1. Angelo Armandi
Journal Club 17/09/2018

2. PRIMARY BILIARY CHOLANGITIS (PBC)
Chronic inflammatory autoimmune cholestatic liver disease
Small biliary ducts involved
European prevalence: /
Female predominance; V-VI decade

3. Unknown etiology: interaction of immune and biliary pathways leads to a chronic inflammation, cholestasis and liver fibrosis

4. Loss of immune tolerance: antimitocondrial antibodies (AMA) targeting PDC-E2, as a hallmark of PBC.
Molecular mimicry? Criptic self epitope exposure?

5. Macrophage and T cell activation: increase in cytokine production (IFN, TNF, IL-12), inducing biliary epithelial cell (BEC) apoptosis or senescence

6. Impaired activity of bicarbonate secretion and hydrophobic bile acids contribute to the damage and perpetuate the proinflammatory state
Activation of stellate cells leads to further inflammation, biliary stasis and fibrosis

7. Peroxisome proliferator- activated receptors (PPARs) are nuclear receptors involved in carbohydrate and lipid metabolism. They have shown to have anti fibrotic, anti inflammatory and insulin sensitizing properties.
Farnesoid X receptor (FXR) is a nuclear receptor expressed in tissues involved in the enterohepatic circulation of bile acids. It regulates the metabolism of bile acids. In addition, its pathway signaling impacts on inflammation and liver fibrosis.

8. Histopatologic features of PBC
Non-suppurative, granulomatous, lymphocitic cholangitis
Periductal inflammatory infiltrate (plasmacells and eosinophils) with disruption of bile duct epithelium
Bile duct loss
Marginal ductular reaction
Copper associated protein deposits
Fibrosis
Cirrhosis

9. Associated diseases: Hashimoto’s thyroiditis, Sjogren disease, celiac disease, systemic sclerosis
Evaluate drug history to rule out DILI (amoxicillin/clavulanate, azathioprine, anabolic steroids)

10. Pruritus
Fatigue
Xanthoma/xanthelasma
Jaundice
Osteoporosis
Decompensated cirrhosis

13. Obeticholic acid vs Fibrates
Semi-synthetic hydrofobic bile acid analogue that is highly selective for FXR
Biochemical efficacy in patients with ALP > 1.67 x ULN and/or bilirubin elevated < 2 x ULN
Dose dependent exacerbation in pruritus (treatment discontinuation in 1-10% of patients)
Increase in LDL and decrease in HDL
Initial dose 5 mg; dose titration to 10 mg according to tolerability at six months
Fibrates
Variable activation of PPARs: inhibition of bile acid synthesis (PPAR-δ) and suppressive effect on immune response
Reduced clearance of NSAIDs
Increase in serum AST/ALT levels
Musculoskeletal pain and creatinine elevation (Bezafibrate)
Improvement in surrogate markers of long-term prognosis

15. Participants
Patients 18 years of age or older with established diagnosis of PBC recruited at 21 centers
Inadequate biochemical response to UDCA according to Paris 2 criteria after at least 6 months of therapy
Patients with total bilirubin level above 3 mg/dl were excluded

16. Trial oversight Trial oversight
Randomized, double-blind, placebo-controlled trial
Patients randomly assigned to receive Bezafibrate (400 mg) or placebo
Both groups received UDCA therapy
Follow up assessments performed at baseline and every 3 months for 24 months

18. Outcomes
Complete biochemical response (ALP, AST, ALT, total bilirubin, albumine, prothrombin time) at 24 months
Normal ALP level at 24 months
Specific changes (AST, ALT, ALP, GGT, total bilirubin) at various time points during the trial
Changes in liver stiffness
Changes in pruritus intensity, fatigue and quality of life
Development of portal hypertension

20. ↓ 60%
↓ 60%
↓ 18%
No significant increase in cirrhosis

21. 67% BZF and 2% placebo had normal ALP at 24 months

22. ↑ 22%
↓ 15%
Histologic data were available only for 28 patients at both baseline and 24 months.
In this subgroup, changes in histologic stage, fibrosis stage and activity grade did non differ significantly between the groups.

23. Diff: -95%

24. Clinical outcomes
Features of portal hypertension developed in 19 patients, with no significant difference between the groups.
Four patients had liver complication:
liver transplantation (Bezafibrate)
placed on a waiting list for transplantation (Bezafibrate)
ascites (placebo)
total bilirubin level more than 3 mg/dl (placebo)

25. ALP > 2.53 x ULN

26. One patient, who concomitantly reseived statin therapy, developed moderate, asymptomatic rhabdomyolysis at 3 months (resolved after discontinuation of bezafibrate)
All cases of elevated aminotransferase levels in the bezafibrate group resolved within 3 months, either spontaneously or after glucocorticoids
↓ 3%
↑ 5%

27. Discussion (1)
One third of patients in the bezafibrate group reached the primary outcome
Changes with respect to pruritus and fatigue were consistent with the primary outcome
Rapid and sustained decrease in ALP and a total bilirubin, the most important prognostic factors in PBC
No increase in total bilirubin in patients with cirrhosis
Decrease in liver stiffness

28. Discussion (2)
Portal hypertension and ALP are independent predictor factors of treatment failure
Increase in serum creatinine level (renal hemodynamic changes? Increased creatinine release by muscle?)
Carefulness with patients with diabetes, hypertension or any known renal disease
Longer and larger studies are needed to assess the effect of bezafibrate on hard outcomes, such as liver transplantation and death