Anna Baiges

Role of calreticulin mutations in the aetiological diagnosis of splanchnic vein thrombosis

BACKGROUND & AIMS Myeloproliferative neoplasms are the most common aetiological cause of splanchnic vein thrombosis (SVT). In these patients, the JAK2V617F mutation has facilitated the diagnosis of an underlying myeloproliferative neoplasm (MPN). Recently, somatic mutations of the calreticulin (CALR) gene have been identified in MPN patients lacking the JAK2 mutation. The aim of the present study was to ascertain whether CALR mutations could also play a role in the diagnosis of masked MPN in SVT. METHODS We included 209 patients with SVT (140 with PVT and 69 with Budd-Chiari syndrome) who had a complete aetiological diagnostic work-out. They were investigated for CALR mutations. RESULTS CALR mutations were found in 4 of the 209 patients (1.9%). They represented 5.4% of patients with an underlying MPN of whom all had already been diagnosed with a MPN using conventional criteria including bone marrow biopsy findings. CONCLUSIONS In the screening of underlying MPNs in patients with SVT, given its high frequency in these disorders, the JAK2 mutation must be evaluated first and, if negative, CALR mutations should also be investigated. This approach would increase the diagnostic yield of masked MPNs by reducing the need for additional studies.

Severe acute kidney injury associated with non-steroidal anti-inflammatory drugs in cirrhosis: A case-control study

BACKGROUND & AIMS Non-steroidal anti-inflammatory drugs (NSAIDs) may cause impairment of kidney function in patients with cirrhosis. Investigational studies demonstrated reversibility of kidney dysfunction after drug withdrawal, but information based on clinical practice is lacking. The aim of the study was to investigate the characteristics and outcome of Acute Kidney Injury (AKI) developing in patients with cirrhosis treated with NSAIDs. METHODS Prospective cohort study in a tertiary referral center of all patients with NSAIDs-associated AKI seen from 2002 to 2014. For comparison, three control groups of patients with hypovolemic-induced AKI, type-1 HRS and ATN, respectively, were also evaluated. Urinary excretion of neutrophil gelatinase-associated lipocalin (uNGAL) was measured in a subset of patients. RESULTS Thirty patients with cirrhosis and NSAIDs-associated AKI were identified. In 19 patients (63%) AKI was transient and kidney function rapidly recovered (4±3 days) after NSAIDs withdrawal. In the remaining 11 patients (37%) AKI was more severe and persisted during hospitalization despite drug withdrawal. Patients with persistent AKI had remarkably higher uNGAL levels compared with those of patients with transient AKI (953±1,198 vs. 83±79 μg/g of creatinine, respectively, p=0.008). Moreover, seven of the 11 patients with persistent AKI (64%) died within three months compared with only one of the 19 (5%) patients with transient AKI (p=0.001). Mortality of persistent AKI was similar in NSAIDs patients compared to control groups. The only independent predictive factor of three-month mortality was persistent AKI. CONCLUSIONS Patients with cirrhosis treated with NSAIDs may develop severe AKI which may be irreversible and associated with poor short-term outcome.

Natural history and management of esophagogastric varices in chronic noncirrhotic, nontumoral portal vein thrombosis.

In patients with chronic noncirrhotic, nontumoral portal vein thrombosis (PVT), the usually recommended strategy for endoscopic screening and management of varices is the same as in cirrhosis. However, the efficacy of this policy in patients with PVT is unknown. We assessed the course of gastroesophageal varices in a large cohort of patients with chronic PVT. Patients prospectively registered in two referral centers for vascular liver disorders were eligible for the study. Endpoints were development and growth of varices and the incidence and outcome of portal hypertension‐related bleeding. Included were 178 patients with chronic PVT. Median follow‐up was 49 (1‐598) months. Variceal bleeding was the initial manifestation in 27 (15%) patients. Initial endoscopy in the remaining 151 patients showed no varices in 52 (34%), small esophageal varices in 28 (19%), large esophageal varices (LEVs) in 60 (40%), and gastric varices without LEVs in 11 (7%). Ascites and splenomegaly were independent predictors for the presence of varices. In patients without varices, the probability of developing them was 2%, 22%, and 22% at 1, 3, and 5 years, respectively. In those with small esophageal varices, growth to LEVs was observed in 13%, 40%, and 54% at 1, 3, and 5 years, respectively. In patients with LEVs on primary prophylaxis, probability of bleeding was 9%, 20%, and 32% at 1, 3, and 5 years, respectively. Nine (5%) patients died after a median 51 (8‐280) months, only one due to variceal bleeding. Conclusions: The course of varices in chronic noncirrhotic, nontumoral PVT appears to be similar to that in cirrhosis; using the same therapeutic approach as for cirrhosis is associated with a low risk of bleeding and death. (Hepatology 2016;63:1640‐1650)

The prognostic value of hepatic venous pressure gradient in patients with cirrhosis is highly dependent on the accuracy of the technique

Hepatic venous pressure gradient (HVPG), the difference between wedged (WHVP) and free hepatic vein pressure (FHVP), predicts survival in patients with cirrhosis. It has been suggested for the use of inferior vena cava (IVC) value instead of FHVP to calculate HVPG when the difference between proximal FHVP (obtained at 2 cm from the hepatic vein outlet) and IVC (measured at the level of the hepatic ostium) is >2 mm Hg. However, there are no data supporting this recommendation. The main aim of the study was to establish which gradient, WHVP‐FHVP (HVPG‐Free) or WHVP‐IVC (HVPG‐IVC), better correlates with orthotopic liver transplantation (OLT)‐free survival. This work was a retrospective evaluation of hepatic hemodynamic studies of 380 consecutive patients with cirrhosis performed from January 2006 to December 2012 with follow‐up until December 2013. Patients had a mean age of 56 ± 10 years and 64.7% were men. Mean Child‐Pugh was 7 ± 2. HVPG‐Free (16 ± 5 mm Hg) was significantly lower than HVPG‐IVC (17 ± 5.5 mm Hg; P < 0.001). During a mean follow‐up of 43 months, 40 patients were transplanted and 111 died. A total of 285 (75%) patients had an FHVP‐IVC difference within ±2 mm Hg (no discrepancy) and 95 (25%) patients <−2 mm Hg or >2 mm Hg (discrepancy). In patients without discrepancy, 16 mm Hg was the best cut‐off value predicting survival, independently of being calculated as HVPG‐Free or HVPG‐IVC. However, in those patients with discrepancy, 16 mm Hg was still the best cut‐off value for HVPG‐Free, but not for HVPG‐IVC, among which 25 patients (26%) were misclassified regarding their risk of OLT/death. Conclusions: Given that WHVP‐FHVP was more accurate in assessing prognosis than WHVP‐IVC, HVPG should be calculated as the gradient between WHVP and FHVP, but not with IVC, in order to optimize its prognostic value and in identifying different risk population. (Hepatology 2015;62:1584–1592)

Acute variceal bleeding: risk stratification and management (including TIPS)

Acute variceal bleeding should be suspected in all patients with cirrhosis presenting with upper gastrointestinal bleeding. Vasoactive drugs and prophylactic antibiotics must be started as soon as possible, even before performing the diagnostic endoscopy. Once the patient is hemodynamically stable, upper gastrointestinal endoscopy should be performed in order to confirm the diagnosis and provide endoscopic therapy (preferably banding ligation). After this initial approach, the most appropriate therapy to prevent both early and late rebleeding must be instituted following a risk stratification strategy. The present chapter will focus on the initial management of patients with acute variceal bleeding, including general management and hemostatic therapies, as well as the available treatments in case of failure to control bleeding or development of rebleeding.

Portal Hypertensive Bleeding

Abstract Variceal bleeding is one of the most severe complications of liver cirrhosis. When cirrhosis is diagnosed, varices are present in approximately 30% to 40% of compensated patients and in 60% of those who present with ascites. Once varices have been diagnosed, the overall incidence of variceal bleeding is 25% within two years. Variceal size is the most useful predictor for variceal bleeding; other predictors being the severity of liver dysfunction (Child-Pugh classification) and the presence of red wale marks on the variceal wall. When a patient presents with acute variceal bleeding, appropriate management with initial general measures such as resuscitation (airway, breathing, and circulation), a restrictive transfusion policy, antibiotic prophylaxis, pharmacological therapy with vasoconstrictors, and endoscopic therapy with endoscopic band ligation is mandatory. After bleeding has been controlled, combination therapy with nonselective β-blockers (NSBBs) and endoscopic band ligation should be used to prevent rebleeding. In patients at high risk of treatment failure identified early after admission, the placement of a preemptive TIPS (transjugular intrahepatic portosystemic shunt) improves control of bleeding, prevents rebleeding, reduces mortality, and should be the treatment of choice if no contraindications are present. When initial endoscopic therapy fails, rescue therapies such as Sengstaken-Blakemore tubes and fully covered self-expandable esophageal metal stents may be required as a bridge toward the definitive treatment with TIPS. Regarding gastric variceal bleeding, data is limited. In acute cardiofundal variceal bleeding, vasoactive agents, together with cyanoacrylate (CYA) injection, seem to be the treatment of choice. Further CA injections and/or NSBB may be used to prevent rebleeding. TIPS, or balloon-occluded retrograde transvenous obliteration when TIPS is contraindicated, may be used as a rescue therapy.

Hepatocyte microvesicle levels improve prediction of mortality in patients with cirrhosis

Microvesicles (MVs) are extracellular vesicles released by cells following activation or apoptosis. Some MV subpopulations augment with cirrhosis severity and contribute to portal hypertension. This study aimed at determining if plasma MV levels can estimate the presence of hepatic venous pressure gradient (HVPG) ≥10 mm Hg and predict mortality in patients with advanced chronic liver disease. All patients with severe fibrosis or cirrhosis undergoing liver catheterization between 2013 and 2015 at two centers were prospectively included. We measured circulating levels of annexin V+, platelet, leukocyte, endothelial, and hepatocyte MVs. The test cohort included 139 patients. Hepatocyte MV levels were 4.0‐fold and 2.2‐fold higher in patients with Child‐Pugh C than in those with Child‐Pugh A or B liver disease, respectively. Levels of other MV subpopulations were not influenced by liver disease severity. Hepatocyte MV levels correlated with HVPG but could not identify patients with HVPG ≥10 mm Hg. Hepatocyte MV level >65 U/L predicted 6‐month mortality independently of Child‐Pugh score and of Model for End‐Stage Liver Disease (MELD). Patients with hepatocyte MV levels >65 U/L and MELD >15 had a higher 6‐month mortality than other patients (23% versus 3%; P = 0.001). These findings were confirmed in a validation cohort including 103 patients. Conclusion: Circulating MV levels cannot identify patients with HVPG ≥10 mm Hg; by contrast, hepatocyte MV levels strongly improve prediction of 6‐month mortality in patients with advanced chronic liver disease; therapies associated with decreased levels of circulating hepatocyte MV might be attractive strategies in patients with severe cirrhosis. (Hepatology 2018).

Idiopathic Portal Hypertension

Idiopathic portal hypertension (IPH) is a rare disorder characterized by clinical portal hypertension in the absence of a recognizable cause such as cirrhosis. Laboratory tests often reveal a preserved liver function with anemia, leukopenia, and thrombocytopenia due to splenomegaly. Imaging studies reveal signs of portal hypertension, whereas liver stiffness and portal pressure values are usually normal or slightly elevated. Liver biopsy is considered mandatory in order to rule out other causes of portal hypertension, mainly cirrhosis. Liver histology may only show subtle or mild changes, and the definite diagnosis of IPH often requires an expert pathologist and a high‐quality specimen. The most frequent clinical presentation is variceal bleeding. Ascites is rarely observed initially, although it may occasionally appear during follow‐up. Typical histological findings associated with IPH have been described in patients without portal hypertension, probably representing early stages of the disease. Although the pathophysiology of this entity remains largely unknown, it is frequently associated with underlying immunological disorders, bacterial infections, trace metal poisoning, medications, liver circulatory disturbances, and thrombotic events. The long‐term prognosis of patients with IPH, where ascites and the underlying condition are important prognostic factors, is better than in patients with cirrhosis. Treatments that modify the natural history of the disease remain an unmet need, and management of IPH is frequently restricted to control of portal hypertension–related complications.