Does Atorvastatin has Adding Effect to Propranolol in Control of Portal ‎Hemodynamics in Patients with Liver Cirrhosis

Document Type : Original Article

Authors

1 Department of Hepatology, Gastroenterology and Infectious Diseases, Faculty of Medicine, Kafrelsheikh ‎University, Kafrelsheikh, Egypt‎.‎

2 Department of Radiology, Faculty of Medicine, Kafrelsheikh University,Kafrelsheikh, Egypt.

3 Department of Community Medicine, Faculty of Medicine, Kafrelsheikh University, Kafrelsheikh, Eygpt. Public health Department

Abstract

Background and study aim: Portal hypertension is abnormal increase in portal pressure. Vasoreactivity, vascular ‎remodeling, and hepatic fibrosis contribute to increased intrahepatic resistance. β ‎blockers decrease cardiac output and mediate splanchnic vasoconstriction. Statins have ‎antioxidant, antiproliferative, and anti-inflammatory properties. We aimed to assess ‎portal vein pressure using Doppler ultrasound in cirrhotic patients before and after ‎atorvastatin administration‎.‎
Patients and Methods: ‎‎‎ This study was conducted on 58 patients Randomized controlled study was done at the hepatology gastroenterology and ‎infectious diseases department of Kafrelsheikh University Hospital on 40 cirrhotic ‎patients who were randomly assigned to either: Group A: included 20 cirrhotic patients ‎who were administered 20 mg of atorvastatin and 40 mg of propranolol daily for two ‎months (n=20) or Group B: patients who received 40 mg of propranolol alone  daily ‎for two months (n=20). Clinical and laboratory evaluation, abdominal Doppler ‎ultrasound and upper endoscopy was done at the start and after two months‎.‎
Results: There was a significant difference in portal vein diameter before and after treatment (P-‎value = .039). Portal vein velocity, portal vein flow volume, hepatic artery resistance ‎index, and hepatic artery pulsatility index showed significant difference between both ‎groups. There was a significant difference in endoscopic grading before and after ‎treatment (P value = .000)‎‎‎‎.
Conclusion: For lowering portal hypertension, atorvastatin and propranolol is more effective than ‎propranolol alone‎ ‎‎‎‎‎‎‎‎.

Highlights

  • For lowering portal hypertension, atorvastatin and propranolol are more effective ‎than propranolol alone.‎
  • Statin could be a valuable therapy for PHT.
  • Statin significantly improved liver perfusion, as demonstrated  by the increased ‎modified liver vascular index in patients with cirrhosis.

Keywords

Main Subjects

Full Text

INTRODUCTION

Portal hypertension (PHT) is a central cause of hospital admissions and morbidity. The ‎role of sinusoidal endothelial modulating the development of intrahepatic resistance and ‎gastroesophageal varices. Endothelial dysfunction due to hepatic injury leads to a ‎reduction in the production of vasoconstrictors from endothelial cells. Also, hepatic ‎satellite cell contraction and matrix deposition increase intrahepatic resistance [1-6]. The ‎prognosis of liver cirrhosis improved with a significant decrease in portal pressure ‎‎[7]. The main therapy for portal hypertension (PHT) is nonselective beta blockers ‎‎(NSBBs), such as propranolol, which can decrease the incidence of recurrent variceal ‎hemorrhage when used in conjunction with endoscopic ligation. Patients who cannot ‎tolerate β-blockers or have contraindications. The addition of other drugs, such as ‎statins or isosorbide-5 mononitrate, may help in reducing vascular resistance [9,10]. ‎Statins decrease the activation of hepatic stellate cells. Statins also have anti-‎inflammatory, antioxidant, and immunomodulatory effects [11]. Atorvastatin may be an ‎effective therapeutic agent for PHT. It has a beneficial antifibrotic effect and enhance ‎hepatic cell function [12-16]. However, in advanced cirrhosis,

organic nitrates (e.g., ‎nonselective NO donors) increase peripheral vasodilatation, leading to a decrease in ‎arterial pressure, and sympathetic system stimulation [17]‎.

Many studies suggest that statins reduce vascular resistance and  enhance vasodilatation ‎of the hepatic vasculature. These effects is due to increase of NO in the liver vessels ‎‎[18,19]. Doppler ultrasound, in addition to upper endoscopy, is a non-invasive method ‎to assess blood flow inside portal veins [19]. ‎

Aims: ‎

Our aim was to evaluate the benefits of adding atorvastatin to propranolol to decrease ‎portal pressure and consequently decrease variceal size as assessed by Doppler ‎ultrasound and upper endoscopy.‎

Patients‎ AND METHODS

Type and site of the study: This randomized controlled study was done in the, Hepatology, Gastroenterology and infectious disease department in collaboration with the radiological department at Kafrelsheikh University Hospital.

Patient selection

 We included forty cirrhotic patients with PHT from September 2019 to September 2020. Patients were randomized  by use of a computer generated random sequence into two groups: Group A cirrhotic  patients who administered 20 mg of atorvastatin and 40 mg of propranolol daily for two months (n=20); (and) Group B:included 20 cirrhotic  Patient who received 40 mg of propranolol daily alone for two months (n=20) (Figure 1).

Inclusion Criteria:

  1. Liver cirrhosis confirmed clinically, in the laboratory, or through radiology by ultrasonography (classical finding of cirrhosis) -(Child–Pugh A or B).
  2. Patients with esophageal or fundal varices.
  3. No previous history of gastrointestinal bleeding.

Exclusion Criteria:

  1. Age < 16 and  > 75 years.
  2. History of recurrent bleeding varices and band ligation or injection sclerotherapy.
  3. Portal vein thrombosis.
  4. Hepatocellular carcinoma.
  5. Patients with  Child–Pugh score  C.
  6. Comorbid renal failure, COPD, or bronchial asthma.
  7. Renal impairment
  8. Contraindications or allergy to atorvastatin.
  9. 9.    Contraindications to beta-blockers (COPD, aortic stenosis, bronchial asthma).

Sample size: The sample size was estimated using Epi-info software created by WHO and CDC, version 2002. We considered 95% confidence limit. -80% power of the study. -expected outcome (portal venous pressure reduction) in the treatment group 90% compared to 50% for control group.

The total sample size based on the above criteria was calculated  40 ,at N ≥20 for each study group.

Methods:

All patients subjected to :

  • · Full history, clinical examinations, and laboratory investigations and abdominal ultrasonography.
  • Also, Doppler ultrasound and upper endoscopy for both groups before and after two months of starting treatment.

Doppler Ultrasound

Doppler ultrasound assessments were performed in the diagnostic radiology department with a Philips (EPIQ 7) using a 3.5 MHz convex probe. Evaluation was done in the supine position after 6 hours fasting using both B mode and Doppler ultrasound. Patients were asked to hold breath for appropriate Doppler assessment.

All parameters were measured by a radiology specialist. The probe was placed in the porta hepatis and at the splenic hilum. We tried to unify the method for measurement to avoid interobserver variability. Portal vein diameter (PVD) was measured in millimeters (Fig.2). The peak, smallest, and mean  flow velocity was recorded in CC/min  then portal vein flow volume (PVFV) was  automatically calculated.

Hepatic artery resistance index (HARI) was calculated using the following formula: [peak systolic velocity (V max) – end diastolic velocity/peak systolic velocity (V min)/mean velocity].

We also assess the direction of flow in portal vein, portal vein velocity (PVV) in (cm/sec).   hepatic artery pulsatility index, and splenic artery resistance index (SARI).

Upper endoscopy:

Before and after patients received treatment, upper endoscopy was carried out by a single endoscopist using a Pentax EG-3490 k type gastroscope at the same endoscopy unit after overnight fasting and conscious sedation. Grading of the size of esophageal varices was done  by  the Paquet grading system [20]

The presence of fundal varices, portal hypertensive gastropathy were also evaluated.

Statistical analysis

We used Statistical Package for Social Sciences (SPSS) version 21. The qualitative variables were presented as number and percent, We used  Chi-square test for analysis.  We used independent samples and paired t- test for comparison of means values between groups. Sign test was used for analysis of paired ordinal categorical variables. P value (≤ 0.05) was considered significant.

RESULTS:

Our study enrolled 40 patients with Child–Pugh A cirrhosis were enrolled from ‎September 2019 to September 2020. The patients in the study were randomized to ‎either receive 40 mg of propranolol and 20 mg of atorvastatin daily or 40 mg of ‎propranolol alone daily for 2 months. Our study showed  no differences between the ‎both groups regarding age, sex, and laboratory investigation (Table 1).‎

Doppler study of the groups showed:‎

There was a statistically significant difference in PVD before and after two months of ‎atorvastatin and propranolol (P-value = .039); also, there were highly statistically ‎significant differences in both groups (A and B) in PVV and PVFV. There was a ‎statistically significant difference in each group in HARI and HAPI before and after ‎receiving the treatment. No significant difference was found in SPARI in both groups ‎‎(A and B).‎

The detailed baseline and hemodynamic parameters of patients who received ‎atorvastatin and 40 mg of propranolol and propranolol alone are shown in Table 2.‎

Endoscopic comparison of the studied groups showed:‎

There was a highly statistically significant difference in endoscopic grading (variceal ‎size) before and after two months of 40 mg of propranolol and 20 mg of atorvastatin (P-‎value = .000). However, there was no statistically significant difference in endoscopic ‎grading in patients who received 40 mg of propranolol alone (P-value = .687; Table 3).‎

Table (1): Baseline Clinical and Hemodynamic Characteristics of Patients.

P value

propranolol

Statin and propranolol

 

.468

49.75 ± 7.86

51.50 ± 7.21

Age(year)

 

.602

 

12 (60)

 8  (40)

 

11  (55)

9 (45)

Sex

Male, n (%)

Female, n (%)

 

 

 

Laboratory Investigation

.755

14.34 ± 1.13

14.22 ± 1.27

Hb (g/dl)

.817

5.86 ± 2.47

6.02 ± 1.81

WBCs (g/dl)

.607

4.92 ± .29

4.86 ± .45

RBCs (g/dl)

.867

88.55 ± 4.52

88.25 ± 6.52

MCV (g/dl)

.08

161.80 ± 73.00

131.20 ± 21.38

PLT (g/dl)

 

.130

.034*

.008*

.178

.698

.029*

.323

.465

.095

.425

.053

 

13.58 ± 11.35

6.27 ± 4.76

78.74 ± 5.58

33.02 ± 12.81

 67.00 ± 34.94

56.47 ± 20.52

118.22 ± 69.66

98.45 ± 43.71

12.88 ± 1.06

81.82 ± 15.66

1.09 ± .09

 

18.37 ± 7.95

9.87 ± 5.57

72.54 ± 8.15

26.36 ± 17.50

70.88 ± 27.43

72.98 ± 25.30

157.40 ± 160.64

108.60 ± 43.18

13.87 ± 2.34

77.52 ± 17.96

1.18 ± .19

Liver function tests:

      Total BIL(mg/dl)

      Direct BIL(mg/dl)

      Total Protein

      Albumin

      SGPT

      SGOT

      GGT

      ALP

Prothrombin time

Prothrombin conc.

 INR

 

.069

.115

 

4.87 ± .94

87.99 ± 12.08

 

7.28 ± 5.67

98.63 ± 26.91

Renal function tests:

     Urea (mmol/l)

    Creatinine (mmol/l)

*significant

Data expressed as range and mean± SD. PT: prothrombin time, PC: prothrombin concentration, INR: international normalized ratio, ALP: alkaline phosphatase, WBCs: white blood cells, RBCs: red blood cells, Hb: hemoglobin, MCV: mean corpuscular volume.

Table (2): Doppler parameters of the studied groups‎.

P value

T

propranolol

Statin and propranolol

 

 

.206

.352

 

1.288

.942

 

 14.35 ± 1.95

14.46 ± 1.87

.414

 

13.47 ± 2.36

13.86 ± 2.13

.039*

PVD

    Baseline

    2 months after     P value

 

.000*

.000*

 

5.178

4.135

 

12.42 ± .56

13.35 ± .66

.000*

 

10.42 ± 1.62

12.08 ± 1.21

.000*

PVV

    Baseline

    2 months after

    P value 

 

.000*

.000*

 

4.225

3.966

 

882.70 ± 174.73

920.51 ± 158.71

.001*

 

647.59 ± 177.23

739.66 ± 128.07

.000*

PVFV

    Baseline

    2 months after

    P value

 

.167

.516

 

1.407

.655

 

.72 ± .06

.69 ± .04

.000*

 

.75 ± .07

.70 ± .05

.000*

HARI

    Baseline

    2 months after

     P value

 

.150

.248

 

1.468

1.173

 

1.55 ± .24

1.45 ± .18

.000*

 

1.67 ± .29

1.51 ± .16

.000*

HAPI

    Baseline

    2 months after

    P value

 

.682

.370

 

.413

.906

 

.71 ± .06

.69 ± .038

.175

 

.71 ± .05

.67 ± .11

.126

SPARI

    Baseline

    2 months after

    P value

‎*significant‎

PVD: Portal vein diameter, PVV: Portal vein velocity, PVFV, HARI: Hepatic ‎artery resistance index,‎

HAPI: Hepatic artery pulsatility index ‎

Modified liver vascular index, SPARI: Splenic artery ‎‎

Table (3): Endoscopic comparison of the studied groups‎.‎

P value

OV GIII,

 

 

n (%)

OV GII,

fundal extension

n (%)

OV GII

 

 

n (%)

OV GI,

fundal extension

n (%)

OV GI

 

 

n (%)

No varices

 

n (%)

 

.000*

 

 

6 (30%)

 

 

0 (0%)

 

 

2 (10%)

 

 

0 (0%)

 

 

8 (40%)

 

4 (20%)

 

 

 

2 (10%)

 

2 (10%)

 

 

 

2 (10%)

 

9 (45%)

 

 

 

0 (0%)

 

 

5 (25%)

Group A

 

Endoscopic before:

 

Endoscopic after:

.687

 

 

3 (15%)

 

 

0 (0%)

 

 

0 (0%)

 

 

0 (0%)

 

 

6 (30%)

 

 

11 (55%)

 

 

3 (15%)

 

 

3 (15%)

 

 

8 (40%)

 

 

6 (30%)

 

 

0 (0%)

 

 

0 (0%)

Group B

 

Endoscopic before:

 

Endoscopic after:

‎*significant‎

OV: esophageal varices.

DISCUSSION

Dietary components, especially the type and the Portal hypertension, considered to be a serious complication of liver cirrhosis, with increase in  the  flow resistance inside the portal vein, leading to the formation of GOVs (16). This study was a randomized controlled clinical trial to evaluate the effect of adding statins to decrease portal pressure; Doppler ultrasound and upper endoscopy were performed on cirrhosis patients prior to and after starting one group on 20 mg of atorvastatin and 40 mg of propranolol and another control group on 40 mg of propranolol alone.

Our study showed  no significant difference in the age or laboratory study between the both studied groups, However Doppler study and upper endoscopic findings before and after the start of treatment  showed significant difference between the two groups.

This study showed that there is a statistically significant difference in PVD before and after two months of statin and propranolol (P-value = .039). A similar finding was in a study by   Nadia et al. who concluded that statin could lower the intrahepatic resistance and PHT [17].

Our result showed that the mean PVV and mean PVFV were less than 16 cm/sec in both groups. This was similar to the findings of Lafortune and colleagues [21] who claimed that decrease the velocity [22, 23].

Our study showed that there were increase in the baseline HARI and HAPI in both groups. Increase in the intrahepatic arterial  resistance with portal hypertension may be the cause. This was in line with  Yu Ya study that revealed that HARI increase in patients with portal hypertension than those without [24].

Furthermore, there was a statistically significant difference in each group in HARI and HAPI before and after receiving the treatment, and the decrease in HARI and HAPI was greater in group A.  Treatment induced hepatic satellite cell modification and lowering the portal pressure may be the cause of this decrease in the hepatic resistance. Abraldes et al. found that statin exert intrahepatic vasodilatation through upregulation of NO production [10].

An interesting finding of our study that there was no statistically significant difference between both groups (A and B) in terms of SPARI.  This in agreement with Zhang et al. observed that SPARI not significantly affected by change in the portal pressure. [25].

Our study showed that  there was a statistically significant difference in endoscopic grading (variceal size) before and after two months of 40 mg of propranolol and 20 mg of atorvastatin. However, there was no statically significant difference in endoscopic grading in patients who received 40 mg of propranolol alone.This was in line with   Vargas et al. [26]  that reported that statins  could decrease the portal pressure and control the portal hypertension.

Our study limitation include: relatively small size and short period of follow up we did not include cirrhotic patients child C.

CONCLUSION

In conclusion, atorvastatin significantly decreased  the intrahepatic resistance and PHT in  cirrhotic patients. Statin significantly enhance  liver blood flow, as demonstrated  by the increased modified liver vascular index in patients with cirrhosis and PHT. So, statin could be a safe therapy for PHT in patient with Child A and B.

Abbreviations: ‎

PHT: portal hypertension, PVD: portal vein diameter, PVV: portal vein velocity, ‎PVFV: portal vein flow volume, HARI: hepatic artery resistance index, HAPI: hepatic ‎artery pulsatility index, and SARI: splenic artery resistance index

Conflict of Interest: None.

Funding: None.

Ethical considerations: This study was approved by Kafrelsheikh university ethical committee and followed the Declaration of Helsinki. Written consent was obtained after explanation of the research.

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