Preprocedural prophylaxis with blood products in patients with cirrhosis: Results from a survey of the Italian Association for the Study of the Liver (AISF).

INTRODUCTION: The concept of rebalanced hemostasis in cirrhosis challenges the policy of transfusing plasma or platelets before invasive procedures in patients with prolonged PT or severe thrombocytopenia. Recent guidelines recommend against plasma transfusion and suggest avoiding/minimizing platelet transfusions. AIM: We assessed how hepato-gastroenterologists manage prolonged PT/INR or severe thrombocytopenia before invasive procedures. METHODS: On May 2021, AISF members were sent a questionnaire addressing the PT/INR and platelet thresholds required before invasive procedures, the use of other markers of bleeding risk or other hemostatic treatments and the burden of pre-emptive plasma and platelet transfusions. RESULTS: Of 62 respondents, 94% and 100% use PT/INR and platelet count to assess bleeding risk, respectively. Only 37% and 32% require less conservative PT/INR or platelet counts thresholds for low-risk procedures, respectively. As for those applying single thresholds, 68% require PT/INR <1,5 and 86% require platelet counts ≥50 × 109/L. Half respondents use additional indicators of bleeding risk and 63% other hemostatic treatments. Low-risk procedures account for 70% of procedures, and for 50% and 59% of plasma and platelets units transfused, respectively. CONCLUSIONS: the survey indicates lack of compliance with guidelines that advise against plasma and platelet transfusions before invasive procedures and the need for prospective studies and inter-society consensus workshops.

Feasibility and reproducibility of spleen transient elastography and its role in combination with liver transient elastography for predicting the severity of chronic viral hepatitis.

Liver transient elastography (L-TE) is a reliable, noninvasive predictor of disease severity in chronic liver disease of viral aetiology (CLD). Owing to the relationships among severity of CLD, portal hypertension and spleen involvement, the assessment of splenic stiffness (S-TE) may have an added value in staging CLD. Of 132 CLD patients of viral aetiology, 48 with myeloproliferative disorders (MD) and 64 healthy volunteers (HV), were concurrently investigated by both L-TE and S-TE. Liver disease severity was staged by liver biopsy (LB; Metavir) taken concurrently with TE examination and upper gastrointestinal tract endoscopy for gastro-oesophageal varices. The S-TE inter-observer agreement was analysed by an intra-class correlation coefficient (ICC); L-TE and S-TE accuracy was evaluated by receiver operating characteristic (ROC) curve analysis. Logistic regression analysis assessed the independent effect of L-TE and S-TE as predictors of hepatic fibrosis stage. S-TE failed in 22 CLD (16.6%), 12 (25%) MD and 12 (18%) HV. In the three groups, the ICC was 0.89 (0.84-0.92), 0.90 (0.85-0.94) and 0.86(0.80-0.91), respectively. In the CLD group, L-TE and S-TE independently predicted significant fibrosis (OR 5.2 and 4.6) and cirrhosis (OR 7.8 and 9.1), but at variance from L-TE, S-TE was independent from liver necroinflammation and steatosis. The NPV of S-TE for gastro-oesophageal varices was 100% using a 48 kPa cut-off. In CLD, spleen stiffness alone or in combination with hepatic stiffness can be reliably and reproducibly assessed by TE with the added value of improving the noninvasive diagnosis of severe liver disease and excluding the presence of oesophageal varices.

Hypercoagulability in cirrhosis: causes and consequences.

Decreased levels of most coagulation factors and thrombocytopenia are the main haemostatic abnormalities of cirrhosis. As a consequence, this condition was, until recently, considered as the prototype acquired coagulopathy responsible for bleeding. However, recent evidence suggests that it should, rather, be regarded as a condition associated with normal or even increased thrombin generation. The bleeding events that occur in these patients should, therefore, be explained by the superimposed conditions that frequently occur in this setting. Due to elevated levels of factor VIII (procoagulant driver) in combination with decreased protein C (anticoagulant driver), which are typically found in patients with cirrhosis, a procoagulant imbalance, defined as a partial resistance to the in vitro anticoagulant action of thrombomodulin, can be demonstrated. Whether this in vitro hypercoagulability is truly representative of what occurs in vivo remains to be established. However, the hypothesis that it may have clinical consequences is attractive and deserves attention. The possible consequences that we discuss herein include whether (i) cirrhosis is a condition associated with increased risk of venous thromboembolism or portal vein thrombosis; (ii) the hypercoagulability associated with cirrhosis has any other role outside coagulation (i.e. progression of liver fibrosis); and (iii) anticoagulation should be used in cirrhosis. Although apparently provocative, considering anticoagulation as a therapeutic option in patients with cirrhosis is now supported by a rationale of increasing strength. There may be subgroups of patients who benefit from anticoagulation to treat or prevent thrombosis and to slow hepatic fibrosis. Clinical studies are warranted to explore these therapeutic options.

Primary prophylaxis of variceal bleeding in cirrhotic patients: a cohort study.

BACKGROUND: Current guidelines recommend beta-blockers for primary prevention of variceal haemorrhage in cirrhotic patients, and band ligation for patients with contraindications or intolerance to beta-blockers. However, it has been suggested that these patients may respond poorly to band ligation. AIM: We evaluated the usefulness of a strategy in which band ligation was used to treat patients with contraindications or intolerance and patients not responding to beta-blockers identified by hepatic vein pressure gradient measurement. Haemodynamic responders and patients refusing hepatic vein pressure gradient measurement were given long-term beta-blockers. METHODS: One hundred and thirty-five consecutive patients with high-risk oesophageal varices and no prior bleeding were enrolled. Twenty-five patients with contraindications (group A), 26 with intolerance to beta-blockers (group B) and 25 showing a poor haemodynamic response (Group C) underwent band ligation. Twenty-two haemodynamic responders (Group D) and 37 refusing hepatic vein pressure gradient measurement (Group E) were treated with beta-blockers. RESULTS: Median follow-up was 32 months. 12/135 patients (8.9%) bled: 3/25 (12%) in group A, 1/26 (3.8%) in group B, 0/25 (0%) in group C, 0/22 (0%) in group D and 8/37 (22.2%) in group E. Mortality was 8/135 (5.9%). CONCLUSIONS: Patients with contraindications, intolerance or not responding to beta-blockers treated with band ligation achieve protection from variceal bleeding comparable to that of good responders to beta-blockers.

High-D-dimer plasma levels predict poor outcome in esophageal variceal bleeding.

BACKGROUND AND AIM: Variceal bleeding carries a high-mortality rate in patients with liver cirrhosis. Since coagulation and fibrinolysis are abnormal in these patients we evaluated whether or not abnormalities of these haemostasis systems were independently related to mortality. METHODS: Global coagulation, coagulation activation and fibrinolysis measurements were performed in 43 cirrhotics bleeding from esophageal varices at baseline and during follow-up and in 43 non-bleeding cirrhotic patients at baseline only. RESULTS: Baseline measurements of coagulation activation and fibrinolysis were more impaired in bleeders. In bleeders, prothrombin time, tissue type plasminogen activator antigen and D-dimer plasma levels were persistently more abnormal in patients who died. High-D-dimer, infection, Child-Pugh C class and MELD score >or=17 were the significant predictors of death at univariate analysis. Two different multivariate analyses to assess the independent prognostic value of these variables, one including the Child-Pugh class, the other including MELD, were performed. Independent predictors of death were high-D-dimer and infection, but not Child-Pugh class, in the former; MELD and infection, but not D-dimer, in the latter. CONCLUSIONS: Beside infection, high-D-dimer is a stronger predictor of death as compared to Child-Pugh C class, but not to a MELD score >or=17.

Diagnosis and monitoring of portal hypertension.

Currently, oesophago-gastroduodenoscopy is the standard method to diagnose the presence of oesophago-gastric varices and to estimate the risk of bleeding. It is recommended that all patients undergo endoscopic screening for varices at the time when cirrhosis is diagnosed. After screening endoscopy, patients with medium or large varices should be treated to prevent bleeding, while all other patients should undergo periodic surveillance endoscopy. However, at a given point in time a variable proportion of patients will not have varices, since the prevalence of varices is variable. Thus, screening all cirrhotic patients with endoscopy to detect the presence of varices implies a number of unnecessary endoscopies. In recent years a wealth of new methods have been proposed as alternatives to conventional oesophago-gastroduodenoscopy for the non-invasive or minimally invasive diagnosis of oesophageal varices. Three of these methods (the platelet count/spleen diameter ratio, Fibrotest and Fibroscan) are truly non-invasive. Of these, the former is promising and needs a proper validation, Fibrotest appears to be insufficiently precise, while Fibroscan needs further evaluation. Multidetector CT oesophagography and capsule endoscopy are not entirely "non-invasive", since the first requires air insufflation into the oesophagus via an orally passed tube, and the latter requires swallowing the capsule. Multidetector CT oesophagography is promising, but needs further evaluation; capsule endoscopy is safe and reliable and might be proposed as an alternative to oesophago-gastroduodenoscopy in patients unable or unwilling to undergo oesophago-gastroduodenoscopy.

Increased expression of vascular endothelial growth factor in small hepatocellular carcinoma.

Vascular endothelial growth factor (VEGF) is involved in both development and progression of several epithelial tumours, but its role in hepatocellular carcinoma (HCC) is unclear. Assessment of liver and blood levels of VEGF may provide further insights on angiogenesis in HCC. Tissue mRNA of VEGF-165, VEGF-189 and their receptor KDR was assessed by a semi-quantitative retro-transcriptase polymerase chain reaction, and expressed as target transcript/beta-actin ratio, in 29 patients with HCC, 26 with cirrhosis and 15 with chronic hepatitis. VEGF-165 was also measured by ELISA in plasma samples obtained from both hepatic and femoral veins in additional 58 patients, including 15 with HCC. The liver expression of mRNA of VEGF-165, VEGF-189 and KDR was higher in HCC than in chronic liver diseases (1.54 +/- 0.89 vs 0.62 +/- 0.47, P < 0.0001; 1.09 +/- 0.65 vs 0.64 +/- 0.54, P = 0.003; 1.30 +/- 1.09 vs 0.69 +/- 0.72, P = 0.014). VEGF-165 was higher in HCC tissue than in extra-tumoural tissues (1.44 +/- 0.31 vs 1.03 +/- 0.21, P = 0.0009) and in the cirrhotic tissue of HCC patients than in HCC-free cirrhosis (1.03 +/- 0.23 vs 0.45 +/- 0.45, P = 0.0002). Tissue VEGF-189 mRNA inversely correlated with tumour size and degree of tumour cell proliferation. The hepatic and femoral vein levels of VEGF-165 protein were significantly higher in HCC patients than in cirrhotic patients (66.7 +/- 57.1 vs 24.2 +/- 16.4 pg/mL, P = 0.0001 and 37.1 +/- 42.2 vs 13.5 +/- 9.6 pg/mL, P = 0.001). There was a gradient of VEGF-165 between hepatic and femoral veins in both HCC and cirrhosis. In conclusion, VEGF appears to be involved in the development of HCC and it could be a predictor of HCC development in patients with cirrhosis.

Medical treatment of portal hypertension.

Prevention of the first variceal haemorrhage should start when the patients have developed medium sized to large varices. Non-selective beta-blockers are the first-line treatment; band ligation is roughly equivalent to beta-blockers and is the first choice for patients with contraindications or intolerance to beta-blockers. Treatment of acute bleeding should aim at controlling bleeding and preventing early rebleeding and complications, especially infections. Combined endoscopic and pharmacological treatment with vasoactive drugs can control bleeding in up to 90% of patients. All patients who survive a variceal bleed should be treated with beta-blockers or band ligation to prevent rebleeding. All patients in whom bleeding cannot be controlled or who continue to rebleed can be treated with salvage TIPS or, in selected cases, with surgical shunts. Liver transplantation should be considered for patients with severe liver insufficiency in which first-line treatments fail.

Unsuspected ileal stenosis causing obscure GI bleeding in patients with previous abdominal surgery--diagnosis by capsule endoscopy: a report of two cases.

Peri-anastomotic ulcerations may occur in patients with previous abdominal surgery. They may present only with obscure GI bleeding. We report two cases in whom capsule endoscopy identified postsurgical stenoses with ulcers as the cause of obscure GI bleeding. Case 1. A 57-year-old male operated on in 1970 for a post-traumatic diaphragm hernia followed by displacement of the caecum in the upper left abdominal quadrant. Case 2. A 32-year-old female with a salpingectomy for tuberculosis (1978) followed by segmental ileal resection for intestinal obstruction. Both patients had undergone extensive work-up including bidirectional endoscopies and enteroclysis with negative results. Capsule endoscopy with the GIVEN diagnostic system was done. Ileal stenoses with mucosal ulcers in dilated prestenotic loops were observed in both cases. The capsule was retained at the stenosis site, requiring ileal resection and anastomosis. Pathology reports showed mucosal ulcers. In case 2, tuberculosis was ruled out by tissue and faecal polymerase chain reaction and culture. Ileal stenoses with prestenotic ulcerations causing GI bleeding may occur in patients with previous abdominal surgery. Capsule endoscopy may clarify the diagnosis and shorten the diagnostic work-up. However, these patients should be warned that capsule retention requiring surgery might occur.

Natural history of portal hypertension in patients with cirrhosis.

All patients with cirrhosis will eventually develop portal hypertension and esophagogastric varices. Bleeding from ruptured esophagogastric varices is the most severe complication of cirrhosis and is the cause of death in about one third of patients. The rate of development and growth of esophageal varices is poorly defined but in general seem to be related to the degree of liver dysfunction. Once varices have formed, they tend to increase in size and eventually to bleed. In unselected patients, the incidence of variceal bleeding is about 20% to 30% at 2 years. Variceal size is the single most important predictor of a first variceal bleeding episode. Several prognostic indexes based on endoscopic and clinical parameters have been developed to predict the risk of bleeding; however, their degree of accuracy is unsatisfactory. Death caused by uncontrolled bleeding occurs in about 6% to 8% of patients; the 6-week mortality rate after a variceal hemorrhage is 25% to 30%. There are no good prognostic indicators of death caused by uncontrolled bleeding or death within 6 weeks. Untreated patients surviving a variceal hemorrhage have a 1- to 2-year risk of rebleeding of about 60% and a risk of death of about 40% to 50%. The risk of bleeding is greatest in the first days after a bleeding episode and slowly declines thereafter. All patients surviving a variceal hemorrhage must be treated to prevent rebleeding. Varices can also be found in the stomach of cirrhotic patients, alone or in association with esophageal varices. Gastric varices bleed less frequently but more severely than esophageal varices. Portal hypertensive gastropathy is a common feature of cirrhosis, and its prevalence parallels the severity of portal hypertension and liver dysfunction. Portal hypertensive gastropathy can progress from mild to severe and vice-versa or even disappear completely. Acute bleeding from portal hypertensive gastropathy seems to be relatively uncommon, and less severe than bleeding from varices.

[Portal hypertensive gastropathy in patients with cirrhosis of the liver]. / Gastropatia da ipertensione portale nei pazienti con cirrosi epatica.

Portal hypertensive gastropathy (PHG) is characterized by changes in the endoscopic appearance of the gastric mucosa, specific for portal hypertension. The identification of the elementary lesions of PHG allowed the development of a reproducible classification, defining mild and severe pictures, and the execution of a natural history study. This study showed a 80% overall prevalence of PHG in patient with cirrhosis of the liver and a correlation between duration of the disease and development of PHG. PHG has often been shown to be a fluctuating condition, thus suggesting that its pathophysiology is not only related to portal hypertension, but also to other, yet unknown, factors. Bleeding from PHG did not occur in patients with a recent diagnosis of liver cirrhosis. Acute and chronic bleeding occurred in 2.5% and 12% of patients, respectively. The death rate from acute PHG bleeding was lower (12.5%) than the death rate of variceal bleeding (39.1%). Vasoactive drugs can be used in the treatment of acute PHG bleeding. For chronic bleeding, non selective 13-blockers and, if needed, iron, are the treatment of choice. TIPS or surgical portosystemic shunt may be considered for acute or chronic PHG bleeding, if medical treatment fails. Clinical controlled trials are needed to evaluate the efficacy of these or other treatments.

Incidence of post-endoscopic retrograde-cholangiopancreatography/sphincterotomy pancreatitis depends upon definition criteria.

BACKGROUND: The reported incidence of post-endoscopic retrograde-cholangiopancreatography/sphincterotomy pancreatitis ranges between 1.3% and 12.8%. This may likely reflect different definitions of pancreatitis and methods of data collection, rather than differences in patient populations, indications and endoscopic expertise. AIMS: The present study evaluated the incidence of post-endoscopic retrograde-cholangiopancreatography/sphincterotomy pancreatitis using different definition criteria and different data collection methods. PATIENTS: The 24-hour clinical and enzymatic course of 1185 procedures was recorded. METHODS: Pancreatic-like pain and hyperamylasaemia were evaluated either 6 to 8 hours or 24 hours after the procedure; computed tomography scan was performed in those patients with 24-hour pancreatic pain associated with hyperamylasaemia more than three times the upper normal limit. Results. Computed tomography scan findings consistent with pancreatitis were observed in 1.9% of cases, only among those patients with 24-hour pancreatic-like pain and hyperamylasaemia over five times the upper normal limit. The 6-8-hour and 24-hour pancreatic-like pain was associated with serum amylase levels at least three times higher in 11.7% and 6.6% and five times higher or more in 7.4% and 5.1%, respectively; 6-8 and 24-hour hyperamylasaemia higher than five times the upper normal limit, irrespective of pancreatic-like pain, was reported in 8.3% and in 6.9% of cases. No patients with serum amylase values lower than three times the upper normal limit had clinical symptoms. CONCLUSIONS: The incidence of post-procedure pancreatitis ranged from 1.9% to 11.7% depending on the definition criteria adopted.

Natural history of portal hypertensive gastropathy in patients with liver cirrhosis. The New Italian Endoscopic Club for the study and treatment of esophageal varices (NIEC).

BACKGROUND & AIMS: The clinical importance of portal hypertensive gastropathy (PHG) as a source of gastrointestinal bleeding in patients with cirrhosis is poorly defined. We investigated the natural history of this condition in a large series of patients. METHODS: All patients with cirrhosis seen at 7 hospitals during June and July 1992 were followed up with clinical and endoscopic examinations every 6 months for up to 3 years. Gastropathy was classified according to the classification of the New Italian Endoscopic Club. RESULTS: The prevalence of gastropathy was 80% and was correlated with the duration of disease, presence and size of esophagogastric varices, and a previous history of endoscopic variceal sclerotherapy. During 18+/-8 months of follow-up, gastropathy was stable in 29% of patients, deteriorated in 23%, improved in 23%, and fluctuated with time in 25%. The evolution of gastropathy with time was identical in patients with and without previous or current sclerotherapy. Acute bleeding from gastropathy occurred in 8 of 315 patients (2.5%). The bleeding-related mortality rate was 12.5%. Chronic bleeding occurred in 34 patients (10.8%). CONCLUSIONS: PHG is common in patients with cirrhosis, and its prevalence parallels the severity of portal hypertension. Gastropathy can progress from mild to severe and vice versa or even disappear completely. Bleeding from this lesion is relatively uncommon and rarely severe. Sclerotherapy of esophageal varices does not seem to influence the natural history of this condition.