomized trial. Gastroenterology 1988;94:488–493. 3. Bachs LP, Pares A, Elena M, Piera C, Rodes J. Comparison of rifampicin with phenobarbitone for treatment of pruritus in biliary cirrhosis. Lancet 1989;1:574–576. 4. Podesta AL, Terg P, Villamil R, Flores F, Mastai D, Udaondo R, et al. Treatment of pruritus in primary biliary cirrhosis with rifampicin. Results of a doubleblind, cross-over, randomized trial. Gastroenterology 1991;94:488–493. 5. Bachs LP, Elena M, Piera M, Rodes J. Effects of long-term rifampicin administration in primary biliary cirrhosis. Gastroenterology 1992;102:2077–2080. 6. Tandon P, Rowe BH, Vandermeer B, Bain VG. The efficacy and safety of bile acid binding agents, opioid antagonists or rifampin in the treatment of cholestasis-associated pruritus. Am J Gastroenterol 2007; 102:1528–1536. 7. Khurana S, Singh P. Rifampin is safe for treatment of pruritus due to chronic cholestasis: a meta-analysis of prospective randomized-controlled trials. Liver Int 2006;26:943–948. 8. EASL Clinical Practice Guidelines: management of cholestatic liver diseases. J Hepatol 51:237–267, 2009. 9. Sampaziotis F, Griffiths WJ. Severe coagulopathy caused by rifampicin in patients with primary sclerosing cholangitis and refractory pruritus. Br J Clin Pharmacol 2012;73:826–827. EASL recommends monitoring serum liver tests after initial use (at 6 and 12 weeks following drug initiation) The agent should be stopped if toxicity is observed. 100
  101. 101. Pruritus: management: SSRI: opiate antagonists • Oral opiate antagonists (naltrexone and nalmefene) are used as third-line therapy as they can reduce the sensation of itching [1,2,3]. • Naltrexone (20-50 mg per day) should be started at a low dose to avoid opioid withdrawal–like reaction( restlessness, anxiety, muscle pain, and confusion) in the first few days of treatment [4]. 1. Bergasa NV, Talbot TL, Alling DW, Schmitt JM, Walker EC, Baker BL, et al. A controlled trial of naloxone infusions for the pruritus of chronic cholestasis. Gastroenterology 1992;102:544–549. 2. Wolfhagen FHJ, Sternieri E, Hop WCJ, Vitale G, Bertoletti M, Van Buuren HR. Oral naltrexone for cholestatic pruritus-a double-blind, placebo-controlled study. Gastroenterology 1997;113:1264– 1269. 3. Terg R, Coronel E, Sorda J, Munoz AE, Findor J. Efficacy and safety of oral naltrexone treatment for pruritus of cholestasis, a crossover, double blind, placebo-controlled study. J Hepatol 2002;37:717–722. 4. Jones EA, Neuberger JM, Bergasa NV. Opiate antagonist therapy for the pruritus of cholestasis: the avoidance of opioid withdrawal-like reactions. Q J Med 2002;95:547–552. 101
  102. 102. Pruritus: management: SSRI and others • Selective serotonin reuptake inhibitors (SSRIs; e.g. sertraline) and gabapentin are used empirically in the MX of cholestatic itch, typically in pts with pruritus unresponsive to other agents. SSRIs are presumed to act via altering the concentrations of neurotransmitters within the CNS. • There are some reports of efficacy in the literature but only a single small placebo-controlled trial [1]. Side effects of SSRIs include dry mouth. The optimum dose is 75 to 100 mg/day, and is usually well tolerated. • Gabapentin has been suggested as a potential RX due to its proposed effect, increasing nociception threshold. However, a small trial failed to show benefit over placebo [2]. • Anti-histamines sometimes have a non-specific anti-pruritic effect, which may be due to their sedative properties but are not recommended as specific therapy; they are, however, useful adjuncts for some. 1. Mayo MJ, Handem I, Saldana S, Jacobe H, Getachew Y, Rush AJ. Sertraline as a first-line treatment for cholestatic pruritus. Hepatology 2007;45:666–674. 2. Bergasa NV, McGee M, Ginsburg IH, Engler D. Gabapentin in patients with the pruritus of cholestasis: a double-blind, randomized, placebo-controlled trial. Hepatology 2006;44:1317–1323. 102
  103. 103. Pruritus: management: others • Physical approaches, such as nasobiliary drainage [1,2,3], molecular absorbance recirculating system (MARS) [4] and UV light therapy [5] are all experimental, with case reports/series showing benefit but no formal trial evaluation [6]. • UV light therapy is relatively easy to access in comparison to the other treatments. • Nasobiliary drainage appears to provide transient relief from itching but requires repeated treatments, is technically complicated and difficult to tolerate; pancreatitis is recognised as a potentially significant complication. • Their use should be as salvage therapy for pts with extreme pruritus unresponsive to medical therapy. 1. Beuers U, Gerken G, Pusl T. Biliary drainage transiently relieves intractable pruritus in primary biliary cirrhosis. Hepatology 2006;44:280–281. 2. Hofmann AF, Huet PM. Nasobiliary drainage for cholestatic pruritus. Hepatology 2006;43:1170–1171. 3. Hegade VS, Krawczyk M, Kremer AE, Kuczka J, Gaouar F, Kuiper EM, et al. The safety and efficacy of nasobiliary drainage in the treatment of refractory cholestatic pruritus: a multicentre European study. Aliment Pharmacol Ther 2016;43:294–302. 4. Pares A, Herrera M, Aviles J, Sanz M, Mas A. Treatment of resistant pruritus from cholestasis with albumin dialysis: combined analysis of patients from three centers. J Hepatol 2010;53:307–312. 5. Decock S, Roelandts R, Steenbergen WV, Laleman W, Cassiman D, Verslype C, et al. Cholestasis-induced pruritus treated with ultraviolet B phototherapy:an observational case series study. J Hepatol 2012;57:637–641. 6. Leckie P, Tritto G, Mookerjee R, Davies N, Jones DEJ, Jalan R. ‘‘Out-patient” albumin dialysis for cholestatic patients with intractable itch. Aliment Pharmacol Therap 2012;35:696–704. 103
  104. 104. Pruritus: management: LT • 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. 2. Borgeat A., Wilder-Smith O.H., Mentha G. Subhypnotic doses of propofol relieve pruritus associated with liver disease Gastroenterology 1993 ; 104 : 244-247 3. Villamil A.G., Bandi J.C., Galdame O.A., Gerona S., Gadano A.C. Efficacy of lidocaine in the treatment of pruritus in patients with chronic cholestatic liver diseases Am J Med 2005 ; 118 : 1160-1163 4. Bachs L., Pares A., Elena M., Piera C., Rodes J. Comparison of rifampicin with phenobarbitone for treatment of pruritus in biliary cirrhosis Lancet 1989 ; 1 : 574-576 5. Walt R.P., Daneshmend T.K., Fellows I.W., Toghill P.J. Effect of stanozolol on itching in primary biliary cirrhosis Br Med J (Clin Res Ed) 1988 ; 296 : 607 6. Schworer H., Hartmann H., Ramadori G. Relief of cholestatic pruritus by a novel class of drugs: 5-hydroxytryptamine type 3 (5-HT3) receptor antagonists: effectiveness of ondansetron Pain 1995 ; 61 : 33-37 7. Bergasa N.V. Medical palliation of the jaundiced patient with pruritus Gastroenterol Clin North Am 2006 ; 35 : 113-123 As experimental drug therapies propofol [2], lidocaine [3], phenobarbital [4], stanozolol [5], ondansentrone [6], and butorphanol [7] have been used in the past with variable success. 104
  105. 105. Fatigue: Management • Fatigue is not related to severity of liver disease [1], and it is not responsive to UDCA or OCA [2,3]. • A structured approach to management, quantifying fatigue and its impacts (through the use of tools such as the PBC-40 QoL measure), addressing contributing factors and helping pts to cope with its impact have been shown to be effective [4]. 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. 4. Jones DE, Sutcliffe K, Pairman J, Wilton K, Newton JL. An integrated care pathway improves quality of life in Primary Biliary Cirrhosis. QJM 2008;101:535–543. 105
  106. 106. PBC-40 – Quality of Life for PBC[1] • 40 questions, each scored on a scale of 1 to 5 (where 1 = least impact, 5 = greatest impact) grouped into six domains (symptoms, itch, fatigue, cognition, social, and emotional). For each domain, scoring involved summing individual question response scores. • Explanation of Result : Higher scores indicate a poorer quality of life. 1. Jacoby A1, Rannard A, Buck D, Bhala N, Newton JL, James OF, Jones DE. Development, validation, and evaluation of the PBC-40, a disease specific health related quality of life measure for primary biliary cirrhosis. Gut. 2005 Nov;54(11):1622-9. PMID: 15961522. 106
  107. 107. PBC-40 – Quality of Life for PBC: sample Available from http://gihep.com/pbc40/ 107
  108. 108. Fatigue: Management: Exercise • There is no evidence to suggest that exercise is harmful for pts with PBC fatigue. There are pilot data to suggest that exercise may be beneficial when initiated at levels which can be tolerated by fatigued pts [1]. 1. Dilger K, Hohenester S, Winkler-Budenhofer U, Bastiaansen BA, Schaap FG, Rust C, et al. Effect of ursodeoxycholic acid on bile acid profiles and intestinal detoxification machinery in primary biliary cirrhosis and health. J Hepatol 2012;57:133–140. 2. 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. • Pts with post-transplant PBC typically experience ongoing fatigue, and thus, LT for severe fatigue in the absence of other indications is not appropriate [2]. 108
  109. 109. Fatigue: Management • Neither ondansetron, a 5-HT3 receptor antagonist [1], nor antioxidants [2], nor the antidepressant fluvoxamine [3] have shown an improvement in symptoms in RCT. • Modafinil, a neurostimulant (used for the RX of narcolepsy), has been successful at doses of 100–200 mg day in small open-label trials of PBC [4,5]. However, enthusiasm for its use is hampered by the risk of addiction and chronic headaches. • Coffee contains caffeine, another neurostimulant with a more favorable side effect profile. Although coffee has not been rigorously tested as a MX for fatigue in PBC, it is readily available without prescription, has antifibrotic properties, and is a/with decreased progression to cirrhosis in other CLD [6]. 1. Theal JJ, Toosi MN, Girlan L, et al. A randomized, controlled crossover trial of ondansetron in patients with primary biliary cirrhosis and fatigue. Hepatology 2005;41(6):1305–12. 2. Prince MI, Mitchison HC, Ashley D, et al. Oral antioxidant supplementation for fatigue associated with primary biliary cirrhosis: results of a multicentre, randomized, placebo-controlled, cross-over trial. Aliment Pharmacol Ther 2003;17(1):137–43. 3. van Os E, van den Broek WW, Mulder PG, ter Borg PC, Bruijn JA, van Buuren HR. Depression in patients with primary biliary cirrhosis and primary sclerosing cholangitis. J Hepatol 2007;46(6):1099–103. 4. Jones DE, Newton JL. An open study of modafinil for the treatment of daytime somnolence and fatigue in primary biliary cirrhosis. Aliment Pharmacol Ther 2007;25(4):471–6. 5. Ian Gan S, de Jongh M, Kaplan MM. Modafinil in the treatment of debilitating fatigue in primary biliary cirrhosis: a clinical experience. Dig Dis Sci 2009;54(10):2242–6. 6. Kennedy OJ, Roderick P, Buchanan R, Fallowfield JA, Hayes PC, Parkes J. Systematic review with meta-analysis: coffee consumption and the risk of cirrhosis. Aliment Pharmacol Ther 2016;43(5):562–74.109
  110. 110. 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]. • Pts with severe xerostomia should be given oral hygiene advice to prevent the development of dental caries. Clinicians should also be vigilant of the risk of oral candidiasis in pts with severe xerostomia. 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. 110
  111. 111. Miscellaneous • Up to one-quarter of pts with PBC have Raynaud’s phenomenon which occurs due to spasmodic arterial contraction in the extremities (usually fingers and toes, but sometimes ears and nose) [1]. • Pts should be asked specifically about the classical symptoms of their extremities turning white, then blue and finally red, often a/with pain/burning/tingling when the blood flow returns. Practical measures, such as wearing gloves, using hand warmers and avoiding cold environments, are often all that are needed for mild symptoms. • For more marked symptoms, vasodilators such as calcium channel blockers, can be used [2]. • Approx 8% of pts with PBC have limited scleroderma (CREST syndrome: calcinosis, Raynaud’s phenomenon, oesophageal dysmotility, sclerodactyly, telangiectasia). • These symptoms should be sought and if present, pts should be referred for rheumatology advice. 1. Watt FE, James OFW, Jones DEJ. Patterns of autoimmunity in PBC patients and their families. QJM 2004;97:397–406. 2. Excellence NIfHaC. Raynaud’s Phenomenon NICE Clinical Knowledge Summary. 2014 [cited; Available from: http://cks.nice.org.uk/raynaudsphenomenon – !scenario. 111
  112. 112. Metabolic Bone Disease:Osteoporosis • EASL recommends considering the risk for osteoporosis in all pt with PBC . • Bone mineral density assessment (dual-energy X-ray absorptiometry [DEXA]) should be undertaken at presentation, with follow-up assessment between 1 & 5 yrs later depending on outcome and general osteoporosis risk [2]. (AASLD: at baseline and every 2-3 yrs) • Any intervention for osteoporosis must account for overall fracture risk, which can be calculated by the WHO FRAX score . • Several trials have demonstrated that bisphosphonates, especially weekly alendronate and monthly ibandronate, are effective in increasing bone mass in pts with PBC [1]. 1. Guanabens N, Monegal A, Cerda D, Muxi A, Gifre L, Peris P, et al. Randomized trial comparing monthly ibandronate and weekly alendronate for osteoporosis in patients with primary biliary cirrhosis. Hepatology 2013;58:2070–2078. 2. Newton J, Francis R, Prince M, James O, Bassendine M, Rawlings D, et al. Osteoporosis in primary biliary cirrhosis revisited. Gut 2001;49:282–287. 3. EASL Clinical Practice Guidelines: management of cholestatic liver diseases. J Hepatol 51:237–267, 2009. The European clinical practice guidelines suggest the use of alendronate for those pts with a T score of less than −2.5 by DEXA scan or following pathologic fracture.[3] In particular, bisphosphonates should be considered for osteopenic pts when there is a 10-yr hip fracture probability ≥3%, or a 10-year major osteoporosis related fracture probability ≥ 20% based on the WHO fracture risk model. 112
  113. 113. WHO FRAX score calculator (sample) Available at: http://www.shef.ac.uk/FRAX 113
  114. 114. 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. • Vitamin D levels can be monitored. There is no agreement concerning the appropriate time to start treatment, however, it seems reasonable to treat pts with a femur T-score <1.5 [1]. • Hormone replacement therapy is effective in post-menopausal female pts [2]. 1. Guanabens N, Cerda D, Monegal A, Pons F, Caballeria L, Peris P, et al. Low bone mass and severity of cholestasis affect fracture risk in patients with primary biliary cirrhosis. Gastroenterology 2010;138:2348–2356. 2. Pereira SP, O’Donohue J, Moniz C, Phillips MG, Abraha H, Buxton-Thomas M, et al. Transdermal hormone replacement therapy improves vertebral bone density in primary biliary cirrhosis: results of a 1- year controlled trial. Aliment Pharmacol Ther 2004;19:563–570. 114
  115. 115. 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]. • In most pts with PBC, serum levels of 25-hydroxy vitD and 1–25 dihydroxy-vitD are normal, apart from in pts with prolonged jaundice, pts awaiting LT, and pts with osteomalacia. 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. Patients with advanced-stage PBC should be tested annually for deficiencies of vitamins A, D, E, and K, and replacement should be prescribed as indicated, followed by a maintenance dose. The replacement and maintenance doses, respectively, are as follows: • vitamin A, 50,000 U/day for 3 days and 10,000 U/day • Vitamin D, 50,000 U/week for 8 to 12 doses and 1000 U/day • vitamin E, 10 U/kg/day and 30 U/day • vitamin K, 50 mg/day and 5 mg/day ZAKIM SCHIFF 115
  116. 116. Hyperlipidaemia: Management • To date, no correlation has been found with respect to an increased risk of cardiovascular events in the setting of hyperlipidemia of PBC. • Therefore treatment should be offered according to the pt’s individual risk factors for cardiovascular disease. • Statins have proven safe in small studies in this population. In the subgroup of pts with PBC and metabolic syndrome (with high cholesterol, low HDL cholesterol and high LDL cholesterol levels), EASL suggests considering a pharmacologic approach with cholesterol-lowering agents on a case-by-case basis; treatment is not contraindicated. EASL 116
  117. 117. Steatorrhea • Steatorrhea can occur in pts with advanced PBC. Several causes have been described. • The most important cause is decreased bile acid delivery with insufficient micellar concentration of bile acids in the small intestine. • Occasionally, exocrine pancreatic insufficiency can be found as part of a widespread glandular dysfunction seen in some pts with PBC. • Coexisting celiac disease has been reported in a small number of pts with PBC, and SIBO may be the cause of steatorrhea in some pts with PBC and scleroderma. • Because each of these causes has specific and different treatments, determining the exact cause of steatorrhea is important. • Pts with decreased intestinal bile acid concentrations usually benefit from substitution of medium-chain TGs for long-chain TGs in their diets and a decrease in total fat intake . • Pts with exocrine pancreatic insufficiency will benefit from pancreatic replacement therapy; • Pts with celiac disease require gluten withdrawal from the diet; and pts with SIBO should receive intermittent broad-spectrum oral antibiotic therapy. 117Sleisenger
  118. 118. VARICES: Management • The management of gastroesophageal varices and Variceal haemorrhage in pts with PBC be led by the Baveno-VI guidelines [1]. EASL 1. de Franchis R. Expanding consensus in portal hypertension: Report of the Baveno VI Consensus Workshop: Stratifying risk and individualizing care for portal hypertension. J Hepatol 2015;63:743–752. 1. EASL-EORTC clinical practice guidelines: Management of hepatocellular carcinoma. J Hepatol 2012;56:908–943. 118
  119. 119. Liver transplantation • It is the only definitive RX for pts with advanced PBC. • The greatest challenge is not to determine who will need a transplant, but to decide when the transplant will be needed but however it is same as for other CLD (eg MELD>15). • A study using the Mayo risk score to evaluate pts undergoing LT in 3 large centers in the US suggested that the risk of death after transplant, is lower when transplant is performed for pts with Mayo risk scores ≤7.8, although pts can certainly be transplanted with higher MRS.[1] • Alternatively, serum T bilirubin level can be used as a single indicator. Pts should be referred to a transplant center when the bilirubin concentration reaches 5.9 mg/dL, and transplant should be considered before the bilirubin level reaches 10 mg/dL. (EASL: persistent elevated bilirubin values >3 mg/dl) 1. Milkiewicz P: Liver transplantation in primary biliary cirrhosis.Clin Liver Dis 12:461–472, 2008. ZAKIM 119
  120. 120. Liver transplantation • The outcome of LT usually is favourable, and with 5-yr pt survival rates of 80–85%, better than for most other indications for LT [1,2,3]. • QOL rapidly improves following LT due to improvement in symptoms related to PBC as well as complications of CLD such as HE and VH. Pruritus usually improves promptly; however, fatigue may only improve in up to 56% of LT recipients, and one report even suggests that males may experience worsening fatigue following LT[4,5]. • Metabolic bone disease, particularly osteoporosis, typically worsens during the initial 3–6 mnths following LT but bone mineral density returns to baseline by 12–18 mnths post LT . • The etiology of accelerated loss of bone mineral density following LT is multifactorial: use of high-dose corticosteroids and other immunosuppressive agents such as calcineurin inhibitors, immobility, and poor nutrition. • Fracture rates of 15–27% have been reported in LT recipients with PBC, with the majority occurring during the 1ST yr post transplant [6]. 1. Adam R, Karam V, Delvart V, O’Grady J, Mirza D, Klempnauer J, et al. Evolution of indications and results of liver transplantation in Europe. A report from the European Liver Transplant Registry (ELTR). J Hepatol 2012;57:675–688. 2. Singal AK, Guturu P, Hmoud B, Kuo YF, Salameh H, Wiesner RH. Evolving frequency and outcomes of liver transplantation based on etiology of liver disease. Transplantation 2013;95:755–760. 3. Carbone M, Neuberger JM. Autoimmune liver disease, autoimmunity and liver transplantation. J Hepatol 2014;60:210–223. 4. 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(3):490–4. 5. Pells G, Mells GF, Carbone M, et al. The impact of liver transplantation on the phenotype of primary biliary cirrhosis patients in the UK-PBC cohort. J Hepatol 2013;59(1):67–73. 6. Wariaghli G, Allali F, El Maghraoui A, Hajjaj-Hassouni N. Osteoporosis in patients with primary biliary cirrhosis. Eur J Gastroenterol Hepatol 2010;22(12):1397–401. 120
  121. 121. Terminal stage • If liver transplantation is not an option, the terminal stages onsues and are marked by a rapid deepening of jaundice with the disappearance of both xanthomas and pruritus. • Serum albumin and total cholesterol levels fall. • Oedema and ascites develop. • The final events include episodes of hepatic encephalopathy with uncontrollable bleeding, usually from the oesophageal varices. • An intercurrent infection, sometimes a Gram - negative septicaemia, may be terminal. SHERLOCK121

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