Evaluation of Changes Liver Hemodynamics with Color Doppler Ultrasound in the Cholestatic Patients

  

    
Parameters 
    
Groups 
    
n 
    
Avarage 
    
SD 
    
p 
  
  

    
CI 
    
Enzyme
      
Cholestasis 
    
42
      
41
    
0,0345
      
0,0861
    
0,1400
      
0,03153
    
0,001* 
  
  

    
FI 
    
Enzyme 
      
Cholestasis 
    
42
      
41
    
3,1019
      
5,1395
    
0,6027
      
1,33687
    
0,001* 
  
  

    
HVI 
    
Enzyme 
      
Cholestasis 
    
42
      
41
    
22,7140
      
11,4990
    
6,30967
      
2,18581
    
0,001* 
  
  

    
HA-RI 
    
Enzyme 
      
Cholestasis 
    
42
      
41
    
0,6690
      
0,7278
    
0,05036
      
0,0752
    
0,001* 
  
  

    
HA-PI 
    
Enzyme 
      
Cholestasis 
    
42
      
41
    
1,2512
      
1,5102
    
0,28927
      
0,24878
    
0,001* 
  
  

    
PVH 
    
Enzyme 
      
Cholestasis 
    
42
      
41
    
24,3095
      
17,9756
    
6,08271
      
3,56713
    
0,001* 
  
  

    
PV-CAP 
    
Enzyme 
      
Cholestasis 
    
42
      
41
    
10,9286
      
13,0732
    
1,25704
      
1,69396
    
0,001* 
  
  

    
Spleen length 
    
Enzyme 
      
Cholestasis 
    
42
      
41
    
10,5000
      
12,1556
    
0,99388
      
2,05058
    
0,001* 
  

Table 5: 

Discussion

Cholestasis can develop due to obstruction of bile flow and accumulation of the bile in the liver as a result of various pathologies such as obstructive, inflammatory and genetic processes. Increased pressure in bile ducts blocks bile flow and this in turn leads to accumulation of toxic substances and macroscopic and microscopic changes in the liver. In cases where obstruction persists, fibrosis around the bile ducts can ensue, and a type of cirrhosis called biliary cirrhosis can develop. Further progression of intrahepatic fibrotic changes increase the parenchyma damage by mechanically obstructing the sinusoidal flow, nodular regeneration develops, and with the distortion of vascular structure, hepatic flow deteriorates. PHT that results in as cites, varicose bleeding and hypersplenism can develop [7].

Vanigella et al. reported that PHT and varicose bleedings develop in 40–80% of the children with biliary atresia, one of the causes of cholestasis, at age about 5. They also reported that more than half of the children with Allagille syndrome progressed to cirrhosis [8]. Mwanza et al. performed main bile duct ligation model in dogs. They induced elevated pressure and cholestasis as a result of cessation of bile flow from the gallbladder and intrahepatic bile ducts. As a consequence, they observed cirrhotic changes such as hepatocyte necrosis, degeneration and infiltration in livers of the experimental subjects. In this study, physical examination, laboratory studies and US imaging were found to be consistent with cholestasis. With Doppler US examinations that were carried out weekly until 10^th week, they observed a decrease in PV volume and flow velocity and an increase in PV area and CI as duration of cholestasis prolonged [5].

Yoshioka et al. found that hepatocytes around the proliferated bile ducts atrophied on 4^th week following bile duct ligation in mice [9]. Pastor et al created bile duct obstruction in rats and observed secondary biliary cirrhosis on 28^th day [10]. Brodie et al. detected a decrease and an inversion in the hepatic artery diastolic flow in severe biliary cirrhosis that develops secondary to biliary atresia. They also reported that HA–RI values are correlated with degree of cirrhosis and useful in follow up of clinical course in children with biliary atresia [11]. Chawla et al reported that secondary PHT developed as a result of PV obstruction in patients with extrahepatic (such as chronic pancreatitis, local tumor invasion) or intrahepatic (such as recurrent cholangitis, primary sclerosing cholangitis) bile duct anomalies [12].

In other studies, it was reported that valuable information on severity and prognosis of the disease was obtained by evaluating the liver hemodynamic and morphology in patients with cirrhosis. A relation between hemodynamic changes in PV and histological changes in chronic hepatitis was found. Besides, it was observed that liver blood flow could be changed by diseases such as hepatocellular disorders, tumors and porto–systemic shunts [13,14]. Liver biopsy is required to make the diagnosis of cirrhosis certain in patients without prominent clinical and laboratory findings. Prognosis of cirrhosis varies depending on the cause, stage of the disease and possibilitiesof treatment. Child score is used to determine the prognosis. In this scoring, ascites, albumin and bilirubin levels, encephalopathy and prothrombin time are taken into account [15]. Portal angiography and splenoportography are the most valuable methods in diagnosis of PHT which often develops as a complication of cirrhosis. However, they cannot be used as convenient imaging methods because they are invasive and have a limited repeatability. Therefore a simple and noninvasive method that could provide reliable data on portal hemodynamic was needed. It was reported that Doppler US could be used as a safe, reliable, noninvasive, and easily repeatable test in assessment of portal hemodynamics [16,17].

Al–Nakshabandi a PVD wider than 13 mm showed PHT with a high specificity (reported as 100%), but a low sensitivity (45%–50%) [18]. Shi et al reported that contrary to PVV, there was not any relation among Child stages between wide PVD and high PV pressure and severity of cirrhosis [13]. Tong et al reported a relation between severe intraocular degeneration and necrosis and increase in PVD [19]. Er et al reported that a PV flow velocity of 15 cm⁄sec and below and a PVD of more than 13 mm were significant in diagnosis of PHT [20]. Yalniz et al. noted that PVV decreased as severity of cirrhosis worsened [16].

We found that there was not any statistically significant difference between control group and patient with elevated enzyme group in terms of PVD (p>0,05, p=0,1). However, we found that there was a statistically significant difference between control group and patients with cholestasis group (p<0,05, p=0,001) and between elevated enzyme group and patients with cholestasis group (p<0,05, p=0,001) in terms of PVD.

Most researchers reported that PVV decreased significantly in the patients with cirrhosis compared with healthy individuals. Sabba et al. demonstrated that though some variations existed, PVV was declined in cirrhosis compared with healthy people [21]. Kok et al. reported that PVV decreased significantly in patients with cirrhosis and esophageal varices [22]. Aube et al. observed that there was a close relation between histological degree of fibrosis and decline in portal venous velocity [23]. Shi et al showed that as Child’s classification stage increased, portal flow velocity decreased. They reported that portal flow velocity is a parameter that reflects degree of portal pressure and it is more useful in diagnosis of PHT [13]. Gaiani et al. demonstrated a significant difference between cirrhotic and non cirrhotic cases in terms of PVV [24]. Haktanir et al. reported that PV flow velocity is a useful index in diagnosis of cirrhosis [25]. Chawla et al showed that PV flow velocity is slower in cirrhotic patients compared to the patients with chronic liver disease who do not have cirrhosis yet and PVV declined as severity of the cirrhosis is increased [26].

In this study, we found that there was not any statistically significant difference between control group and patient with elevated enzyme group in terms of PVV (p>0,05, p=0,1). However, we found that there was a statistically significant difference between control group and patients with cholestasis group (p<0,05, p=0,001) and between elevated enzyme group and patients with cholestasis group (p<0,05, p=0,001) in terms of PVD.

Sacerdotal et al. showed that HA–PI values increased in patient with cirrhosis compared to healthy individuals [27]. Iwao reported that HA–PI in patients with cirrhosis and PHT was higher than control group. He considered the threshold of HA–PI in PHT diagnosis was 1.1 84% sensitivity as and 81% specificity [28]. Schneider et al. found higher HA–PI values in cirrhotic patients compared to control group. In this study a weak correlation between Child staging and HA–PI was observed. They considered threshold value of HA–PI was 1.0 with 82% sensitivity, and 74% specificity [29].

In our study we found that there was a statistically significant difference between control group and elevated enzyme group, between control group and patients with cholestasis group, between elevated enzyme group and patients with cholestasis group in term of HA–PI. We calculated that HA–PI value was 1.1 in control group; 1.25 in elevated enzyme group and 1.51 in patients with cholestasis group.

Normally, low–resistance waveform is seen in hepatic artery. Hepatic artery flow resistance is increased in chronic liver diseases and PHT [17]. Erden et al. showed that HA–RI is related with portal pressure and hepatic venous pressure gradient [30]. Previous studies indicated that HA–RI was increased in chronic liver diseases. It was showed that although increased HA–RI is closely related withdeposition of large amounts of fibrotic tissue in the patients with chronic hepatitis, degeneration, inflammation and necrosis were not affected prominently. Besides this, when the patients were analyzed according to degree of liver fibrosis, changes in HA–RI do not show parallelism with the changes in PV flow velocity. As a result, it was observed that in viral hepatitis, level of HA–RI probably became apparent in presence of fibrous tissue deposits which reflect the severity and duration of the liver damage [13]. Alpern et al reported that a HA–RI higher than 0.78 was specific for PHT diagnosis, however it was not sensitive [31]. Marder et al observed an increase in pulsation and RI value because of increase in arterial bed [32].

Sacerdoti et al. reported that HA–PI (1.30) and HA–RI (0.71) values were markedly high in the patients with cirrhosis. Pierce et al. found that there was a significant difference between cirrhotic patients and control group in terms of RI value (0.82 vs. 0.72). They reported that when RI value is considered as 0.77, sensitivity was 6% and specificity was 90% [33]. Piscaglia et al. reported that high HA–RI values were not specific for cirrhosis or PHT, however they could be useful in chronic hepatitis [34]. In another study, it was reported that HA–RI values ranged between 0.62 and 0.69 in healthy people [35]. Tanaka et al. reported that 68 hepatic RI showed an increase in acute occlusion of PV as well [36]. Walsh et al. demonstrated that HA–RI, which is thought to be related to structural deterioration in the liver, increased as the severity of the liver disease worsens [37].

In our study we found that there was not any a statistically significant difference between control group and elevated enzyme group in terms of HA–RI, however there was a statistically significant difference between control group and patients with cholestasis group, between elevated enzyme group and patients with cholestasis group in terms of HA–RI. We calculated that HA–RI value was 0.65 in control group; 0.66 in elevated enzyme group and 0.72 in patients with cholestasis group.

Iwao et al defined a parameter that represents afferent vascularity of the liver. They named it as HVI (HVI=PVH⁄HA–PI). In a study, they found that HVI values in cirrhotic patients were significantly lower compared to control group. (8,7±2,1 and 17,2±4,3 cm⁄sec, respectively p<0,001). They found that HVI had a threshold of 12 cm⁄ sec with 97% sensitivity and 93% specificity in the diagnosis of PHT. Also they demonstrated a significant negative correlation betweenHVI and Child stage [28]. Serhatlioglu et al. reported that HVI can be used as a reliable and objective criterion in the diagnosis, staging of cirrhosis and in monitoring the progression of cirrhosis [38].

In our study we found that there was a statistically significant difference between control group and elevated enzyme group, between control group and patients with cholestasis group, between elevated enzyme group and patients with cholestasis group in term of HVI.

Splenomegaly is one of the major characteristics of liver cirrhosis. Shi et al. found that splenomegaly is seen in 36–92% of the cases with cirrhosis [13]. Several mechanisms such as increased pooling enhanced destruction of blood cells in the spleen, dilutional effect of increased blood volume and humeral factors play role in development of hypersplenism in PHT. Tarantino et al observed between Spleen Diameter (≥150 mm) and development splenorenal shunt that increased risk in cirrhosis [39]. Lim et al observed that spleen dimensions increased in patients with hepatitis who develop cirrhosis [40].

In our study, 36% of the patients with cholestasis had splenomegaly and this was consisted with literature. In our study we also found that there was not any a statistically significant difference between control group and elevated enzyme group in terms of spleen dimensions, however there was a statistically significant difference between control group and patients with cholestasis group, between elevated enzyme group and patients with cholestasis group in termsof spleen dimensions.

Prognosis is poor in patients who clinically develop reverse flow in PV. Shaheen et al. reported that reverse flow occurred in 5–8% of the patients with PHT, Gaiani et al. found this rate as 4–8% [41,42].

In our study reverse flow was present in 5 cases with cholestasis (5%) and this was consistent with literature.

Sabba et al. observed a decline in PV in PHT, and an increase in PV area [21]. There was PV dilatation and decrease in velocity in PHT, CI was calculated by these. CI is ratio of PV area to average PV velocity on same section. Al–Nakshabandi reported that this index was 0.07 in normal individuals and values over 0.1 indicated portal hypertension with 95% sensitivity and specificity [18].

PV area, flow velocity and CI change in the liver cirrhosis. In a patient with cirrhosis, portal blood flow stays normal; a decline is seen in terminal phase. However, CI is 2.5 times higher than normal people because velocity is decreased. In chronic stage of the cirrhosis, a marked increase in CI and PVD is observed. CI and portal blood flow velocity allow diagnosis of liver disease noninvasively. CI is also affected by other factors such as PV pressure, portal venous resistance in the liver, portal blood flow and development of portosystemic shunt [18]. In an experimental cholestasis induced in dogs, Mwanza et al reported that CI increased as duration of cholestasis is increased [5]. Bessi et al. found a statistically significant difference in cirrhosis and PTH patients in terms of CI [43]. Haag et al demonstrated that a CI value above 0.1 has a 95% sensitivity and specificity [44]. Dragoni et al reported that CI is strongly correlated with presence and size of esophageal varies as well as with severity of cirrhosis [45].

In our study we found that there was not any a statistically significant difference between control group and elevated enzyme group in terms of CI, however there was a statistically significant difference between control group and patients with cholestasis group, between elevated enzyme group and patients with cholestasis group in terms of CI.

Doppler US is the primary imaging method in chronic liver disease such as cirrhosis. Today gold standard for the diagnosis of the liver cirrhosis is biopsy, a histopathological diagnostic method. However it has some morbidity and mortality risks [15]. Therefore another method has been searched instead of biopsy. FI (HA–RI⁄PVHx100) is an index calculated by multiplying the ratio of HA–RI to PVH with 100 and has been developed by Mazeher et al. to detect development of fibrosis in the liver without performing a biopsy. In this study it was found that FI has a high sensitivity (94.4%), specificity (100%) and accuracy (90%) levels, therefore it is a useful noninvasive test in diagnosis of the liver cirrhosis (5.55±1.53) and in chronic hepatitis (2.63±0.43) and it can decrease the need for liver biopsy [46].

Conclusion

In our study we found that there was a statistically significant difference between control group and elevated enzyme group, between control group and patients with cholestasis group, between elevated enzyme group and patients with cholestasis group in term of FI. We noted that these results were consistent with those in Mazeher et al.’s study. We concluded that fibrous tissue is increased in biliary cirrhosis. These results demonstrate that there are changes in portal, hepatic arterial hemodynamics and Doppler US parameters in normal population, patients with elevated enzyme and patients with cholestasis. We found that Doppler US has an important role in diagnosis and follow up of biliary cirrhosis developing secondary to cholestasis. Doppler US is considered as a method which has a warning role because it can detect antecedent findings that reflect changes in hepatic hemodynamic before the possible complications of cirrhosis such as PTH occur. It attracts attention that HVI, FI and CI are sensitive in terms of the changes that occur in liver hemodynamic in the cases with cirrhosis and they correlate with the severity of the disease. Doppler US diminishes the need for invasive procedures by providing functional information about liver. Also, it enables assessment of the changes in portal blood flow which can affect the liver functions. As a result, Doppler US examination method is a very beneficial method in noninvasively defining the changes in liver hemodynamic, in follow up of the disease and in early detection of the complications such as biliary cirrhosis and PHT.

References

1. Sherlock S, Dooley J. Diseases of the Liver and Biliary System. Oxford: Blackwell Science Ltd; 1997.
2. Oyar O. Sindirim Sistemi Radyolojisi. Isparta. SDÜ Yayin Evi 2003: 144-167.
3. Zech CJ, Schoenberg SO, Reiser M, Helmberger T. Cross-sectional imaging of biliary tumors: current clinical status and future developments. Eur Radiol. 2004; 14: 1174-1187.
4. Haktanir A, Karagöz I. Kronik karaciger hastaliklarinda radyolojik tani. Tip Arastirmalari Dergisi 2004; 2: 41-46.
5. Mwanza T, Miyamoto T, Okumura M, Kadosawa T, Fujinaga T. Ultrasonographic evaluation of portal vein hemodynamics in experimentally bile duct ligated dogs. Jpn J Vet Res. 1998; 45: 199-206.
6. Tarantino G, Citro V, Esposito P, Giaquinto S, de Leone A. Blood ammonia levels in liver cirrhosis: a clue for the presence of portosystemic collateral veins. BMC Gastroenterol. 2009; 9: 21.
7. Boyer JL. New perspectives for the treatment of cholestasis: lessons from basic science applied clinically. J Hepatol. 2007; 46: 365-371.
8. Venigalla S, Gourley GR. Neonatal cholestasis. Semin Perinatol. 2004; 28: 348-355.
9. Yoshioka K, Mori A, Taniguchi K, Mutoh K. Cell proliferation activity of proliferating bile duct after bile duct ligation in rats. Vet Pathol. 2005; 42: 382-385.
10. Pastor A, Collado PS, Almar M, González-Gallego J. Antioxidant enzyme status in biliary obstructed rats: effects of N-acetylcysteine. J Hepatol. 1997; 27: 363-370.
11. Broide E, Farrant P, Reid F, Baker A, Meire H. Hepatic artery resistance index can predict early death in children with biliary atresia. Liver Transpl Surg. 1997; 3: 604-610.
12. Chawla Y, Sreedharan A, Dhiman RK, Jain S, Suri S. Portal hemodynamics in fulminant hepatic failure as assessed by duplex Doppler ultrasonography. Dig Dis Sci. 2001; 46: 504-508.
13. Shi BM, Wang XY, Mu QL, Wu TH, Xu J. Value of portal hemodynamics and hypersplenism in cirrhosis staging. World J Gastroenterol. 2005; 11: 708-711.
14. Vezozzo DC, Farias AQ, Cerri GG, Da Silva LC, Carrilho FJ. Assessment of portal hemodynamics by Doppler ultrasound and of liver morphology in the hepatosplenic and hepatointestinal forms of schistosomiasis mansoni. Dig Dis Sci. 2006; 51: 1413-1419.
15. Iliçin G, Süleymanli G, Ünal S, Biberoglu K. Iç Hastaliklari 2. Baski, Ankara. Günes Kitapevi 2003: 1659-1704.
16. Yalniz M, Demir A, Arslan A, Cihangiroglu M. Doppler ultrasonografi ile farkli evrelerdeki sirozlu hastalarda hemodinamik inceleme. Akademik Gastroenteroloji Dergisi 2004; 3; 14-19.
17. Ohnishi K, Saito M, Nakayama T, Iida S, Nomura F. Portal venous hemodynamics in chronic liver disease: effects of posture change and exercise. Radiology. 1985; 155: 757-761.
18. Al-Nakshabandi NA. The role of ultrasonography in portal hypertension. Saudi J Gastroenterol. 2006; 12: 111-117.
19. Tong MJ, el-Farra NS, Reikes AR, Co RL. Clinical outcomes after transfusion-associated hepatitis C. N Engl J Med. 1995; 332: 1463-1466.
20. Er R, Ünal Ö, Tuncer I, Harman M, Etlik Ö. PHTda portal ve hepatik venlerin Doppler. ultrasonografi bulgulari. Van Tip Dergisi 2000; 7: 94-97.
21. Sabbá C, Weltin GG, Cicchetti DV, Ferraioli G, Taylor KJ. Observer variability in echo-Doppler measurements of portal flow in cirrhotic patients and normal volunteers. Gastroenterology. 1990; 98: 1603-1616.
22. Kok T, van der Jagt EJ, Haagsma EB, Bijleveld CM, Jansen PL. The value of Doppler ultrasound in cirrhosis and portal hypertension. Scand J Gastroenterol Suppl. 1999; 230: 82-88.
23. Aubé C, Oberti F, Korali N, Namour MA, Loisel D, et al. Ultrasonographic diagnosis of hepatic fibrosis or cirrhosis. J Hepatol. 1999; 30: 472-478.
24. Gaiani S, Gramantieri L, Venturoli N, Piscaglia F, Siringo S. What is the criterion for differentiating chronic hepatitis from compensated cirrhosis? A prospective study comparing ultrasonography and percutaneous liver biopsy. J Hepatol. 1997; 27: 979-985.
25. Haktanir A, Cihan BS, Celenk C, Cihan S. Value of Doppler sonography in assessing the progression of chronic viral hepatitis and in the diagnosis and grading of cirrhosis. J Ultrasound Med. 2005; 24: 311-321.
26. Chawla Y, Santa N, Dhiman RK, Dilawari JB. Portal hemodynamics by duplex Doppler sonography in different grades of cirrhosis. Dig Dis Sci. 1998; 43: 354-357.
27. Sacerdoti D, Merkel C, Bolognesi M, Amodio P, Angeli P. Hepatic arterial resistance in cirrhosis with and without portal vein thrombosis: relationships with portal hemodynamics. Gastroenterology. 1995; 108: 1152-1158.
28. Iwao T, Toyonaga A, Oho K, Tayama C, Masumoto H. Value of Doppler ultrasound parameters of portal vein and hepatic artery in the diagnosis of cirrhosis and portal hypertension. Am J Gastroenterol. 1997; 92: 1012-1017.
29. Schneider AW, Kalk JF, Klein CP. Hepatic arterial pulsatility index in cirrhosis: correlation with portal pressure. J Hepatol. 1999; 30: 876-881.
30. Erden E. Renkli Doppler ultrasonografinin fizik prensipleri, sinirlamalari ve hata, kaynaklari. T Klin Tip Bilimleri 1991; 11: 326-351.
31. Alpern MB, Rubin JM, Williams DM, Capek P. Porta hepatis: duplex Doppler US with angiographic correlation. Radiology. 1987; 162: 53-56.
32. Marder DM, DeMarino GB, Sumkin JH, Sheahan DG. Liver transplant rejection: value of the resistive index in Doppler US of hepatic arteries. Radiology. 1989; 173: 127-129.
33. Pierce ME, Sewell R. Identification of hepatic cirrhosis by duplex doppler ultrasound value of the hepatic artery resistive index. Australas Radiol. 1990; 34: 331-333.
34. Piscaglia F, Gaiani S, Zironi G, Gramantieri L, Casali A. Intra- and extrahepatic arterial resistances in chronic hepatitis and liver cirrhosis. Ultrasound Med Biol. 1997; 23: 675-682.
35. Lamb CR, Burton CA, Carlisle CH. Doppler measurement of hepatic arterial flow in dogs: technique and preliminary findings. Vet Radiol Ultrasound. 1999; 40: 77-81.
36. Tanaka K, Mitsui K, Morimoto M, Numata K, Inoue S. Increased hepatic arterial blood flow in acute viral hepatitis: assessment by color Doppler sonography. Hepatology. 1993; 18: 21-27.
37. Walsh KM, Leen E, MacSween RN, Morris AJ. Hepatic blood flow changes in chronic hepatitis C measured by duplex Doppler color sonography: relationship to histological features. Dig Dis Sci. 1998; 43: 2584-2590.
38. Serhatlioglu S, Kocaöz Ö, Kiris A,Uysal H, Yalniz M, Ogur AYE. Karaciger, Sirozunda Hepatik ve Renal Hemodinamik Degisikliklerin Doppler US ile, Degerlendirilmesi. Firat Tip Dergisi 2007; 12: 28-33.
39. Tarantino G, Citro V, Conca P, Riccio A, Tarantino M. What are the implications of the spontaneous spleno-renal shunts in liver cirrhosis? BMC Gastroenterol. 2009; 9: 89.
40. Lim AK, Patel N, Eckersley RJ, Kuo YT, Goldin RD. Can Doppler sonography grade the severity of hepatitis C-related liver disease? AJR Am J Roentgenol. 2005; 184: 1848-1853.
41. Shaheen F, Gojwari T, Singh M, Rasool R, Banday HH. Colour Doppler of abnormal liver circulation. JK-Pract 2006; 13: 183-185.
42. Gaiani S, Bolondi L, Li Bassi S, Zironi G, Siringo S. Prevalence of spontaneous hepatofugal portal flow in liver cirrhosis. Clinical and endoscopic correlation in 228 patients. Gastroenterology. 1991; 100: 160-167.
43. Bezzi M, Mitchell DG, Needleman L, Goldberg BB. Iatrogenic aneurysmal portal-hepatic venous fistula. Diagnosis by color Doppler imaging. J Ultrasound Med. 1988; 7: 457-461.
44. Haag K, Rössle M, Ochs A, Huber M, Siegerstetter V. Correlation of duplex sonography findings and portal pressure in 375 patients with portal hypertension. AJR Am J Roentgenol. 1999; 172: 631-635.
45. Dragoni F, Gentile G, Cartoni C, Chiarotti F, Puopolo M. The role of real-time ultrasonography in predicting esophageal varices in hemophiliacs co-infected with hepatitis C and human immunodeficiency virus. Haematologica. 2005; 90: 207-213.
46. Mazaher H, Kashani S. Fibrosis index: A new Dopplerindex for differentiation of cirrhosis from chronic hepatitis. Iran J Radiol 2006; 4: 7-10.