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

• 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.

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.

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

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.