Introduction
Classification of EV: Size, Location, Presence of Red Spots, Low Versus High Risk
Non-invasive Screening for Any Esophageal Varices and “Varices Needing Treatment” (Table 1)
Author, journal, year | Design and etiology | N patients overall N patients with any EV (%) N patients with VNT (%) | TE-cutoffs and AUC any EV/VNT | Main conclusions (specificity/sensitivity, PPV/NPV) | Additional parameters used in the study and comments |
---|---|---|---|---|---|
Foucher, Gut, 2006 [17] | Prospective Mixed etiology | n = 144 patients with F3/F4 fibrosis n with any EV: n/a n = 42 (29%)/85 (59%) with VNT | LSM: Any: n/a VNT 27.5 kPa, AUC 0.73 | LSM: Any: n/a VNT: Sens. 88%, Spec. 53%, PPV 45%, NPV 90% | • The main focus was diagnosis of fibrosis stages using TE |
Kazemi, J Hepatol, 2006 [18] | Prospective Mixed etiology | N = 165 patients analyzed n = 74 (44.8%) with EV n = 47 (28.5%) with VNT | LSM: Any 13.9 kPa, AUC 0.84 VNT 19.0 kPa, AUC 0.83, | LSM: Any: Sens. 92%, Spec. 39%, PPV 55%, NPV 85% VNT Sens. 89%, Spec. 59%, PPV 47%, NPV 93% | • Parameters: PLT, spleen diameter, PLT, LSM/spleen size |
Vizzutti, Hepatology, 2007 [19] | Prospective Etiology: HCV | n = 61 patients analyzed n = 30 (49.2%) with esophageal EV n = 18 (38.2%) with large EV/VNT | LSM: Any 17.6 kPa, AUC 0.76 VNT 27.4 kPa, AUC 0.76 | LSM: Any Sens. 90%, spec. 43%, PPV 77%, NPV 66% VNT Sens. 70%, spec. 78%, PPV 90%, NPV 55% | |
Bureau, Aliment Pharmacol Ther, 2008 [20] | Prospective Mixed etiology | n = 150 patients analyzed n = 64 (42.6%) with EV n = 43 (28.6%) with VNT | LSM: Any 21.1 kPa, AUC 0.85 VNT/large 29.3 kPa AUC 0.76 | LSM: Any Sens. 84%, Spec. 71% VNT Sens. 81%, Spec. 61% | • Parameters: Prothrombin index • VNT: large EV |
Castéra, J Hepatol, 2009 [21] | Prospective Etiology: HCV | n = 70 patients with cirrhosis analyzed n = 25 with EV n = 13 with VNT | LSM: * Any 13.9 kPa (Kazemi 2006) 17.6 kPa (Vizutti 2007) 21.5 kPa, AUC 0.96 * VNT 19 kPa (Kazemi 2006) 21.5 kPa, AUC 0.87 30 kPa, AUC 0.87 | LSM: *Any: Cutoff 13.9 kPa: Sens. 96%, Spec. 39%, PPV 49%, NPV 94% Cutoff 17.6 kPa: Sens. 84%, Spec. 61%, PPV 57%, NPV 86% Cutoff 21.5 kPa: Sens. 76%, Spec. 78%, PPV 68%, NPV 84% *VNT: Cutoff 19.0 kPa: Sens. 85%, Spec. 62%, PPV 35%, NPV 94% Cutoff 21.5 kPa: Sens. 85%, Spec. 68%, PPV 39%, NPV 95% Cutoff 30.5 kPa: Sens. 77%, Spec. 5%, PPV 56%, NPV 94%10 | • Parameters: PLT, FibroTest, prothrombin index, AST/ALT ratio, APRI, Lok index |
Kim, Am J Gastroenterol, 2010 [22] | Prospective Etiology: HBV | n = 391 n = 184 (47%) with EV n = 133 (34%) with VNT | LSM: n/a LSPS: Any: n/a VNT 3.5, AUC 0.95 | LSM: n/a LSPS: VNT: Cutoff 3.5: Sens. 88%, Spec. 91%, PPV 82%, NPV 94% VNT: Cutoff 5.5: Sens. 72%, Spec. 98% PPV 94%, NPV 88% | • Diagnostic accuracy varies with severity of cirrhosis: LPS: AUC 0.94 (Child-Pugh A), AUC 0.88 (Child-Pugh B/C). • Included cirrhosis Child-Pugh A-C, training cohort and validation cohort |
Nguyen-Khac, Alcohol Clin Exp Res, 2010 [23] | Prospective Mixed etiologies | n = 183 patients analyzed n = 41 (22%) with large EV/VNT | LSM: VNT 48 kPa; AUC 0.75 VNT (ALD) 47.2 kPa, AUC 0.77 VNT (viral) 19.8 kPa, AUC 0.73 | LSM: VNT: Sens. 73%, Spec. 73%, PPV 44%, NPV 90% VNT (ALD): Sens. 85%, Spec. 64%, PPV 44%, NPV 93% VNT (viral): Sens. 89%, Spec. 55%, PPV 27%, NPV 96% | |
Stefanescu, J Gastroenterol Hepatol, 2011 [24] | Prospective Etiology: ALD and/or HCV or healthy controls | n = 137 with cirrhosis analyzed n = 116 (85%) with EV n = 60 (44%) with VNT | LSM: Any 28 kPa, AUC 0.75 SSM: Any 46.4 kPa, AUC 0.78 LSM + SSM: Any: LSM 19 kPa, SSM 55 kPa | LSM: Any: Sens. 74%, Spec. 64%, PPV 92%, NPV 31% SSM: Any: Sens. 84%, Spec. 71%, PPV 94%, NPV 46% LSM (19 kPa) + SSM (55 kPa): Any: Sens. 93%, Spec. 40%, PPV 95%, NPV 33% | • Parameters: PLT/spleen size ratio; LSM × SSM • VNT: cutoffs n/a |
Stefanescu, J Gastrointest Liver Dis, 2011 [25] | Prospective Etiology: ALD and/or HCV | n = 231 patients analyzed n = 157 (68%) with EV n = 68 (30%) with VNT | LSM: Any 19 kPa, AUC 0.66 VNT 38 kPa, AUC 0.69 | LSM: Any: Sens. 84%, Spec. 32%, PPV 72%, NPV 49% VNT: Sens. 56%, Spec. 75%, PPV 47%, NPV 81% | • Included cirrhosis • Excluded decompensated cirrhosis, co-infection with viral hepatitis • Parameters: APRI, Forns Index, Lok Score, FIB4 • VNT: grades 2–3 EV |
Chen, J Gastroenterol Hepatol, 2012 [26] | Prospective Etiology: HBV | n = 222 patients analyzed n = 96 (43%) with EV n = 82 (40%) with VNT | LSM: VNT 17.1 kPa, AUC 0.73 (all) VNT 36.1 kPa, AUC 0.92 (ALT > 5 × ULN) VNT 7.9 kPa, AUC 0.79 (Child-Pugh A, rule out EV) VNT 34.6 kPa (Child-Pugh A, rule in EV) LSPS: VNT Cutoff 3.5, cutoff 5.5; AUC 0.81 | LSM: VNT: Cutoff 17.1 kPa: Sens. 90%, Spec. 44%, PPV 47%, NPV 88% VNT: Cutoff 36.1 kPa: PPV 73%, NPV 100% VNT: Cutoff 7.9 kPa: Sens. 97%, NPV 95% VNT: Cutoff 34.6 kPa: Spec. 94%, PPV 73% LSPS: VNT: Cutoff 3.5: Sens. 78%, NPV 86% (exclusion) VNT: Cutoff 5.5: Spec. 90%, PPV 76% (inclusion) | • Included cirrhosis • Excluded history of variceal bleeding, NSBB therapy, TIPS • VNT: medium or large EV, or small with RSS, or decompensated cirrhosis • Parameters: USLS; LSM × ALT, LSM × Child-Pugh, LSPS, age-PLT-AST/ALT ratio, PLT/spleen diameter ratio |
Wang, J Gastroenterol Hepatol, 2012 [27] | Prospective Etiology: HBV | n = 126 patients analyzed n = 48 (38%) with EV n = 13 (10%) with VNT | LSM: Any 12.0 kPa, AUC 0.79 VNT 21.0 kPa, AUC 0.87 | LSM: Any: Sens. 67%, Spec. 77%, PPV 64%, NPV 79% VNT: Sens. 77%, Spec. 87%, PPV 40%, NPV 97% | • Parameters: • APRI, PLT, AST/ALT ratio |
Colecchia, Gastroenterology, 2012 [28] | Prospective Etiology: HCV | n = 100 patients analyzed n = 53 (53%)with EV n = 26 (26%) with VNT | LSM (AUC 0.90): Any: cutoff 16.4 kPa Any: cutoff 25.0 kPa SSM (AUC 0.94): Any: cutoff 41.3 kPa Any: cutoff 55.0 kPa LSPS (AUC 0.91) Any: cutoff 1.32 Any: cutoff 3.83 | LSM: Any: cutoff 16.4 kPa; Sens. 96%, Spec. 60% (rule out) Any: cutoff 25.0 kPa, Sens. 57%, Spec. 98% (rule in) SSM: Any: cutoff 41.3 kPa, Sens. 98%, Spec. 66% (rule out) Any: cutoff 55.0 kPa, Sens. 72%, Spec. 96% (rule in) LSPS: Any: cutoff 1.32: Sens. 98%, Spec. 64% (rule out) Any: cutoff 3.83: Sens. 60%, Spec. 98% (rule in) | • LSM and SSM for detection of HVPG > 12 mmHg and EV • Parameters: • LSPS, PLT/spleen size |
Calvaruso, J Viral Hepat, 2013 [29] | Prospective Etiology: HCV | n = 96 patients analyzed n = 54 (56.3%) with EV n = 26 (27.1%) with VNT | LSM: Any 17.0 kPa, AUC 0.71 VNT 19.0 kPa, AUC 0.71 Modified SSM (0-150 kPa): Any 50.0 kPa, AUC 0.70 VNT 54.0 kPa, AUC 0.82 | LSM: Any: Sens. 71%, Spec. 57%, PPV 67%, NPV 62% VNT: Sens. 72% Spec. 55%, PPV 38%, NPV 84% Modified SSM: Any: Sens. 65%, Spec. 61%, PPV 69%, NPV 57% VNT: Sens. 80%, Spec. 70%, PPV 47%, NPV 90% | • Modified SSM: values 0–150 kPa • Parameters: Gender, age, AST, ALT, PLT, AST/ALT ratio, APRI, spleen diameter |
Shi, Liver Int, 2013 [30] | Meta-analysis All etiologies, with sub-analyses for viral etiology (HCV + HBV) | n = 3644 patients analyzed n = 1786? (49.0%) with EV n = 1166? (32.0%) with VNT | LSM (pooled): Any: Cutoffs 15.1–28.0 kPa; AUC 0.84 VNT: Cutoffs: 17.8–48.0 kPa; AUC 0.78 | LSM (pooled): Any: Cutoffs 15.1–28.0 kPa: Sens. 87%, Spec. 53%, PPV 79%, NPV 64% VNT: Cutoffs: 17.8–48.0 kPa: Sens. 86%, Spec. 59%,, PPV 79%, NPV 66% | |
Sharma, Am J Gastroenterol, 2013 [31] | Prospective Mixed etiologies | n = 174 patients analyzed n = 124 patients with EV n = 78 with large EV/VNT | LSM: Any 27.3 kPa, AUC 0.91 VNT: n/a SSM: Any 40.8 kPa, AUC 0.90 LSPS: Any 3.09, AUC 0.87 | LSM: Any: Sens. 91%, Spec. 72%, PPV 89%, NPV 76% SSM: Any: Sens. 94%, Spec. 76%, PPV 91%, NPV 84% LSPS: Any: Sens. 89%, Spec. 76%, PPV and NPV not reported | • Only LS und SS independently associated with presence of EV; • SSM: can differentiate between large and small EV • LSM: Cannot differentiate between large and small EV • Included cirrhosis • Excluded decompensated cirrhosis, ACLF, active alcohol abuse • Parameters: LSPS, PLT/spleen diameter ratio |
Binţinţan, Med Ultrason, 2015 [32] | Prospective Etiology: viral and/or ALD | n = 60 patients with cirrhosis n = 47 (78%) with EV n = 32 (53%) with VNT | LSM: Any 15 kPa, AUC 0.96 VNT 28.8 kPa, AUC 0.90 | LSM: Any: Sens. 95%, Spec. 100%, PPV 100%, NPV 86% VNT: Sens. 87%, Spec. 83%, PPV 84%, NPV 86% | • Parameters: hemodynamic liver index, portal vascular resistance, spleno-portal index |
Hu, Ultrasound Med Biol, 2015 [33] | Prospective Etiology: viral (HBV, HCV) | n = 200 patients analyzed n = 110 (55%) with EV n = 69 (35%) with large EV | LSM: Any 20.3 kPa, AUC 0.84 VNT 25.6 kPa, AUC 0.86 | LSM: Any: Sens. 84%, Spec. 73%, PPV 72%, NPV 91% VNT: Sens. 86%, Spec. 72%, PPV 79%, NPV 81% | • VNT: grade 2 or 3 EV • Parameters: LSM x PLT (no detailed description available) |
Marot, Liver Int, 2017 [34] | Meta-analysis Mixed etiologies | n = 3364 n = (49.0%) with EV n = (32.0%) with VNT | LSM: Any 20 kPa* LSM and PLT (150 G/L): VNT 20 kPa × PLT 150 G/L* | LSM and PLT (150 G/L): Any: Sens. 89%, Spec. 38%, PPV 43%, NPV 86% VNT: Sens. 93%, Spec. 30%, PPV 14%, NPV 97% | • Focus on risk of bleeding rather than finding cutoffs for prediction of EV • VNT: variable definition between studies |
Pu, J Gastroenterol, 2017 [35] | Meta-analysis Mixed etiologies | n = 2697 patients analyzed Patients with EV: n/a | LSM (pooled): Any 20 kPa, AUC 0.83 VNT 30 kPa, AUC 0.83 | LSM: Any (pooled): Sens. 84%, Spec. 62%, Any: Cutoff 20 kPa: Sens. 83%, Spec. 68%, PPV: n/a, NPV: n/a VNT (pooled): Sens. 78%, Spec. 76%, VNT: Cutoff 30 kPa: Sens. 73%, Spec. 74%, PPV: n/a, NPV: n/a | • VNT: large EV |
Llop, J Gastroenterol Hepatol, 2017 [36] | Retrospective analysis of prospective data Mixed etiology | n = 161 patients analyzed n = 25 (15.5%) with EV VNT: n/a | LSM Any 20.0 kPa* LSM + PLT:* Any 20.0 kPa x PLT 150 G/L* LSPS: Any: cutoff 3.21; | LSM: Any: Cutoff 20 kPa*: Sens. 76%, Spec. 71%, PPV 32%, NPV 94% LSM and PLT (150 G/L)*: Any: Cutoff 20 kPa*: Sens. 88%, Spec. 38%, PPV 21%, NPV 94% LSPS: Any: Sens. 36%, Spec. 84%, PPV 30%, NPV 88% | • TE is the best single method to predict EV; LSPS had high and Baveno VI criteria low risk of misclassifying patients with EV • Included LSM >10 kPa • Excluded decompensated cirrhosis • Parameters: PLT, spleen diameter, LSPS, variceal risk index • Augustin algorithm, Baveno VI • AUC was calculated but not reported |
Wong, Liver Int, 2018 [37] | Prospective | LSM: Total n = 274/548 n = 51 (18.6%) with EV n = 11 (4.0%) with VNT | LSM: Any 12.5 kPa* VNT 20.0 kPa × PLT 150 G/L* SSM: VNT 41.3 kPa | LSM: Any: Cutoff 20 kPa*: Sens 96%, Spec. 91%, PPV 26%, NPV 47% VNT: Cutoff 12.5 kPa: Sens. 98%, NPV: 94% VNT: Cutoff 20 kPa*: Sens. 91%, Spec. 18.1%, PPV 10%, NPV 96% SSM: Any 98%, NPV 94% | • LSM (12.5 kPa) × SSM (41.3 kPa) |
Manatsathit, J Gastroenterol Hepatol, 2018 [38] | Meta-analysis Mixed etiologies | Any EV: n = 1681/3001 (56% of LSM) and n = 968/1911 (51% of SSM) with EV VNT: n = 1466/4337 (34% of LSM) and n = 383/1119 (34% of SSM) with VNT | LSM (pooled): Any: AUC 0.82 VNT: AUC 0.83 SSM (pooled): Any: AUC 0.90 VNT: AUC 0.81 LSPS (pooled): Any: AUC 0.85 VNT: AUC 0.86 | LSM (pooled): Sens. 84%, Spec. 64% Any: Sens. 85%, Spec. 64% VNT: Sens. 85%, Spec. 63% SSM (pooled): Sens. 91% Spec. 66% Any: Sens. 90%, Spec. 73% VNT: Sens. 87%, Spec. 52% LSPS (pooled): Any: Sens. 91%, Spec. 67% VNT: Sens. 82%, Spec. 87% | • Sub-analyses regarding method (TE, ARFI, others), etiology (ALD vs viral), ethnicity (Asian vs Western), and cACLD vs decompensated cirrhosis • No cutoffs calculated! |
Natural History of Small Varices and Incidence of Bleeding
Pathophysiological Considerations Supporting Current Recommendations for the Management of Portal Hypertension/Patients with Small Varices
Impact of Etiological Treatment on Small Varices
Treatment of Small Varices with Non-selective Betablockers (Table 2)
Author, journal, year | Design | N patients overall N with small EV (%) | NSBB (dose) | HVPG measurement | Main conclusions |
---|---|---|---|---|---|
The PROVA Study Group, Hepatology, 1991 [70] | RCT | 286/166 (58%) | Propranolol (160–400 mg/day) | No | • Small EV had a considerable risk of bleeding • The incidence of variceal hemorrhage and overall mortality was not significantly different between patients receiving NSBB, sclerotherapy or combination therapy |
Calès, Eur J Gastroenterol Hepatol, 1999{Cales, 1999 #1480} | RCT | 206/127 (62%) | Propranolol (160 mg) | No | • NSBB therapy did neither prevent occurrence/growth of EV or variceal bleeding and did not reduce mortality in patients without/with small EV |
Merkel, Hepatology, 2000 [71] | RCT | 146/6 (4.1%) | Nadolol (40–160 mg/day) | No | • NSBB plus ISMN was more effective than NSBB alone in the long-term prophylaxis of first variceal bleeding |
Merkel, Hepatology, 2000 [72] | RCT | 49/2 (4.1%) | Nadolol (40–80 mg/day) | Yes (all) | • HVPG reponse was the best predictor of efficacy in patients receiving NSBB or NSBB plus ISMN for primary prophylaxis |
Abraczinskas, Hepatology, 2001 [73] | RCT | 49/32 (65.3%) | Propranolol (dose not specified) | No | • NSBB therapy in small and large EV is effective in preventing of first variceal bleeding • After discontinuation of NSBB therapy, the risk of variceal bleeding persisted |
Merkel, Gastroenterology, 2004 [7] | RCT | 161 (100%) | Nadolol (mean dose 62 ± 25 mg/day) | Yes (11.8%) | • Primary prophylaxis with NSBB should be considered in patients with small EV • NSBB delay the growth of small EV |
Turnes, Am J Gastroenterol, 2006 [74] | RCT | 71/4 (6.6%) | Propranolol (54 ± 14 to 79 ± 12 mg/day) | Yes (all) | • Positive impact of HVPG response in the setting of primary prophylaxis • Insufficient data on patients with small EV |
Reiberger, Gut, 2013 [75] | Non-randomized clinical trial | 104/41 (39.4%) | Propranolol (80–160 mg/day) Carvedilol (6.25–50 mg/day) | Yes (all) | • Carvedilol induces HVPG response in a considerable proportion of patients with propranolol non-response • Patients with small EV were included and also benefited from hemodynamic response to carvedilol |
Sarin, Hepatol Int, 2013 [8] | RCT | 150 (100%) | Propranolol (40 mg/day followed by dose titration) | Yes (66%) | • NSBB therapy did neither prevent growth of EV or variceal bleeding and did not reduce mortality in patients with small EV |
Je, Clin Mol Hepatol, 2014 [76] | Retrospective study | 504/92 (18.3%) | Propanolol (20 mg/day followed by dose titration) | No | • NSBB plus EBL was more effective than NSBB alone in primary prophylaxis • However, EBL was performed only in patients with large EV |
Bhardwaj, Gut, 2016 [77] | RCT | 70 (100%) | Carvedilol (mean dose 12 ± 1.67 mg/day) | Yes (all) | • Reduction of progression to large EV |
Kim, Dig Dis Sci, 2016 [78] | Retrospective study | 898/775 (86.3%) | 48.6% of 898 patients were on NSBB therapy | No | • Variceal bleeding was a risk factor for mortality in patients with hepatocellular carcinoma |
Pfisterer, Aliment Pharmacol Ther, 2018 [1] | Retrospective study | Primary prophylaxis: 281/48 (17.1%) | Propranolol (median dose 40 mg/day) Carvedilol (median dose 12.5 mg/day) | No | • Addition of EBL to NSBB therapy did not further reduce the risk of first variceal bleeding or mortality • Patients receiving HVPG-guided primary prophylaxis (including patients with small EV) tended to have a better prognosis than patients receiving non-HVPG-guided NSBB therapy or combination therapy |