Chiefs’ Inquiry Corner – 1/31/22

   Brain natriuretic peptide (BNP) levels can be useful in evaluating patients presenting with dyspnea for the presence of heart failure, with levels less than 100 pg/mL unlikely to be consistent with heart failure, and heart failure being very likely at BNP values >500 pg/mL. However, the caveat is that obesity can lead to lower BNP levels than would otherwise be expected, even for someone in acute decompensated heart failure. While obesity itself is associated with sodium retention and increased cardiac output, which would seemingly result in increased natriuretic peptide levels, the decreased levels actually seen are likely due to a combination of non-hemodynamic factors. Firstly, large numbers of natriuretic peptide clearance receptors  (NPR-C) are found in adipose tissue, suggesting that adipocytes have a role in removing natriuretic peptides from the circulation. Secondly, studies have suggested that people with obesity have diminished myocardial hormone release or impaired synthesis, which would also lead to lower circulating levels of natriuretic peptides in the first place, although the exact mechanisms of this have not yet been elucidated. Interestingly, there is also evidence that the binding of natriuretic peptides to their biologic receptors in adipose tissue induces lipolysis, and therefore low natriuretic peptide levels would lead to reduced lipolysis, perpetuating the obese state and suggesting that there is likely a bidirectional relationship between obesity and levels of natriuretic peptide levels.

References: Impact of Obesity on Plasma Natriuretic Peptide Levels

  Macrocytic anemia is defined as macrocytosis (mean corpuscular volume (MCV) of red blood cells > 100 fL) in the setting of anemia (in men,  hemoglobin < 14 g/dL (140 g/L), hematocrit < 42% (< 0.42) , or RBC < 4.5 million/mcL (< 4.5 × 1012/L); in women, hemoglobin < 12 g/dL (120 g/L), hematocrit < 37% (< 0.37), or RBC < 4 million/mcL (< 4 × 10 12/L). This can be further classified as either megaloblastic macrocytic anemia (i.e., typically with evidence of macro-ovalocytes and hypersegmented neutrophils on peripheral smear) or non-megaloblastic macrocytic anemia (i.e., typically with evidence of round macrocytes and absence of hypersegmented neutrophils on peripheral smear).  Megaloblastic anemia results from defective synthesis of RNA and DNA in the setting of folate and/or vitamin B12 deficiency. Folate deficiency can be seen due to diminished nutritional intake (such as in malnutrition or alcohol use disorder), increased consumption (seen in hemolytic disorders and pregnancy), or malabsorption (inherited familial syndromes, gastric bypass, or use of certain medications including cholestyramine or metformin). Vitamin B12 deficiency can result also from diminished intake, malabsorption (including immune and non-immune atrophic gastritis [e.g, H. pylori infection, Zollinger-Ellison syndrome], gastric bypass, ileal resection), and medications such as metformin. Additional medications that are implicated in impairment of DNA synthesis include folic acid analogs such as methotrexate and trimethoprim-sulfamethoxazole, as well as hydroxyurea and phenytoin.  Non-megaloblastic anemia is seen in a variety of other conditions and the pathological processes underlying many of these processes is incompletely understood. Macrocytosis can occur when there is increased RBC production in the setting of red blood cell destruction (hemolysis) or loss (hemorrhage). Other conditions to consider include hypothyroidism, liver disease (not related to alcohol), and alcohol use (which causes direct toxicity to red blood cells, and is thought to be the main reason for macrocytosis seen in people with alcohol use disorder, although malnutrition and folate/B12 deficiency can often worsen the problem).  Degree of macrocytosis can sometimes provide a starting point for developing a differential diagnosis. Mild macrocytic anemia (MCV 100-110 fL) is more likely to be seen with chronic alcohol use. Marked macrocytic anemia (MCV > 110 fL) is more likely to be seen with primary bone marrow disease or megaloblastic anemia from folate or B12 deficiencies. Extremely high MCV (>130 fL) is usually seen with ART for HIV infection, use of hydroxyurea, and vitamin B12 or folate deficiency. Of note, spuriously high MCV values can be seen in the setting of significant reticulocytosis, hyperglycemia, significant leukocytosis, and the presence of cold agglutinins. 

References: Diagnosis and treatment of macrocytic anemias in adults

  Hereditary hemochromatosis is an autosomal recessive disorder characterized by a deficiency in hepcidin, a protein responsible for modulating intestinal iron absorption, resulting in systemic iron overload. Deposition of iron into various organ parenchymal cells leads to tissue damage and ultimately organ failure. The most commonly affected organs and tissues are the liver, pancreas, joints, heart, skin, and pituitary glands.  Since there are no pathognomonic signs and symptoms of hereditary hemochromatosis, and presentations can vary based on site(s) of excess iron accumulation, diagnosis is contingent on maintaining an index of suspicion for this disorder. Biochemical expression of hereditary hemochromatosis occurs first; clinical signs and symptoms manifest in later stages of disease. A common presentation is a clinically asymptomatic patient who has abnormal hepatic transaminase levels and then elevated serum ferritin and/or transferrin saturation on subsequent testing. Elevated transferrin saturation (particularly that > 45%) is thought to appear first even before ferritin levels are affected.  Once clinical signs are apparent, presentation will depend on the organ system affected. Fatigue and arthralgias are the most common early clinical symptoms. Presentations include diabetes mellitus, hypothyroidism, and/or hypopituitarism (endocrine manifestations), arrhythmias, cardiomegaly and/or heart failure (cardiac manifestations), cirrhosis, ascites, and/or abdominal pain (hepatic manifestations), arthralgias (particularly in the second and third metacarpophalangeal joints), decreased grip strength, and/or arthritis with boggy, tender joints (joint manifestations), and skin hyperpigmentation (bronzing). Note that hereditary hemochromatosis is classically taught as presenting as a triad of diabetes mellitus, cirrhosis, and abnormal skin pigmentation, but this late-stage clinical picture is now uncommon due to increases and advances in early diagnosis and treatment. 

References: Hereditary Hemochromatosis: Rapid Evidence Review