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Keywords:

  • alkaline phosphatase;
  • combination therapy;
  • fenofibrate;
  • fibrate;
  • primary biliary cirrhosis;
  • ursodeoxycholic acid

Abstract

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. ACKNOWLEDGMENT
  8. REFERENCES

OBJECTIVE:  To investigate the efficacy of fenofibrate combination therapy in Chinese patients with primary biliary cirrhosis (PBC) who had a partial response to standard dose of ursodeoxycholic acid (UDCA) for at least one year.

METHODS:  PBC patients were treated with UDCA (13–15 mg/kg/day) for more than one year. The biochemical response to UDCA treatment was evaluated after treatment. Fenofibrate (200 mg/day) was added to 22 patients with partial response to UDCA.

RESULTS:  In patients with partial response to UDCA, serum alkaline phosphatase (ALP) and γ-glutamyl transpeptidase levels significantly decreased after 3-month combination therapy of UDCA and fenofibrate, 68% of these patients even reached normal ALP level. Serum triglyceride (TG) and cholesterol levels were improved, and alanine transaminase (ALT) and aspartate transaminase (AST) were also decreased during the combination therapy. However, fenofibrate had no significant effect on serum bilirubin levels. The improvement of liver biochemical tests was maintained in some patients with long-term therapy (at least 6 months). No obvious adverse effects were observed in patients taking fenofibrate.

CONCLUSIONS:  Fenofibrate is effective for improving liver biochemical tests in patients who have partial response to UDCA monotherapy. It is worth exploring the efficacy of fenofibrate on histological changes in PBC patients.


INTRODUCTION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. ACKNOWLEDGMENT
  8. REFERENCES

Primary biliary cirrhosis (PBC) is a chronic autoimmune disease mainly targeting the cholangiocytes of interlobular ducts in the liver.1 Clinical features of PBC include female preponderance, fatigue, pruritus, jaundice, hyperlipidemia, xanthoma, liposoluble vitamin deficiency and portal hypertension; however, most patients are asymptomatic.2 Some autoimmune disorders are associated with PBC, such as thyroid dysfunction, Sjögren's syndrome, Raynaud's disease and inflammatory bowel disease.2 The diagnostic hallmark of PBC is serum high-titer antimitochondrial antibody (AMA). Typical biochemical changes are preferential elevation of serum alkaline phosphatase (ALP), γ-glutamyl transpeptidase (γ-GT) and immunoglobulin M (IgM).

Ursodeoxycholic acid (UDCA) is recommended for patients with abnormal liver function at a dose of 13–15 mg/kg/day.1 UDCA administration may improve liver function, and a meta-analysis study demonstrates that UDCA administration can delay the histological progression in early-stage PBC.3 PBC patients with complete biochemical response to UDCA therapy have similar life expectancy to that of the matched control population.4,5 However, one out of three patients does not adequately respond to UDCA therapy and may need additional medical therapy or liver transplantation, or both.1 The absence of biochemical response to UDCA is an important predictive factor for death or liver transplantation in PBC patients, independent of pretreatment serum bilirubin level or histological stage.5 A previous study showed that bezafibrate, a lipid-lowering drug, was effective for PBC patients refractory to UDCA monotherapy.6 The benefits of fibrate on biliary enzymes such as ALP and γ-GT were found by chance when it was used to treat hyperlipidemia in PBC patients. Since then, further studies have been conducted to confirm the role of fibrate in PBC, either with bezafibrate7,8 or fenofibrate9–11. Fibrate appears to be effective for the improvement of liver function tests in various degrees in PBC patients. Besides these short-term clinical trials, a case report has suggested that fibrate can maintain these benefits in long-term follow-up cases, even in advanced PBC.12 The aim of this study was to investigate the efficacy of fenofibrate in Chinese PBC patients who partially responded to standard UDCA therapy.

PATIENTS AND METHODS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. ACKNOWLEDGMENT
  8. REFERENCES

Patients

Patients diagnosed and treated in Outpatient Center of Shanghai Jiao-Tong University School of Medicine Renji Hospital from January 2007 to March 2011 were enrolled in the study. All the patients were diagnosed as PBC following the American Association for the Study of Liver Diseases Practice Guidelines if two of the following criteria were met: (i) biochemical evidence of cholestasis based mainly on ALP elevation; (ii) presence of AMA; (iii) histological evidence of nonsuppurative destructive cholangitis and destruction of interlobular bile ducts (Class I, Level B).13 The histological stage was defined according to Ludwig's classification.14 Hepatitis virus infection, alcohol, drug and other etiology had been excluded, and all the enrolled patients were treated with UDCA at a dose of 13–15 mg/kg/day for at least one year (mean 18.14 months, range 12–48 months). A complete biochemical response to treatment was defined as ALP level decreases by more than 40% of the baseline values or normal range after one year of UDCA treatment (Barcelona criteria).4 Patients who did not fulfill the Barcelona criteria were defined as partial responders. Fenofibrate 200 mg was given to partial responders every night in addition to UDCA for at least 3 months (mean 7.23 months).

Laboratory examinations

Serum liver function as well as lipid levels were measured before and every month during the combination treatment. Antinuclear antibodies, smooth muscle antibodies and AMA had been assessed via indirect immunofluorescence on the HEp-2 cell line, monkey liver, rat kidney and rat stomach tissue slides, respectively. Presence of AMA-M2 antibody was assessed using immunoblot assay (EUROASSAY test kit; EUROIMMUN Medizinische Labordiagnostika AG, Lübeck, Germany) according to the manufacturer's instructions.

Statistical analysis

All analyses were carried out using SPSS 16.0 (SPSS Inc., Chicago, IL, USA). Data were expressed as mean ± standard deviation (SD). The statistical analysis was performed using paired-samples t-test. A P value < 0.05 was considered as statistically significant.

RESULTS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. ACKNOWLEDGMENT
  8. REFERENCES

In all, 22 PBC patients (20 women) had partial response to UDCA therapy, with a mean age of 51.4 years and mean weight of 61.7 kg. Nineteen of them were AMA-positive, while the other three (all women) were AMA-negative. Liver biopsy was performed in 11 patients, with a histological stage of II, III and IV in 5, 5 and one patient, respectively.

Serum ALP and γ-GT levels decreased to some degree after standard UDCA therapy for at least one year, while there was no significant change in alanine transaminase (ALT), aspartate transaminase (AST) and lipid levels (Table 1). After the addition of fenofibrate, serum ALP and γ-GT levels decreased significantly after one-month combination treatment, from 237.14 U/L to 132.68 U/L and 328.68 U/L to 207.38 U/L, respectively. After 3-month combination treatment, 68% of the patients reached a normal ALP level, while only two reached normal γ-GT levels. Serum ALT and AST levels were also significantly improved after the combination therapy (Fig. 1). However, fenofibrate had no effect on total bilirubin (TB) and direct bilirubin (DB) levels. Triglyceride (TG) and cholesterol (TC) levels were also improved markedly after the combination treatment. Three AMA-negative patients showed a good response to the combination therapy as well. Twelve patients accepted continuous combination therapy for more than 6 months and maintained the efficacy on liver biochemical tests (Fig. 2). Once the finofibrate was stopped, ALT, AST and other liver function parameters elevated gradually, however, these patients still responded well to finofibrate therapy (data not shown).

Table 1.  The changes of liver biochemical tests and lipid levels in primary biliary cirrhosis patients with a combination therapy of fenofibrate and ursodeoxycholic acid (UDCA)
 Baseline (before UDCA treatment)Baseline (before combination treatment)Three months after combination treatmentP value*
  • *

    Comparison between the values before and after 3 months of fenofibrate treatment in combination with UDCA.

  • ALT, alanine aminotransferase; AST, aspartate aminotransferase; ALP, alkaline phosphatase; γ-GT, γ-glutamyl transpeptidase; TB, total bilirubin; DB, direct bilirubin; TG, triglyceride; TC, cholesterol.

ALT (U/L)78.64 ± 53.2191.55 ± 55.2857.40 ± 38.940.000
AST (U/L)78.36 ± 54.3971.22 ± 28.8257.39 ± 33.390.012
ALP (U/L)304.05 ± 167.58237.14 ± 113.03124.32 ± 44.930.000
γ-GT (U/L)459.32 ± 436.08328.68 ± 201.71180.97 ± 118.680.000
TB (µmol/L)32.17 ± 33.0627.50 ± 34.4322.16 ± 17.450.216
DB (µmol/L)16.41 ± 20.0412.51 ± 18.9011.12 ± 12.080.469
TG (µmol/L)2.08 ± 0.762.09 ± 0.851.47 ± 0.670.000
TC (µmol/L)7.84 ± 2.246.95 ± 0.396.12 ± 1.740.007
image

Figure 1. Biochemical changes of (a) alkaline phosphatase (ALP), (b) γ-glutamyl transpeptidase (γ-GT), (c) alanine aminotransferase (ALT), and (d) aspartate aminotransferase (AST) in primary biliary cirrhosis (PBC) patients before and 3 months after a combination treatment of fenofibrate and ursodeoxycholic acid (UDCA). Each line represents one PBC patient.

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image

Figure 2. Serum alkaline phosphatase (ALP) and γ-glutamyl transpeptidase (γ-GT) levels of 12 primary biliary cirrhosis (PBC) patients after long-term combination treatment. Each line represents one PBC patient.

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Only one patient complained of apparent pruritus after fenofibrate administration, so fenofibrate was stopped and UDCA was maintained for 6 months. When the condition of this patient was steady, the combination treatment was performed again after the patient's permission was obtained. The patient responded well and did not show any adverse effect this time.

DISCUSSION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. ACKNOWLEDGMENT
  8. REFERENCES

Our study showed that fenofibrate administration could significantly improve serum biochemical parameters and lipid levels in Chinese PBC patients who had partial response to UDCA therapy. ALP level of 68% patients even fell back to normal after 3-month combination therapy. A long-term use of fenofibrate in combination with UDCA could maintain or even further improve the beneficial effect.

Recently, fibrate is attracting more and more attention in the treatment of PBC, for its effect on not only hyperlipidemia but also biliary enzymes. We chose fenofibrate in this study because fenofibrate is commonly used in China. Fenofibrate as a treatment for PBC has been mentioned in several studies. In an early study, UDCA (600–900 mg/day) plus fenofibrate (150–200 mg/day) treatment for 6 months improved serum ALP, γ-GT and IgM in all seven patients resistant to UDCA monotherapy.11 Another study applied this combination therapy to nine patients with asymptomatic PBC.9 The changes of serum ALP and IgM levels were similar to those in the former study, but the differences of liver function and lipid levels before and after treatment were not statistically significant. Similar results were obtained from a long-term follow-up study in five PBC patients who received combination therapy (fenofibrate in two and bezafibrate in three) for more than 25 months.12 But in the recent study, beside the significant decrease in ALP and γ-GT, lipid levels in all ten patients during an 8-week combination therapy, no significant changes were observed in TB and DB.10 These findings are consistent with our results. Apart from the retrospective analysis from the UK, all the sample groups enrolled in these studies were from Japan.15

Although the distinct benefits of fibrate have been observed, the mechanism remains unclear. The inference that fibrate plays a role in PBC through the activation of peroxisome proliferator-activated receptor α (PPAR-α), a member of the nuclear hormone receptor superfamily, has been widely accepted. Fibrate is an agonist of PPAR-α, which is involved in the suppression of the inflammatory response and immunoregulation by inactivating leukotriene B4, a leukocyte activator.16 Fenofibrate is more powerful than bezafibrate as an activator of PPAR-α.

Another possibility is that fibrate acts on human PBC by way of multiple drug resistance 3 (MDR3). Fibrate facilitates the expression of the MDR2-associated protein in mice, which can increase in biliary phospholipid secretion and the inactivation of hydrophobic bile acid by micellization.17 The latter is a toxic to bile duct epithelial cells. MDR2 knockout mice develops liver disease that is similar to PBC. MDR3 gene in humans shares 90% homology at the amino acid level with mdr2 gene in mice and these two genes have similar functions. Mutation of the human MDR3 gene causes progressive familial intrahepatic cholestasis type 3, and the histological observations of these patients are very similar to that in the MDR2 knockout mice.18 These findings may provide a new view to interpret the role of fibrate in improving PBC.

None of the studies mentioned above discussed whether fenofibrate has an effect on the histological improvement in PBC. We cannot answer this question either because repeated biopsies are not accepted by most Chinese patients. Another limitation of our study is that the sample size was relatively small and the duration of follow-up was short.

In conclusion, fenofibrate is well tolerated in most PBC patients and is effective in patients resistant to UDCA monotherapy. Large sample, randomized control trials in the future are needed to confirm the efficacy of fenofibrate on histological changes and its effects on the prognosis of PBC patients, especially in those with an incomplete response to UDCA therapy.

ACKNOWLEDGMENT

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. ACKNOWLEDGMENT
  8. REFERENCES

This work was supported by the Awards from National Natural Science Foundation of China (No. 30770963 and No. 30972751 to Xiong MA), and Shanghai Pujiang Program and the Program for Innovative Research Team of Shanghai Municipal Education Commission (Xiong MA).

REFERENCES

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. ACKNOWLEDGMENT
  8. REFERENCES