Setting Of Advanced Liver Disease Research Articles

Portal Vein Thrombosis in the Setting of Cirrhosis: A Comprehensive Review.

Portal vein thrombosis constitutes the most common thrombotic event in patients with cirrhosis, with increased rates in the setting of advanced liver disease. Despite being a well-known complication of cirrhosis, the contribution of portal vein thrombosis to hepatic decompensation and overall mortality is still a matter of debate. The incorporation of direct oral anticoagulants and new radiological techniques for portal vein recanalization have expanded our therapeutic arsenal. However, the lack of large prospective observational studies and randomized trials explain the heterogenous diagnostic and therapeutic recommendations of current guidelines. This article seeks to make a comprehensive review of the pathophysiology, clinical features, diagnosis, and treatment of portal vein thrombosis in patients with cirrhosis.

Serum keratin 19 (CYFRA21-1) links ductular reaction with portal hypertension and outcome of various advanced liver diseases

BackgroundKeratins (Ks) represent tissue-specific proteins. K18 is produced in hepatocytes while K19, the most widely used ductular reaction (DR) marker, is found in cholangiocytes and hepatic progenitor cells. K18-based serum fragments are commonly used liver disease predictors, while K19-based serum fragments detected through CYFRA21-1 are established tumor but not liver disease markers yet. Since DR reflects the severity of the underlying liver disease, we systematically evaluated the usefulness of CYFRA21-1 in different liver disease severities and etiologies.MethodsHepatic expression of ductular keratins (K7/K19/K23) was analyzed in 57 patients with chronic liver disease (cohort i). Serum CYFRA21-1 levels were measured in 333 Austrians with advanced chronic liver disease (ACLD) of various etiologies undergoing hepatic venous pressure gradient (HVPG) measurement (cohort ii), 231 French patients with alcoholic cirrhosis (cohort iii), and 280 hospitalized Germans with decompensated cirrhosis of various etiologies (cohort iv).Results(i) Hepatic K19 levels were comparable among F0–F3 fibrosis stages, but increased in cirrhosis. Hepatic K19 mRNA strongly correlated with the levels of other DR-specific keratins. (ii) In ACLD, increased serum CYFRA21-1 associated with the presence of clinically significant portal hypertension (CSPH; HVPG ≥ 10 mmHg) (OR = 5.87 [2.95–11.68]) and mortality (HR = 3.02 [1.78–5.13]; median follow-up 22 months). (iii) In alcoholic cirrhosis, elevated serum CYFRA21-1 indicated increased risk of death/liver transplantation (HR = 2.59 [1.64–4.09]) and of HCC (HR = 1.74 [1.02–2.96]) over the long term (median follow-up 73 months). (iv) In decompensated cirrhosis, higher serum CYFRA21-1 predicted 90-day mortality (HR = 2.97 [1.92–4.60]) with a moderate accuracy (AUROC 0.64), independently from established prognostic scores.ConclusionsHepatic K19 mRNA and serum CYFRA21-1 levels rise in cirrhosis. Increased CYFRA21-1 levels associate with the presence of CSPH and reliably indicate mortality in the short and long term independently of conventional liver biochemistry markers or scoring systems. Hence, the widely available serum CYFRA21-1 constitutes a novel, DR-related marker with prognostic implications in patients with different settings of advanced liver disease.

Potential Clinical Targets in Hepatopulmonary Syndrome: Lessons From Experimental Models.

Hepatopulmonary syndrome (HPS) is a relatively common and potentially severe pulmonary complication of cirrhosis with increased risk of mortality. In experimental models, a complex interaction between pulmonary endothelial cells, monocytes, and the respiratory epithelium, which produces chemokines, cytokines, and angiogenic growth factors, causes alterations in the alveolar microvasculature, resulting in impaired oxygenation. Model systems are critical for evaluating mechanisms and for preclinical testing in HPS, due to the challenges of evaluating the lung in the setting of advanced liver disease in humans. This review provides an overview of current knowledge and recent findings in the rodent common bile duct ligation model of HPS, which recapitulates many features of human disease. We focus on the concepts of endothelial derangement, monocyte infiltration, angiogenesis, and alveolar type II cell dysfunction as main contributors and potential targets for therapy.

Intrahepatic Sampling for the Elucidation of Antiviral Clinical Pharmacology.

Although the importance of the liver in clinical pharmacology is widely recognized, little is known in humans concerning its function in vivo at the hepatocyte level and how pharmacological functions are altered in the setting of advanced liver disease. Several recent proof-of-principle studies with first-generation DAAs have demonstrated the feasibility of serial liver sampling for pharmacological studies. These studies have begun to describe the liver-to-plasma concentration ratio and how this ratio is altered in the setting of advanced liver disease. These data are particularly relevant to individuals with substance-use disorders because many have advanced liver disease as a consequence of long-standing viral hepatitis infection or continued use of hepatotoxins such as alcohol. Future research should attempt to develop standardized and reproducible methods to assess liver drug concentration, complex drug interactions, and pharmacogenomics in humans to permit elucidation of the clinical pharmacology within the liver.

Management of thrombocytopenia in advanced liver disease.

Thrombocytopenia (defined as a platelet count <150×10(9)) is a well-known complication in patients with liver cirrhosis and has been observed in 76% to 85% of patients. Significant thrombocytopenia (platelet count <50×10(9) to 75×10(9)) occurs in approximately 13% of patients with cirrhosis. Thrombocytopenia can negatively impact the care of patients with severe liver disease by potentially interfering with diagnostic and therapeutic procedures. Multiple factors can contribute to the development of thrombocytopenia including splenic platelet sequestration, immunological processes, bone marrow suppression by chronic viral infection, and reduced levels or activity of the hematopoietic growth factor thrombopoietin. The present review focuses on the etiologies and management options for severe thrombocytopenia in the setting of advanced liver disease.

Decision Making in Liver Transplant Selection Committees

To receive a liver transplant, patients must first be placed on a waiting list-a decision made at most transplant centers by a multidisciplinary committee. The function of these committees has never been studied. To describe decision making in liver transplant committees and identify opportunities for process improvement. Observational multicenter study. 4 liver transplant centers in the United States. 68 members of liver transplant committees across the 4 centers. 63 meetings were observed, and 50 committee members were interviewed. Recorded transcripts and field notes were analyzed by using standard qualitative sociologic methods. Although the structure of the meetings varied by center, the process was uniform and primarily involved inductive reasoning to review possible reasons for patient exclusion. Patients were excluded if they were too well, too sick (in the setting of advanced liver disease), or too old or had nonhepatic comorbid conditions, substance abuse problems, or other psychosocial barriers. Dominant themes in the discussions included member angst over deciding who lived or died, a high correlation between psychosocial barriers to transplantation and the patient's socioeconomic status, and the influence of external forces on decision making. Unwritten center policies and confusion regarding advocacy versus stewardship roles were consistently identified as barriers to effective group decision making. The use of qualitative methods provides broad understanding but limits specific inferences. The 4 centers may not reflect the practices of every transplant center nationwide. The difficult decisions made by liver transplant committees are reasonably consistent and well-intentioned, but the process might be improved by having more explicit written policies and clarifying roles. This may inform resource allocation in other areas of medicine. The Greenwall Foundation and the National Institutes of Health.

Hepatopulmonary Syndrome: Monitoring at Your Fingertip

Hepatopulmonary syndrome (HPS) is the triad of arterial hypoxemia due to pulmonary vascular dilatation induced by liver disease [1]. Diagnosis of HPS relies on measurement of arterial blood gas (ABG) to determine the severity of hypoxemia, whereas vascular dilatation is demonstrated by positive contrast-enhanced transthoracic echocardiography (CE). An invasive test, ABG is usually obtained via a radial artery stick. Approximately 5 cc arterial blood is drawn into a sealed, heparinized syringe and inserted into a blood-gas analyzer within 30 min of collection. Oxygenation is quantified by two measures. PaO2 in mmHg (partial pressure of oxygen dissolved in the plasma; normal considered by most authorities[80 mmHg at sea level) or the calculated alveolar–arterial oxygen gradient (A–a O2 grad) in mmHg (difference between alveolar oxygen and PaO2; normal is age-dependent and\15–20 mmHg). A-a O2 grad is the more sensitive measure that takes into account the degree of ventilation within the lung [1], but it is not calculated in all pulmonary function laboratories. Importantly, oxygenation in patients with HPS can differ significantly (up to 20 mm Hg) as body position changes (orthodeoxia) with PaO2 supine [ sitting [ standing and is worse with exercise [1]. Fortunately, an easier measure of arterial oxygenation has evolved—pulse oximetry [2]. Simply, pulse oximetry allows noninvasive measurement of arterial hemoglobin saturation by oxygen, without the risks associated with arterial puncture [2]. Via a sensor placed on the finger tip (earlobe or forehead as needed), pulse oximetry determines the percentage of oxygen that saturates circulating hemoglobin (SaO2) [2]. This measurement is based upon light absorption within arterial blood at specific wavelengths; red (640 nm) and infrared (940 nm) [3]. Unfortunately, this method cannot distinguish between oxygen and carbon monoxide attached to hemoglobin [2]. The measurement can be one-time or continuous over time. The latter is particularly important during sleep in the setting of advanced liver disease, because SaO2 can frequently drop below 90% [4]. Is there a close relationship between PaO2 and SaO2? Indeed there is via the oxyhemoglobin dissociation curve [2]. Although beyond the scope of this editorial, recall this relationship is sigmoid, not linear. Therefore, under normal conditions, big change in PaO2 (100 ? 50 mmHg) can occur in association with a relatively small change in SaO2 (98 ? 89%). By any measure (PaO2 or A-a O2 grad) hypoxemia has common causes (40–50%) in advanced liver disease; COPD, hepatic hydrothorax, interstitial lung disorders, massive ascites, or obesity, to name a few. Hypoxemia due to HPS is of particular interest because oxygenation can worsen after the diagnosis is made, but it is unclear how rapidly and why change occurs without obvious deterioration in hepatic function. Such change is not trivial, because current organ procurement/liver allocation policy states that once PaO2 is less than 60 mmHg (sitting position, breathing room air) MELD (model for end-stage live disease) exception may be granted to enhance priority for pediatric and adult liver transplantation [5]. How can change in oxygenation be sequentially monitored in HPS patients? Kochar and colleagues in this issue [6] describe pulse oximetry to assess change in oxygenation over time in HPS. They reported periodic, one-time SaO2 measurements obtained in the sitting position, breathing room air. Retrospectively, worsening oxygenation was documented M. J. Krowka (&) Division of Pulmonary and Critical Care Medicine, Mayo Clinic, Rochester, MN 55905, USA e-mail: Krowka@mayo.edu

How should we treat portopulmonary hypertension?

The development of pulmonary arterial hypertension in the setting of advanced liver disease (portopulmonary hypertension (POPH)) has certainly captured the attention of all liver transplant centres, but why? For patients with moderate-to-severe POPH (mean pulmonary artery pressure (mPAP) >35 mmHg and pulmonary vascular resistance (PVR) >400 dyne·s·cm-5), the risk of intra-operative death and post-transplant hospitalisation mortality in otherwise acceptable liver transplant candidates is high 1. The American Association for the Study of Liver Disease Practice Guidelines have espoused Doppler echocardiography screening for all liver transplant candidates 2. However, once POPH is confirmed by right-heart catheterisation, what therapeutic approach should be considered? More generally, what should the approach be to treating POPH, irrespective of liver transplant candidacy? POPH is not simply a liver transplant issue, but that area of clinical medicine has raised awareness of this entity over the past few years. Recent evidence from France underscores the importance of POPH: it was the third-most common type of pulmonary hypertension seen in a consortium of 17 French hospitals 3. The French evidence mirrors that of the Mayo Clinic (Rochester, MN, USA) over the past 10 yrs. POPH is the third-most common disorder documented in the Mayo Pulmonary Hypertension Clinic since 1996. In the current issue of the European Respiratory …

Hepatocellular carcinoma in the setting of liver transplantation

Hepatocellular carcinoma (HCC) is a frequent complication and leading cause of mortality among patients with cirrhosis. In the setting of advanced liver disease, many patients with HCC are not candidates for hepatic resection due to inadequate functional hepatic reserve and the risk of postoperative decompensation. In these patients, liver transplantation (LT) offers curative therapy, as well as amelioration of their underlying chronic liver disease. Among appropriately selected candidates, LT for HCC provides excellent technical results with 5-yr overall survival rates exceeding 70%, similar to patients undergoing LT for other indications. 1-4 The size and number of tumors plays an important role in determining an individual patient’s candidacy for LT. However, patients on the LT waiting list are at risk for tumor progression leading to ineligibility for LT and death. Given the significant impact of HCC on patients with cirrhosis, healthcare providers caring for this patient population need to be familiar with the diagnostic criteria, pretransplantation management, transplantation criteria, and organ allocation policies associated with LT for HCC.

Infections bactériennes et cirrhose alcoolique

Bacterial infections are frequent and severe complications of alcoholic cirrhosis. Their in-hospital incidence rate fluctuates between 30 and 50%. Spontaneous bacterial peritonitis (SBP) with or without bacteremia, urinary tract infections and pneumonia are the most frequent. SBP and bacterial pneumonia prognosis are the most severe (30 to 40% of death). These bacterial infections are almost always seen in the setting of advanced liver disease. Organisms normally found in the gastrointestinal tract are the predominant causative agents of SBP. The pathogenesis of these infections involves bacterial translocation and ascitis is colonised from an episode of bacteremia. Severe cellular insufficiency and low ascitis protid are predictive factors of SBP. Gastrointestinal bleeding is another predisposing factor and furthermore, infection predisposes to portal hypertension-related bleeding recurrence. Treatment of active infection is an emergency and is based on non nephrotoxic antibiotics such as IV cefotaxime or oral fluoroquinolones in patients with no encephalopathy or renal insufficiency. Antibiotic prophylaxis is justified in patients recovering from a first spontaneous bacterial peritonitis episode or admitted for variceal bleeding. Bacteremia is due to the same bacteria as spontaneous bacterial peritonitis and their treatment is based on the same antibiotics. Urinary tract infections are mainly due to E Coli and are responsible for 5 to 15% of SBP and bacteremia cases. The causative germs of pneumonia and meningitis are pneumococcus but also gram-negative organisms. When the SBP outcome is unusual the diagnosis of tuberculosi must be ruled out. Finally, early diagnosis and treatment have improved severe bacterial infections prognosis in alcoholic cirrhotic patients but survivors of SBP should be considered for liver transplantation.