The current decade has been called “the decade of biomarkers,” and physicians are increasingly searching for and reliant on these markers in the hopes of simplifying the medical decision-making process. The B-type or brain natriuretic peptide (BNP) is a natriuretic hormone which was initially identified in the brain but is primarily released from the cardiac ventricles in response to increased ventricular filling pressures. The cleavage of its pro-hormone, pro-BNP, results in the production of the biologically inert 76-amino acid peptide N-terminal-pro-BNP (NT-pro-BNP) and the biologically active 32-amino acid peptide BNP, both of which can be measured in clinical assays. Both BNP and the closely related atrial natriuretic peptide (ANP) are significantly increased in heart failure and left-ventricular systolic dysfunction, and as a result BNP is a routinely used biomarker for the diagnosis of decompensated heart failure.
In this issue of Hepatology, Farias et al. describe their experience with the measurement of plasma BNP in the initial workup of patients with new onset ascites. It is well known that ascites in heart failure can mimic ascites in the setting of cirrhosis, and the distinction between the two entities can be challenging. Some patients can have ascites in the setting of both heart failure and cirrhosis; this is becoming more common as obese patients develop cirrhosis due to nonalcoholic fatty liver disease and heart failure due to complications of metabolic syndrome. The usefulness of plasma NT-pro-BNP has been studied in the past and found to be a powerful marker in distinguishing ascites due to cirrhosis from ascites due to heart failure. However, further studies have generally been lacking.
In the present study, plasma BNP was found to be superior to the serum-ascites albumin gradient (SAAG) and the total ascitic fluid protein concentration with regard to discriminating ascites due to heart failure from ascites due to cirrhosis. A plasma BNP cutoff of >364 pg/mL was found to have 98% sensitivity, 99% specificity, 99% diagnostic accuracy, and a positive likelihood ratio of 168.1 for the diagnosis of ascites due to heart failure. Conversely, a plasma BNP cutoff of ≤182 pg/mL had a negative likelihood ratio of 0.0 for ruling out ascites due to heart failure. Their study findings were validated in a 60-patient cohort. The study concludes with a proposal that plasma BNP should be among the initial workup in patients with new onset ascites. Of note, ascites due to both heart failure and cirrhosis are associated with a high SAAG; therefore, the SAAG does not discriminate between these two causes of ascites formation.
The use of plasma BNP measurements is well established in the cardiology literature in the evaluation of acute dyspnea for the diagnosis of decompensated heart failure.[4, 5] Elevated plasma BNP levels have been independently associated with increased risk of death and cardiovascular events. Additional studies have demonstrated that NT-pro-BNP is a marker of long-term mortality in patients with stable coronary disease. However, plasma BNP measurements contain several important limitations. Plasma BNP has been demonstrated to have significant intraindividual biologic variation, and heart failure therapy guided by BNP levels have not been demonstrated to result in improvement in clinical outcomes or quality of life when compared to traditional symptom-guided treatment. Age, gender, hemodynamic, and humoral parameters can also affect circulating plasma BNP levels in a variety of physiologic and pathologic conditions. Besides heart failure, BNP levels can be elevated in patients with acute coronary syndrome, hypertension with left ventricular hypertrophy, supraventricular tachyarrhythmias, pulmonary embolism, hyperthyroidism, Cushing's syndrome, primary hyperaldosteronism, and septic shock. Some patients may present with more than one etiology of elevated BNP levels.
Both plasma BNP and NT-pro-BNP are also elevated in patients with renal failure, irrespective of whether or not patients have clinically diagnosed heart failure. Plasma BNP is cleared through multiple mechanisms, including receptor-mediated binding and removal, neutral endopeptidase, and passive renal excretion. The measurement of plasma BNP therefore becomes inaccurate with renal insufficiency, with the exception of low plasma BNP, which would help exclude systolic heart failure. Plasma BNP levels also tend to be lower in obese patients. Although obesity has become a worldwide problem, its incidence still varies from country to country, and such differences in demographics and disease prevalence can affect the applicability of this Brazilian study to other populations around the world.
In previous studies of natriuretic hormones in patients with cirrhosis, pro-BNP and BNP were found to be significantly increased in patients with cirrhosis compared with age-matched controls and healthy subjects; however, the elevated circulating levels of BNP were thought to more likely reflect increased cardiac dysfunction rather than the hyperdynamic circulatory changes found in patients with cirrhosis. Serum BNP levels may also be elevated in patients with cirrhotic cardiomyopathy, rendering it difficult for a simple plasma BNP measurement to accurately distinguish between ascites due to heart failure and ascites due to cirrhosis. In fact, elevated plasma BNP only rules in heart failure with high probability, but does not rule out the possibility that cirrhosis may also be present.
The present study concludes with a suggestion that the use of plasma BNP as the initial test can forego the need for diagnostic paracentesis. Current guidelines from the European Association for the Study of the Liver (EASL) and from the American Association for the Study of Liver Diseases (AASLD) strongly emphasize the role of diagnostic paracentesis in the diagnosis of new onset ascites (AASLD Class I, Level C recommendation; EASL Level A1 recommendation). EASL guidelines additionally suggest that diagnostic paracentesis should be performed in all patients hospitalized for worsening of ascites or any complication of cirrhosis. The paracentesis is an important tool in the diagnosis of spontaneous bacterial peritonitis, as this life-threatening entity can occur even in the setting of cardiac ascites, and also in the diagnosis of secondary bacterial peritonitis. Even in the setting of elevated plasma BNP, paracentesis is indicated to rule out additional etiologies of ascites, including the possibility of concurrent cirrhosis. When done properly, paracentesis is safe, rapid, and cost-effective. The diagnostic paracentesis is an essential and irreplaceable step in the evaluation of new onset ascites; its omission is akin to foregoing an echocardiogram in the evaluation of new onset heart failure.
As medicine advances, biomarkers will increasingly be used in an effort to simplify the clinical decision-making process and better differentiate between various disease entities. The present study provides intriguing new insight of the role of biomarkers such as BNP in the differential diagnosis of new onset ascites. However, ultimately biomarkers are only “markers,” with both known and unknown limitations, and should not be used as a substitute for the history, physical examination, and careful clinical evaluation and judgment.
Phillip S. Ge, M.D.1
Bruce A. Runyon, M.D.2
1Department of Medicine, 2Division of Digestive Diseases, David Geffen School of Medicine at UCLA, Los Angeles, CA.