Ajeet Singh Bhadoria

Combination of Granulocyte Colony-Stimulating Factor and Erythropoietin Improves Outcomes of Patients With Decompensated Cirrhosis

BACKGROUND & AIMSnPatients with decompensated cirrhosis have significantly reduced survival without liver transplantation. Granulocyte colony-stimulating factor (G-CSF) has been shown to increase survival in patients with acute-on-chronic liver failure, and erythropoietin promoted hepatic regeneration in animal studies. We performed a double-blind, randomized, placebo-controlled trial to determine whether co-administration of these growth factors improved outcomes for patients with advanced cirrhosis.nnnMETHODSnIn a prospective study, consecutive patients with decompensated cirrhosis seen at the Institute of Liver and Biliary Sciences, New Delhi (from May 2011 through June 2012) were randomly assigned to groups given subcutaneous G-CSF (5 μg/kg/d) for 5 days and then every third day (12 total doses), along with subcutaneous darbopoietin α(40 mcg/wk) for 4 weeks (GDP group, n = 29), or only placebos (control group, n = 26). All patients also received standard medical therapy and were followed for 12 months. Histology was performed on liver biopsies. The primary end point was survival at 12 months.nnnRESULTSnBaseline characteristics of patients were comparable; alcohol intake was the most common etiology of cirrhosis. A higher proportion of patients in the GDP group than controls survived until 12 months (68.6% vs 26.9%; P = .003). At 12 months, Child-Turcotte Pugh scores were reduced by 48.6% in the GDP group and 39.1% in the control group, from baseline (P = .001); Model for End Stage Liver Disease scores were reduced by 40.4% and 33%, respectively (P = .03). The need for large-volume paracentesis was significantly reduced in GDP group, compared with controls (P < .05). A lower proportion of patients in the GDP group developed septic shock (6.9%) during follow-up compared with controls (38.5%; P = .005). No major adverse events were observed in either group.nnnCONCLUSIONSnIn a single-center randomized trial, a significantly larger proportion of patients with decompensated cirrhosis given a combination of G-CSF and darbopoietin α survived for 12 months more than patients given only placebo. The combination therapy also reduced liver severity scores and sepsis to a greater extent than placebo. Clinicaltrials.gov ID: NCT01384565.

Role of dual energy spectral computed tomography in characterization of hepatocellular carcinoma: Initial experience from a tertiary liver care institute

OBJECTIVEnTo investigate dual-energy spectral CT in characterization of hepatocellular Carcinoma (HCC) in patients with chronic liver disease.nnnMETHODSnDynamic computed tomography (CT) was performed in 3600 patients (2879 males; 721 females, mean age 50.9xa0±xa011.9 years) with working clinical diagnosis of liver cirrhosis for hepatocellular carcinoma screening and other clinical indications. The study was conducted over a period of 3 years. During dynamic CT scanning, spectral (monochromatic) and routine (polychromatic) CT acquisitions were obtained on a single tube, dual energy, 64 slice multi-detector CT scanner. Imaging findings were studied on routine CT. On the basis of routine CT findings, indeterminate lesions (lesions not showing characteristic hypervascularity followed by washout on dynamic routine CT scan) that were referred for biopsy or surgery were segregated. A retrospective blinded review of the lesions, acquired by the spectral CT acquisitions was done with the help of gem stone imaging (GSI) software to characterize these lesions. All the above lesions were analyzed qualitatively in the arterial phase for lesion conspicuity as well as quantitatively using the monochromatic data sets and nodule Iodine concentration on material density maps, respectively. This data was studied with respect to predictability of HCC using the spectral CT technique. Iodine density of the lesion, surrounding liver parenchyma, and lesion to liver parenchyma ratio (LLR) were derived and statistically analyzed. Histopathology of the lesion in question was treated as gold standard for analysis.nnnRESULTSnIt was observed via statistical analysis that the value of iodine density of the lesion on material density sets of ≥29.5xa0mg/dl, enabled a discriminatory power of 86.5%, sensitivity of 90.5% with 95% confidence Interval (CI) (69.2-98.8%) and specificity of 81.2% with 95% Confidence Interval (54.4-95.9%) in predicting HCC. Qualitative assessment also showed higher lesion conspicuity with spectral CT image sets as compared to routine CT data.nnnCONCLUSIONnThis study reveals that spectral imaging is an excellent qualitative as well as a quantitative tool for assessing and predicting hepatocellular carcinoma in cirrhotic patients.

Extrahepatic portal vein obstruction and portal vein thrombosis in special situations: Need for a new classification

Extrahepatic portal vein obstruction is a vascular disorder of liver, which results in obstruction and cavernomatous transformation of portal vein with or without the involvement of intrahepatic portal vein, splenic vein, or superior mesenteric vein. Portal vein obstruction due to chronic liver disease, neoplasm, or postsurgery is a separate entity and is not the same as extrahepatic portal vein obstruction. Patients with extrahepatic portal vein obstruction are generally young and belong mostly to Asian countries. It is therefore very important to define portal vein thrombosis as acute or chronic from management point of view. Portal vein thrombosis in certain situations such as liver transplant and postsurgical/liver transplant period is an evolving area and needs extensive research. There is a need for a new classification, which includes all areas of the entity. In the current review, the most recent literature of extrahepatic portal vein obstruction is reviewed and summarized.

Platelets contribute to growth and metastasis in hepatocellular carcinoma

To determine the association of platelets with hepatocellular carcinoma (HCC) growth and its metastasis. We examined platelets, laboratory, and radiological data of consecutive 420 HCC and 1008 cirrhosis cases. Follow‐up information of platelet count in cirrhosis to HCC, pre‐ to post‐therapy, and post‐therapy to HCC outcome was analyzed. Cytokine profiling was performed in HCC and cirrhosis (n = 10 each). On the basis of imaging, HCC was divided into six subgroups. Cytosmears of HCC were assessed for platelet clustering around tumor cells. An in vitro Matrigel invasion assay was performed on human HCC cell lines using graded concentration of platelets. Baseline platelet numbers and platelet/lymphocyte ratios (PLRs) were significantly higher (p < 0.001) in HCC than cirrhosis. IL‐1, IL‐6, FGF, G‐CSF, thrombopoietin, and VEGF were higher in HCC than cirrhosis. Platelet counts were increased after HCC conversion of cirrhosis (p < 0.001) and decreased (p < 0.001) after therapy. Platelets and PLR in recurrence cases were higher than in responders at baseline. AFP, PIVKAII, platelets, and PLR increase (p < 0.001 each) with advancement in HCC growth. Multivariate analysis showed platelets (p = 0.002), PLR (p = 0.004), and AFP (p < 0.001) associated with distant metastasis. Platelet clustering seen in 75.7% of HCC group 3, 45% in group 2, and 12.5% in group 1 cases (p < 0.001). Invaded cells in Matrigel assay positively correlated with platelet concentration. Platelets can contribute to the development, growth, invasion, and metastasis of HCC. Rising platelet count after HCC therapy is indicative of incomplete response or recurrence.

Percutaneous endobiliary RFA combined with balloon-sweep for re-opening occluded metallic biliary stents.

Abstract The aim of this report is to discuss the results of percutaneous endobiliary radiofrequency ablation (RFA) combined with balloon-sweep technique in restoring the patency of occluded self-expandable metallic stents (SEMS) secondary to tumor infiltration. A total of eight patients underwent endobiliary RFA for reopening of occluded SEMS at our institute. After endobiliary RFA, all patients showed restoration of stent patency. After a median follow-up of 6.5 months, four patients had succumbed to the underlying disease at 3, 4, 6, and 7 months. Two of these required reinterventions at 2 and 5 months. One patient died of sepsis and aspiration pneumonia at 3 months. Of the remaining three patients, two required re-intervention after 2 months, while the other remained asymptomatic. The mean duration of stent patency after the first session of RFA was 4u2009±u20092.1 months, which was comparable to the primary patency of these stents (4.2 months). Our experience suggests that endobiliary RFA with balloon sweep is a safe and useful technique for re-establishing the patency of occluded SEMS.

Quantitative fibrosis estimation by image analysis predicts development of decompensation, composite events and defines event-free survival in chronic hepatitis B patients.

The extent of fibrosis is a major determinant of the clinical outcome in patients with chronic liver diseases. We undertook this study to explore the degree of fibrosis in baseline liver biopsies to predict clinical outcomes in chronic hepatitis B (CHB) patients. Fibrosis quantification was done by image analysis on Massons trichrome-stained sections and correlated with clinical and biochemical parameters, liver stiffness and hepatic vein pressure gradient (n = 96). Follow-up information collected related to clinical outcome. A total of 964 cases was analyzed. Median quantitative fibrosis (QF) was 3.7% (interquartile range, 1.6%-9.7%) with substantial variation in various stages. Median QF was F0, 1% (0.7%-1.65%); F1, 3.03% (2.07%-4.0%); F2, 7.1% (5.6%-8.7%); F3, 12.7% (10.15%-16.7%); F4, 26.9% (20.3%-36.4%). QF positively correlated with METAVIR staging, liver stiffness measurement, and hepatic vein pressure gradient. Eighty-nine cases developed liver-related events: decompensation, hepatocellular carcinoma, liver transplantation and death. Cox regression analysis after adjusting for METAVIR staging-QF, albumin, and AST for composite events; QF and albumin for decompensation; and only QF for hepatocellular carcinoma-were found to be significant predictors of clinical outcomes. QF categorized into five stages: QF1, 0%-5%; QF2, 5.1%-10%; QF3, 10.1%-15%; QF4, 15.1%-20%; QF5, >20.1%. In patients with advanced stages of QF, probability of event-free survival found to be low. Quantitative fibrosis in baseline liver biopsy predicts progression of the disease and disease outcome in CHB patients. QF defines the probability of event-free survival in CHB cases.

After Proper Optimization of Carvedilol dose, do Different Child Classes of Liver Disease Differ in Terms of dose Tolerance and Response on a Chronic Basis?

BACKGROUND/AIMSnLiterature regarding safe doses of carvedilol is limited, and safe doses across different Child classes of chronic liver disease are not clear.nnnPATIENTS AND METHODSnA total of 102 consecutive cirrhotic patients with significant portal hypertension were included in this study. Hepatic venous pressure gradient was measured at baseline and 3 months after dose optimization.nnnRESULTSnA total of 102 patients (63 males, 39 females) with a mean age of 58.3 ± 6.6 years were included. Among these patients, 42.2% had Child Class A, 31.9% had Class B, and 26.6% had Child Class C liver disease. The mean baseline hepatic venous pressure gradient was 16.75 ± 2.12 mmHg, and after dose optimization and reassessment of hepatic venous pressure gradient at 3 months, the mean reduction in the hepatic venous pressure gradient was 5.5 ± 1.7 mmHg and 2.8 ± 1.6 mmHg among responders and nonresponders respectively. The mean dose of carvedilol was higher in nonresponders (19.2 ± 5.7 mg) than responders (18.75 ± 5.1 mg). However, this difference was not statistically significant (P > 0.05). The univariate analysis determined that the absence of adverse events, the absence of ascites, and low baseline cardiac output were significantly associated with chronic response, whereas, the etiology, Child class, variceal size (large vs small), and gender were not. On multivariate analysis, the absence of any adverse event was determined to be an independent predictor of chronic response (OR 11.3, 95% CI; 1.9-67.8).nnnCONCLUSIONnThe proper optimization of the dose of carvedilol, when administered chronically, may enable carvedilol treatment to achieve a greater response with minimum side effects among different Child classes of liver disease.Background/Aims: Literature regarding safe doses of carvedilol is limited, and safe doses across different Child classes of chronic liver disease are not clear. Patients and Methods: A total of 102 consecutive cirrhotic patients with significant portal hypertension were included in this study. Hepatic venous pressure gradient was measured at baseline and 3 months after dose optimization. Results: A total of 102 patients (63 males, 39 females) with a mean age of 58.3 ± 6.6 years were included. Among these patients, 42.2% had Child Class A, 31.9% had Class B, and 26.6% had Child Class C liver disease. The mean baseline hepatic venous pressure gradient was 16.75 ± 2.12 mmHg, and after dose optimization and reassessment of hepatic venous pressure gradient at 3 months, the mean reduction in the hepatic venous pressure gradient was 5.5 ± 1.7 mmHg and 2.8 ± 1.6 mmHg among responders and nonresponders respectively. The mean dose of carvedilol was higher in nonresponders (19.2 ± 5.7 mg) than responders (18.75 ± 5.1 mg). However, this difference was not statistically significant (P > 0.05). The univariate analysis determined that the absence of adverse events, the absence of ascites, and low baseline cardiac output were significantly associated with chronic response, whereas, the etiology, Child class, variceal size (large vs small), and gender were not. On multivariate analysis, the absence of any adverse event was determined to be an independent predictor of chronic response (OR 11.3, 95% CI; 1.9–67.8). Conclusion: The proper optimization of the dose of carvedilol, when administered chronically, may enable carvedilol treatment to achieve a greater response with minimum side effects among different Child classes of liver disease.

A Haemodynamic Analysis to Assess the Safe Dose of Carvedilol across Different Child Class of Liver Disease

Background: Literature regarding safe dose of carvedilol is limited and also safe dose across different child classes of chronic liver disease is not very clear. Aim: We aimed primarily to study, the effect of reasonably safe dose (12.5 mg) of carvedilol in acute reduction of portal pressure and compared it with chronic reduction of portal pressure, after Original Research Article Wani et al.; BJMMR, 7(5): 355-368, 2015; Article no.BJMMR.2015.342 356 proper optimization of dose of carvedilol. Second aim of our study was to define predictors of response for acute and chronic reduction of portal pressure and to assess difference in dose tolerated and response across different child class on chronic basis. Methods: One hundred two consecutive patients of cirrhosis of liver with significant portal hypertension were included and hepatic venous pressure gradient was measured at the base line and after 90 minutes of administration of 12.5 mg carvedilol. After proper dose optimization of carvedilol, hepatic venous pressure gradient was again measured after 3 months to assess the chronic response. Results: The mean age of study population was 58.3±6.6 years. A total of 42.2%, 31.9% and 26.6% patients had child class A, child class B and Child class C cirrhosis, respectively. Mean pre-drug hepatic venous pressure gradient was 16.75±2.12 mmHg which dropped to 13.07±2.32 mmHg after 90 minutes of administration of 12.5 mg of carvedilol. The mean drop of hepatic venous pressure gradient was 4.5±2.2 mmHg and 2.4±1.9 mmHg among responders and non-responders, respectively. Overall, 51% showed acute response while 49% were nonresponders. Low cardiac output and high mean arterial pressure were significantly predicting the acute response, while, low baseline cardiac output was found as an independent predictor. After dose optimization, number of responders increased from 52 to 62. Mean dose of carvedilol was higher in non–responders as compared to responders, though statistically insignificant (p>0.05). Mean reduction of hepatic venous pressure gradient from baseline and after 3 months was 5.5±1.7 mmHg and 2.8±1.6 mmHg among responders and non responders on chronic basis, respectively (p<0.001). Absence of any adverse events (OR 11.3, 95% CI; 1.9-67.8), and more than 2.5 mmHg fall in hepatic venous pressure gradient during acute response (OR 8.7, 95% CI; 3.1-25.3) were found as independent predictors of chronic response (p<0.05). Univariate analysis found that no adverse events, no ascites, low baseline cardiac output, more than 2.5 mmHg fall in hepatic venous pressure gradient during acute response, as predictors of chronic response. However, etiology, child class, variceal size (large vs small) and gender were not significantly associated with chronic response Conclusion: At safe dose and with proper optimization of dose, carvedilol may achieve greater response with minimum side effects among different child classes of liver disease.

Hepatic visceral larva migrans, a resilient entity on imaging: Experience from a tertiary liver center.

Introduction: Hepatic visceral larva migrans (VLM) is an uncommon parasitic manifestation seen in the liver. It presents as coalescing, conglomerated, or solitary abscess cavities in the liver on imaging. We conducted a retrospective clinico-radiological analysis of 24 patients with biopsy proven VLM who were reviewed and followed up at our tertiary liver institute over a period of 4 years. Materials and Methods: The study was performed to correlate the radiological features and imaging response to therapy for hepatic VLM. The disease course, imaging findings, progressive, absolute eosinophil counts (AEC), hydatid serology, and the extent of radiological regression of the liver lesions, on follow-up were analyzed. Results: Imaging showed a diagnostic accuracy of 42%. Hydatid serology was positive in 46% patients before starting treatment. The median pretreatment AEC of 507 showed a significant posttreatment AEC decline to median value of 117. The Wilcoxon signed ranks test showed significant decline in the AEC (P < 0.001). Radiological regression was present in all lesions. However, patients showed residual abscesses on imaging, up to 2 years on follow-up. Conclusion: This study reveals that AEC has a significant predictive value in diagnosis and as a marker for disease regression. Complete radiological resolution of hepatic lesions does not correlate with total clinical remission. This finding warrants the need for further studies to look into the role of prolonged medical therapy or surgery as an alternate to current therapy module in cases of hepatic visceral larva abscesses.

Procoagulant abnormalities in cirrhosis with portal vein thrombosis

Dear Editor, Chronic liver disease patients remain in a delicately rebalanced hemostatic state which can tilt either in the direction of bleeding or thrombosis. Prothrombotic predominance in cirrhotic patients can lead to various vascular complications, of which portal vein thrombosis (PVT) is the most frequent. This study was undertaken to find out the incidence and to assess the procoagulant abnormalities in cirrhotic patients with PVT. A retrospective study was carried out wherein data of consecutive liver cirrhosis cases (from June 2009 to June 2013) was analyzed. Noncirrhotic PVT and hepatocellular carcinoma were excluded. PVT diagnosis was based on an ultrasound with Doppler, CT angiography, or magnetic resonance imaging. Non-PVT cirrhosis was taken as control group. A retrospective analysis of recorded coagulation profile was done. A total of 3,170 patients with cirrhosis were identified; out of these, 151 (4.7 %) were found to be positive for PVT. Underlying etiologies for cirrhosis were mainly the following: cryptogenic (n=56, 37.08 %), alcohol (n=48, 32 %), HBV (n=18, 11.9 %), and HCV (n=13, 8.6 %). A significantly higher mean age was seen among PVT cases as compared to non-PVT cases. Partial thrombi noted in 79.1 % cases and mainly in portal trunk and intrahepatic portal vein (78.5 %). Majority of the PVT cases were of Child–Turcotte– Pugh (CTP) B and C status. A significantly low prothrombin time (PT) and international normalized ratio (INR) were detected among PVT cases. Platelets were significantly lower in PVT group; however, 5 % PVT cases with platelet counts of >500×10/L were identified. The mean values of natural anticoagulants were well below the normal range, and most of these cases had low anticoagulant levels including the following: antithrombin III (83 %), protein C (85.7 %), and protein S (58.6 %). Protein C levels were also significantly lower in PVT group. Factor VIII levels for cirrhotic with PVT were found to be elevated in 88 % cases and median value was 210.6 % with a range of 90.5 % to 413.4 % (normal range, 70 % to 150 %). Prothrombotic mutational polymorphism details were available in limited number of cases. Mutational polymorphism was detected in methyl tetrahydrofolate reductase (MTHFR) in 11/24 (45.8 %) and Factor V Leiden mutation (FVL) in 1/24 (4.1 %). JAK2 V617 (0/25) and prothrombin mutation (PTM) (0/26) were not detected. CTP and model for end-stage liver diseases (MELD) for PVT cases were not significantly different from the non-PVT cases (results are summarized in Table 1). The prevalence of PVT was found to be 0.6 % to 16 % in different studies; this variation may be due to different patient groups, disease characteristics, and mode of diagnosis, and many of the PVT cases are usually asymptomatic [1]. A significantly low PT and INR have been noted in the PVT group which suggests tilting of hemostatic balance toward prothrombotic state [1]. The classical Virchow’s triad of venous stasis, endothelial injury, and hypercoagulability has been extended to the pathogenesis of PVT in cirrhosis. Hypercoagulability in these patients has been attributed to the reduction of natural anticoagulants and increased C. Bihari (*) : P. Saxena Department of Hematology, Institute of Liver and Biliary Sciences, D-1, Vasant Kunj, New Delhi, Delhi 110 070, India e-mail: drcbsharma@gmail.com