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  Table of Contents    
Year : 2021  |  Volume : 64  |  Issue : 5  |  Page : 127-135
Histological analyses of trucut liver biopsies from patients with noncirrhotic portal fibrosis and extra-hepatic portal vein obstruction

1 Department of Pathology, All India Institute of Medical Sciences, New Delhi, India
2 Department of Gastrointestinal Surgery, All India Institute of Medical Sciences, New Delhi, India
3 Department of Biostatistics, All India Institute of Medical Sciences, New Delhi, India
4 Department of Gastroenterology, All India Institute of Medical Sciences, New Delhi, India

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Date of Submission15-Apr-2020
Date of Decision22-May-2020
Date of Acceptance29-Jun-2020
Date of Web Publication7-Jun-2021


Background: Both noncirrhotic portal fibrosis (NCPF) and extrahepatic portal venous obstruction (EHPVO) are important causes of noncirrhotic portal hypertension (PH) in the Asian region. In this study, we analyzed the histopathological changes of liver needle-core biopsies from patients with NCPF and EHPVO. Patients and Methods: The patients were diagnosed as per the Asia Pacific Association for the Study of Liver (APASL) criteria. Minimum adequacy criteria for liver core biopsies were defined, and finally, 69 liver biopsies from patients with NCPF and 100 liver biopsies from patients with EHPVO were analyzed. All histological parameters were predefined, and three experienced pathologists analyzed the biopsies after reaching consensus. Institute ethics committee clearance was taken. Results: Although some histological features were overlapping, phlebosclerosis of intra-hepatic branches of the portal vein (PV), periportal aberrant vascular channels, remnant portal tracts, and hepatic fibrosis beyond the portal tracts without the formation of complete hepatic nodules (P < 0.001 for all) were common histological characteristics of NCPF on core-needle liver biopsies; while maintained lobular architecture, nonspecific dilatation of PV branches, absence of intra-hepatic PV phlebosclerosis, aberrant vascular channels, and significant fibrosis were characteristics of EHPVO. Conclusions: Despite the considerable histological overlap between NCPF and EHPVO, careful histological evaluation, supplemented by clinical features, radiological and biochemical findings can help in making a conclusive diagnosis. Patients with NCPF and EHPVO with clinical jaundice show transaminitis, high serum alkaline phosphatase level, more variceal bleed, and histological evidences of nodular regenerative hyperplasia.

Keywords: Extra-hepatic portal vein obstruction, histology, noncirrhotic portal fibrosis, portal hypertension, portal vein

How to cite this article:
Vallonthaiel AG, Baloda V, Singh L, Yadav R, Kilambi R, Battu S, Sreenivas V, Pal S, Acharya SK, DattaGupta S, Shalimar, Das P. Histological analyses of trucut liver biopsies from patients with noncirrhotic portal fibrosis and extra-hepatic portal vein obstruction. Indian J Pathol Microbiol 2021;64, Suppl S1:127-35

How to cite this URL:
Vallonthaiel AG, Baloda V, Singh L, Yadav R, Kilambi R, Battu S, Sreenivas V, Pal S, Acharya SK, DattaGupta S, Shalimar, Das P. Histological analyses of trucut liver biopsies from patients with noncirrhotic portal fibrosis and extra-hepatic portal vein obstruction. Indian J Pathol Microbiol [serial online] 2021 [cited 2022 Nov 28];64, Suppl S1:127-35. Available from:

   Introduction Top

Noncirrhotic portal fibrosis (NCPF) and extrahepatic portal venous obstruction (EHPVO) affect branches of the portal vein (PV) at different levels. While in NCPF, segments of small and medium-size intra-hepatic branches of PV are affected; in EHPVO the pre-hepatic branches are involved with or without the involvement of the intrahepatic branches of PV, splenic vein or superior mesenteric veins.[1],[2],[3],[4],[5],[6] There have been few studies that analyzed and compared the differences of hemostatic profile,[7] coagulation profile, platelet function,[8] utility of endoscopic sclerotherapy,[9],[10] between these two entities. However, studies focusing on histological features between these two related entities are sparse. The histological analysis becomes essential in patients with NCPF to rule out cirrhosis and other co-existent diseases; on the other hand, in a patient with suspected EHPVO, a liver biopsy is done when the liver function tests are abnormal, or the extra-hepatic shunt vessels or thrombosis are not visible on radiology and before a shunt surgery.[6],[11],[12] While Okuda et al.[13] compared the cases of NCPF and idiopathic portal hypertension (IPH); Mikkelsen et al.[14] compared the EHPVO, hepatoportal sclerosis and patients with PH having patent PV; and Verheij et al.[15] compared idiopathic noncirrhotic portal hypertension and noncirrhotic patients with PV thrombosis. Different terminologies used in various published studies applying heterogeneous criteria of inclusion mar the overall concept of histological findings between these two entities. In this study, we intended to evaluate the histological features between NCPF and EHPVO on trucut liver biopsies.

   Patients and Methods Top

Percutaneous liver needle biopsies of patients diagnosed with NCPF (n = 78) and EHPVO (n = 101) were retrieved from our departmental archives (January 2004–March 2016). The patients were diagnosed as per the Asia Pacific Association for the Study of Liver (APASL) criteria.[3] The presenting complaint and the baseline characteristics were available in 53 patients of NCPF and 83 patients of EHPVO cases included from our Institutional archives. The study was approved by the Institute's Ethics Committee. Informed consent was obtained from all individual participants included in the study for undergoing liver biopsy.

Case definition

NCPF: Patients presented with evidence of PH in the form of moderate to massive splenomegaly and esophageal varices, however with maintained liver function tests, patent spleno-portal axis, and absence of cirrhosis were considered as NCPF.[3],[16]

EHPVO: Patients presented with splenomegaly and variceal bleed, in the absence of cirrhosis on liver biopsy along with Doppler ultrasound showing obstruction of the extrahepatic PV, with or without the involvement of the intrahepatic branches of PV, splenic vein and/or superior mesenteric veins were considered to have EHPVO.[17],[18]

Tissue blocks were retrieved and sections were stained with Hematoxylin and Eosin, Masson trichrome, silver reticulin, Periodic acid Schiff stains followed by diastase digestion. Histological features were analyzed by three pathologists (PD, LS, AGV) in a blinded manner and discussed later over a multi-head microscope to reach to a conclusion if there is any discrepancy. The presence of at least 10 portal tracts (PTs) in needle liver biopsies with a composite core length of at least 1.5 cm was taken as the adequacy criteria. Histological parameters assessed were: number of PTs, lobular architecture, presence of bile ductular reaction, patency of bile ducts (visibility of lumen), presence of cholestasis, presence of PV thickening, elastosis and luminal narrowing (phlebosclerosis), PV thrombosis, presence of dilated branches of PV, presence of aberrant vascular channels around PTs (even one), presence of PT inflammation, density, and type of inflammatory cell infiltrate, hepatocyte ballooning, spotty necrosis, piecemeal necrosis, sinusoidal dilatation and inflammation, PT fibrosis, remnant PTs, peri-sinusoidal and pericellular fibrosis, abnormal reticulin pattern, Kupffer cell hypertrophy, presence of megasinusoids, HV dilatation, thickening, or obliteration, presence of hepatic regenerative nodules (NRH) and extent of hepatic fibrosis.

Definitions used in this study

Thickened PV and HV––it was defined as fibrous subintimal thickening, incomplete elastosis, and luminal narrowing of the PV or HV, resembling a hepatic artery by its wall thickness, even when present in a single PV or HV.[2],[15]

Dilated PV and HV––it was defined as PV or HV diameter three times the width of an adjacent bile duct, or a hepatic artery diameter when the bile duct is absent.[15]

Remnant portal tracts––a PT measuring smaller than twice the diameter of a bile duct, and the diameter of the bile duct smaller than the size of the periportal hepatocyte.[15]

Nodular regenerative hyperplasia (NRH)- hepatic nodules formed by large polygonal glycogenated hepatocytes, surrounded by layer/s of small, atrophied hepatocytes with dark eosinophilic cytoplasm but no fibrosis.[2],[15]

Perisinusoidal fibrosis––it was defined as fibrosis in the space of Disse with the compressed sinusoidal lumen.

Pericellular fibrosis––fibrosis encircling the hepatocyte perimeters as seen in chronic alcoholic hepatitis.

The extent of hepatic fibrosis beyond the PTs was determined by the parallel laying of stiff reticulin or collagen fibers outside the PTs. The fibrosis was staged according to the modified Ishak's histological activity index (HAI) staging system.[19] Pericellular and perisinusoidal fibrosis were also recorded as defined above.

Statistical analysis

Statistical analysis was performed with Stata 14 software (Stata Corp. LLC, Texas). Data were presented in the mean (standard deviation) and frequency (percentage) modes. For categorical variables, the Chi-square test and Fischer exact test were applied to see the association between the two groups. For continuous variables following the normality, we applied an independent t test. For Continuous variables not following a normal distribution, we applied the Wilcoxon rank-sum test. The odds ratio was calculated along with the confidence interval and was depicted in a forest plot. A value of P < 0.05 was taken as significant.

   Results Top

Patient characteristics

In this study, a total of 78 liver biopsies from patients with NCPF [mean age 28.4 years (age range 13–56 years, ± SD 8.5); M:F––1:1.6] and 101 liver biopsies from patients with EHPVO [mean age 22.4 years (age range 10 to 50 years, ± SD 8.1); M:F––1.2: 1] were evaluated. Nine biopsies from patients diagnosed with NCPF had <5 portal tracts; hence, finally, 69 biopsies were analyzed. Only a single liver biopsy from patients diagnosed with EHPVO was inadequate as per the inclusion criteria; hence, finally, a total of 100 liver biopsies with EHPVO were analyzed. In all cases of EHPVO, liver biopsies were taken by surgeons to rule out cirrhosis before performing shunt surgery. In cases of NCPF, liver biopsies were taken with a clinical diagnosis of chronic liver disease.

Clinical detail

Being a retrospective study spanning over 16 years (2004–2016) the clinical detail was available in 44 patients with NCPF and 83 patients with EHPVO. Variceal bleeding was present more in patients with EHPVO (80.7%) than in patients with NCPF (56.8%) (P = 0.004). All patients with NCPF and EHPVO had splenomegaly and features of PH at presentation. Incidence of ascites and jaundice was present in a small number of patients from both the groups without any significant difference in incidence [Table 1].
Table 1: Presenting complaints of patients with EHPVO and NCPF in the index cohort

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The hematological and biochemical parameters were available in 53 patients with NCPF and 82 patients of EHPVO. While anemia was seen in the majority of the patients (84% EHPVO cases and 95% NCPF cases), thrombocytopenia (<1.5 lakhs/mm3) were noted in 81.2% and 86.8% of these patients, respectively. Serum transaminases (AST, ALT), total protein, and albumin were within normal limits in most patients of both the disease groups. Elevated alkaline phosphatase (ALP) level (>120 IU/L) was noted in 61% of patients with EHPVO and 37% patients with NCPF, with a slightly higher median value in patients with NCPF (P = 0.21) [Table 2].
Table 2: Hematological and biochemical Parameters of EHPVO and NCPF patients

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On ultrasonography, portal cavernoma (dilated collaterals near porta) was present in 95.1% patients and EHPVO and only in 4 patients with NCPF. Dilated extra-hepatic PV was also noted in 88% of patients with NCPF, though they were patent. The average PV diameter in patients with NCPF was 14.8 mm, range 10.8–16.5 mms (normal PV diameter 12–13 mm). The average diameter of the splenic vein in patients with EHPVO (was available in 72 patients) was 11.1 mm (range 4–30 mms) and 14.2 mm in patients with NCPF (range 5–25 mms; normal splenic vein diameter 10 mm).

Histomorphological changes

In patients with NCPF: Histological changes noted in liver core biopsies from patients with NCPF have been mentioned in [Table 3]. The major changes in the PV and around portal tracts noted in these biopsies were: PV thickening (59.4%), thrombosis (5.8%), narrowing of the lumen (39.1%), PV dilatation (59.4%), peri-portal aberrant vascular channels (75.4%) and remnant PTs (59.4%). Despite having mildly elevated serum bilirubin levels in 14 of these patients, in none of the biopsies, intra-cytoplasmic cholestasis was noted, though these patients had serum transaminitis, increased ALP level, variceal bleed, and NRH [Table 4]. Architectural disarray though was seen in 65.2% of the biopsies, none of them showed HAI stage 6 fibrosis or cirrhotic changes. The stage-wise incidence of fibrosis in our cohort of biopsies from patients with NCPF has been detailed in [Table 3] [Figure 1].
Figure 1: Liver biopsies in NCPF showing maintained lobular architecture [a x40], sclerosed PVs with aberrant vascular channels [b and c x 100], regenerative hepatic nodule [d x100], obliterated PV with bland portal fibrosis [e x100] and portal phlebosclerosis [f x 100]. Figures show portal phlebosclerosis with periportal creeping fibrosis [g x200] and extension of short fibrous septate [h x 40]. Sirius red stained section shows incomplete fibrous septa with formation of incomplete hepatic nodules [i x 100 and j x 200], irregular sinusoidal dilatation [k x 100] and a remnant portal tract [l x 200]

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Table 3: Differences of patient parameters and histological parameters assessed on the liver biopsies from patients with EHPVO and NCPF

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Table 4: Clinical and histopathology parameters of patients of EHPVO and NCPF with an elevated bilirubin level

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In patients with EHPVO: Histological changes in liver core biopsies from patients with EHPVO has been mentioned in [Table 3]. In summary, the changes in PV and peri-portal area were as follows: PV thickening (28%), thrombosis (1%), PV narrowing (10%), PV dilatation (70%), peri-portal aberrant vascular channels (46%), and remnant PTs (2%). While clinically mild jaundice was noted in 28% of patients with EHPVO, only 1/3rd of these biopsies showed mild focal cholestasis. In them, serum transaminitis, raised ALP level, variceal bleed, and NRH were also present [Table 4]. Overall, the lobular architecture was abnormal in 36% of biopsies with predominantly Ishak stage 1 to Ishak stage 3 fibrosis. None of the biopsies showed stage 4, 5, or stage 6 fibrosis [Figure 2] and [Table 3].
Figure 2: Liver biopsies in EHPVO showing maintained architecture, dilated PV [a x 40; b x 100; c x 200], occasional periportal aberrant vessels [d x 200], with no significant fibrosis [e, reticulin stain x 40; f, MT stain x 40]. Dilatation and asymmetrical thickening of PV wall (long arrow) [g x40], mild periportal collagenization [h x100], and an occasional extension of short fibrous septae and thin porto-portal fibrous bridges are noted [i x 100]. Figures show irregular sinusoidal dilatation [j x100], perisinusoidal fibrosis [k x100] and focal septae formation [l x 100]

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Comparative Histology in liver core biopsies from patients with NCPF and EHPVO

Patients diagnosed with EHPVO were younger (P < 0.001), predominantly males, in comparison to female predominance among patients with NCPF (M:F- 0.6:1). While most of the liver biopsies with EHPVO showed maintained lobular architecture, lobular architectural disarray was significantly more in NCPF (P < 0.001). Changes in PV, as narrowing and thickening, presence of remnant PTs, and periportal aberrant vascular channels were significantly more in biopsies with NCPF than in EHPVO (all P < 0.001). Irregular sinusoidal dilatation and spotty necrosis of the hepatocytes were noted in both NCPF and EHPVO patients (P = 0.003). Overall, disarrayed reticulin pattern and higher fibrosis stages were common in NCPF than in EHPVO (P < 0.001 and P = 0.001, respectively). Pericellular fibrosis was also noted more in patients with NCPF than in EHPVO (P = 0.006). The following histological findings were present in both the disease groups and did not help in differentiating them: interface hepatitis, bile ductular reaction, portal inflammation, PV dilatation, hepatocyte ballooning, perisinusoidal fibrosis, sinusoidal inflammation, Kupffer cell hypertrophy, thickening of HV and presence of NRH of hepatocytes [Table 3]. Luminal narrowing, wall thickening, or thrombosis of the intra-hepatic branches of PV though could only be detected in about half of the biopsies from patients with NCPF; in EHPVO similar changes were rare [Table 3]. Odds ratios with 95% confidence intervals were depicted in forest plots to see which histological parameters favor a diagnosis over the other in trucut liver biopsies [Figure 3]. While in EHPVO most of the hepatic changes described above were absent with maintained lobular architecture (odds ratio 0.3); the presence of periportal aberrant vascular channels (Odds ratio 3.59), PV thickening (Odds ratio 3.77), PV narrowing (Odds ratio 5.79), hepatocyte regeneration (Odds ratio 5.05), disarrayed reticulin architecture (odds ratio 3.56), and perisinusoidal fibrosis (Odds ratio 11.1) favored a diagnosis of NCPF [Table 3] and [Figure 3].
Figure 3: Forest plots showing histological features that favor a diagnosis of NCPF over EHPVO based on their odds ratio and confidence intervals. (a) shows features of PV and peri-portal aberrant vascular channels; (b) shows features of the portal tract and lobular architecture; (c) shows features of hepatocytes and (d) shows features of hepatic sinusoids in liver biopsies from patients with NCPF and EHPVO

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As described earlier, a subset of patients with NCPF and EHPVO had high bilirubin levels. In them, serum transaminitis, high serum ALP level, features of NRH on histological examination, and variceal bleed were identified [Table 4]. Hence, the subset of these patients with high bilirubin levels was found to have a distinct clinico-serological and histological profile. However, in these patients, the high bilirubin level did not correlate with the extent of liver fibrosis.

   Discussion Top

This study was targeted to find out the histological changes in trucut liver biopsies from patients with NCPF and EHPVO to help pathologists in a clinically dubious scenario. Histological presence of phlebosclerosis of PV, periportal aberrant vascular channels, remnant PTs, inflammation in PTs, interface hepatitis, and fibrous extension beyond the PTs without the formation of complete nodules were characteristics of NCPF in comparison to EHPVO. In an appropriate clinical setting, an absence of these features, along with maintained lobular architecture should indicate an EHPVO.

While, in about one-third of adult female patients with PH have NCPF,[20] EHPVO is the leading cause of PH in children and younger males.[21],[22],[23],[24] While all of our patients with NCPF and EHPVO had PH and splenomegaly at presentation, variceal bleeding was commoner in patients with EHPVO [Table 1]. 'A slight female preponderance has been reported in patients having NCPF.[20],[25],[26],[27],[28],[29] As in NCPF, the intra-hepatic medium to small PV branches are affected, collaterals are mostly identified in peri-portal location as aberrant vascular channels. On the contrary, in EHPVO the extra-hepatic branches of PV or the splenic veins are affected, hence, intra-hepatic periportal aberrant vascular channels were less identifiable and the extra-hepatic collaterals were picked up radiologically. However, in patients with NCPF, an additional dilatation of extra-hepatic PV segments or extra-hepatic collaterals can be identified in 75% of cases, while peri-portal aberrant vascular channels can also be seen in up to 46% of patients with EHPVO, as seen in this study [Table 3].[6] Arora et al.[30] also identified aberrant vascular channels in about half of the cases of both NCPF and EHPVO. The rudimentary or remnant PTs identified in NCPF, possibly represents the withered portal structures due to occlusion of feeding portal vessels, as was proposed by Wanless et al.[2],[13] Vascular pathologies in patients with NCPF and EHPVO, though support the Unifying hypothesis, EHPVO is the result of the severe and progressive occlusion of the extra-hepatic PV, while NCPF is caused by mild and recurrent occlusion of the smaller intrahepatic branches of PV, resulting in considerable histological overlap.[31]

PT inflammation and interface hepatitis were noted in nearly about half and 10% of liver biopsies from patients with NCPF and EHPVO, respectively; however, spotty necrosis of hepatocytes, pericellular and perisinusoidal fibrosis, fibrous bands extending into hepatic lobules and higher fibrotic stages were noted more in patients with NCPF, than in EHPVO. Hence, a “healed chronic viral hepatitis” theory emanated in the past.[13] Also, portal and periportal fibrosis common in patients with NCPF represents regressed lobular units secondary to occlusion of smaller branches of PV, and focal portal inflammation may be the result of the organization of PV thrombosis. Bland portal fibrosis in PTs also may be the result of endothelial-mesenchymal transition cited as one of the pathogenetic mechanisms.[31] Though diffuse perisinusoidal fibrosis has been reported in liver biopsies from patients with NCPF, we did not identify the same in this study.[31],[32] Both Wanless et al.[2] and Verheij et al.[15] identified NRH more often in patients with NCPF than in EHPVO, in our study NRH was noted in both the groups. In a necropsy study, both asymmetrical sclerosis of PV in EHPVO[14] and sclerotic and fibrotic obliteration of PVs were identified in NCPF, which may explain the formation of NRH in both the groups.[33] In our cohort, 18% of patients diagnosed as EHPVO and 22.5% of patients diagnosed as NCPF had mild jaundice, one of the atypical clinical features for diagnosing both the conditions. In the latter group of patients' high serum transaminitis and alkaline phosphatase levels were identified, liver biopsies showed multiple NRH and there was preceding history of variceal bleed [Table 4].

The extent of peri-portal and lobular fibrosis in NCPF patients was more in comparison to the biopsies from patients with EHPVO, as mentioned above. Saigal et al.[34] identified moderate to severe fibrosis in 9 out of 10 cases of the explanted livers with NCPF. In contrast, Mikkelsen et al.[14] and Shah et al.[35] identified progressing hepatic fibrosis in EHPVO after necropsy. Sarin et al.[18] documented peri-portal fibrosis and extension of short fibrous bands into hepatic lobules in EHPVO. Hence, Rangari et al.[36] hypothesized that EHPVO is also a progressive disease. Though NCPF and EHPVO involve two different anatomical territories of the PV, possibly the nature, extent, rapidity of PV infection, host response, and age of acquiring the PV infection influence whether the outcome would be like NCPF or EHPVO. Though the Unitarian hypothesis appears quite attractive, it appears that in some cases there may be simultaneous involvement of both the extra-hepatic and intra-hepatic branches of PV, especially when the etiological insults are almost identical.[5],[18],[37] In this study, no correlation of extent of fibrosis with the presence of jaundice, variceal bleed, and other histological features were noted.

A potential bias in the selection of cases (not consecutive) and limitations of sampling by trucut liver biopsies could not be wholly excluded in this study. Our study was retrospective; hence, we could not retrieve the clinical or follow-up data in all cases included. The fundamental question of this study was to see the histological changes in trucut biopsies from patients with NCPF and EHPVO. Liver biopsy is still relevant as it is often difficult to differentiate a Child-A cirrhosis from NCPF clinically, and surgeons need to rule out cirrhosis before doing a shunt surgery in EHPVO. Our study adds to the available information published by Verheij et al.[15] that histological features on trucut liver biopsies can help in diagnosis in clinically atypical cases, if not all, in conjunction with clinical findings and radiological features. Pathologists should always keep in mind that isolated histological findings may not be diagnostic alone, and clinical and radiological correlation is mandatory. This study also brings out the set of clinical and histological features commonly seen in patients with NCPF and EHPVO with clinical jaundice.

To conclude, trucut liver biopsies from patients with NCPF and EHPVO though show considerable overlap, a careful evaluation of the histological parameters described in combination with clinical findings and radiological features can help to reach to a diagnosis. One important fact should be kept in mind that there are inherent limitations of evaluation of trucut liver biopsies; hence, the absence of the key histological features in a liver biopsy does not rule out a diagnosis of either NCPF or EHPVO, especially in an appropriate clinical context. Patients with NCPF and EHPVO showing increased bilirubin levels show high transaminitis, high serum ALP level, more variceal bleed, and presence of regenerative hepatic nodules on liver biopsies.

Declaration of patient consent

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Conflicts of interest

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Correspondence Address:
Prasenjit Das
Department of Pathology, All India Institute of Medical Sciences, Ansari Nagar, New Delhi - 110 029
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/IJPM.IJPM_387_20

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  [Figure 1], [Figure 2], [Figure 3]

  [Table 1], [Table 2], [Table 3], [Table 4]


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