Bloods Journey Through the Heart

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The heart drives the circulatory system as it pushes blood through an intricate system of blood vessels including arteries, capillaries, and veins. Blood is essential as it carries oxygenated blood from the lungs to the tissues and transports waste products like carbon dioxide away where it is expelled from the body.

The heart is hollow and its strong musculature allows it to contract to pump blood to the arteries to be delivered to the rest of the body. One of the most fundamental aspects of the circulatory system is that veins deliver deoxygenated blood to the heart and arteries deliver oxygenated blood away from the heart. Within the heart there are four chambers; right atrium and ventricle, left atrium and left ventricle. These chambers are separated by valves. There are four valves that separate the different chambers; the mitral valve, tricuspid valve, aortic valve, and the pulmonary valve. The tricuspid valve separates the right atrium and right ventricle. The mitral valve separates the left atrium and left ventricle. The aortic valve is what separates the left ventricle and the aorta. The pulmonary valve separates the right ventricle and the pulmonary artery. Valves work to allow blood flow through into the following chamber while not allowing blood to flow back through. A reverse in the blood flow is called regurgitation and is a serious medical condition that should be addressed. Each valve has two cusps with the exception of the tricuspid valve as it has three.

The heart works like machine constantly pumping blood that is fed to it. There are two venous systems that dump into the right atrium; the inferior vena cava and the superior vena cava. The inferior vena cava carries deoxygenated blood from the lower body back to the heart and conversely the superior vena cava carries deoxygenated blood back to the heart from the upper body and head. The right atrium contracts and pumps blood through the tricuspid valve into the right ventricle. When the right ventricle is filled the tricuspid valve closes off preventing regurgitation.

The right ventricle then contracts that pushes blood through the pulmonary valve and into the pulmonary artery to be carried to the lungs. once inside the lungs blood flows the tiny capillary vessels in the lungs where there is exchange of carbon dioxide and oxygen. Oxygen from the alveolar air sacs diffuses through the capillaries into the blood while at the same time carbon dioxide passes from the blood into the air sacs. The carbon dioxide is then exhaled as one respirates normally. The blood is now oxygenated and travels back through the pulmonary veins where it dumps into the left atrium.

As the left atrium contracts blood is pushed through the mitral valve into the left ventricle. When the ventricle has reached capacity the mitral valve closes, again blocking regurgitation. The left ventricle then contracts and the blood is pushed through the aortic valve into the aorta and the coronary arteries. The aorta supplies the rest of the body with oxygenated blood. The coronary arteries is actually what supplies the heart with oxygen to keep the tissue alive.

There is a right coronary artery and a left coronary artery. The right coronary artery supplies the right atrium and right ventricle. It branches into the posterior descending artery. The left main coronary artery branches into the circumflex artery and the left anterior descending artery. It supplies oxygenated blood to the left atrium and the left ventricle.

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Renin-Angiotensin-Aldosterone System

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The renin-angiotensin-aldosterone system (RAAS) plays a physiological role in regulating blood volume and systemic vascular resistance. The two together have an influence on cardiac output and arterial blood pressure. There are three important components to the RAAS; renin, angiotensin, and aldosterone.

Stimulation of renin from the juxtaglomerular cells (JG) is stimulated by sympathetic nerve activation through B1-adrenoceptors, renal hypotension or decreased sodium in the distal tubules of the kidney. A reduction in blood pressure in the afferent arterioles causes release of renin, and conversely increased arteriole pressure inhibits renin release. Specialized cells of the distal tubules; the macula densa sense the concentration of sodium and chloride ions in normal tubular fluid. When NaCl ions are elevated, renin is inhibited, and when there is a reduction in tubular NaCl the JG is stimulated to release renin. When arteriole pressure is reduced, there is a decreased GFR. The decreased GFR reduces NaCl in the distal tubule which is an important mechanism contributing to renin release.

Renin acts upon the substrate angiotensinogen the undergoes cleavage to form angiotensin I. The vascular endothelium has an enzyme; angiotensin converting enzyme (ACE), that cleaves angiotensin I to form angiotensin II. Angiotensin II carries out several important functions; it causes vasoconstriction resulting in systemic vascular resistance and increase in arterial pressure. It also stimulates sodium reabsorption that increases the sodium and water retention in the body. It acts on the adrenal cortex to release aldosterone. It stimulates the release of vasopressin otherwise known as antidiuretic hormone that increases fluid retention in the kidneys. It stimulates thirst because of the amount of sodium being reabsorbed. Lastly it stimulates cardiac hypertrophy.

The RAAS is not only regulated by internal inhibition and stimulation, but by natriuretic peptides (NPs) that are synthesized in the heart, brain and other organs. The physiological function of NPs is too decrease blood volume and systemic vascular resistance. NPs increase the glomerular filtration rate which causes increased sodium excretion (natriuresis) and increased fluid excretion (diuresis). They also inhibit renin release and decrease circulating levels of angiotensin II and aldosterone. This results in systemic vasodilation.

Biotin Interference on Diagnostic Testing

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Biotin, also known as vitamin B7 is a coenzyme that is involved in carbon dioxide transfer in carboxylase reactions. The USDA recommended dietary reference intake for biotin is 30 ug per day which should mostly come from food. The last few years biotin has been marketed heavily as a beauty supplement. It is used in hair, skin, and nail supplements, and is not FDA regulated and is sold as over-the-counter. Biotin can be found in B-complex vitamins, multivitamins, prenatal vitamins, vitamin H, and vitamin B7 supplements. The only FDA recommended use for biotin is in patients with secondary progressive multiple sclerosis who receive mega-doses of up to 300 mg per day. Even in such large doses biotin is considered nontoxic and has very little adverse effects.

The issue is that serum or plasma biotin may potentially interfere with any assay that uses biotin-streptavidin binding. Biotin is a small molecule that attaches covalently to a variety of targets with minimal effect on their biological activity. The biotin binding makes the target an easy capture because it forms a strong bond with avidin, streptavidin, and NeutrAvidin proteins who have an exceptionally high affinity for biotin. Biotin-streptavidin detection is a favorite among many immunoassays across many manufacturers including Roche, Ortho, Beckman, Siemens, and Dimension.

The direction of interference depends on the design of the assay. Some results may be falsely elevated, and some may be falsely decreased. The sandwich and competitive assays are among the most commonly impacted. Interference can occur with hormone tests such as parathyroid hormone (PTH), thyroid stimulating hormone (TSH), T4, T3, and even troponin tests.

Sandwich assays involve two antibodies that form a sandwich with the analyte being tested to be measured. The first antibody is labeled with a signal that can be quantified and the other antibody to the target is labeled with biotin. When the biotin:antibody complex binds to streptavidin-coated beads, the labeled antibody then binds creating a sandwich. The resulting complex is then measured. The more complexes that are created, the stronger the signal, i.e the more target analyte there is. Excess free biotin interferes by binding to the streptavidin-coated beads, leaving fewer binding opportunities for the antibodies. Antibody complexes that have successfully bound the analyze get washed away and are then undetected, resulting in falsely low results.

Competitive assays consist of an antibody to the analyte that is labeled with biotin. The analyte must compete for antibody binding sites with a reagent that is a supplied version of itself with a label for detection. If no analyte is present, the reagent occupies all the antibody binding sites and the complex is captured by streptavidin, and a strong signal is emitted. If analyte is present, that occupies antibody binding sites that outcompete the labeled reagent. When analyte is present, there is less detection and less signal measured. It is an inverse relationship. When analyte is not present, there is a strong signal detected, when analyte is present, there is a weak signal detected. Free biotin sticks to the streptavidin, leaving fewer antibody binding sites for the analyte:antibody or reagent:antibody complex. The complexes get washed away and causes weakening of the signal. This may give the impression that analyte is present, even in its absence.

This is an ongoing issue and the FDA advises the healthcare community; patients and physicians both to disclose any supplements that are being taken that contain biotin. Physicians should advise laboratory if interference from biotin is a possibility. Practice should be implemented to counsel patients to abstain from oral biotin 2-3 days before blood tests. Biotin has a rapid half-life of 2 hours, but patients taking mega-doses (>30 mg) have demonstrated interference on laboratory tests for up to 24 hours.

Physicians should educate patients to increase awareness of biotin interference. Adverse health effects can occur if test results are falsely skewed in any direction.

Liver Enzymes

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The liver is the largest internal organ. It is incredibly functionally complex. It carries out more than 500 different functions that include detoxification, protein synthesis and chemical synthesis to aid in digestion. Some of the livers main functions will be talked about. Bile produced by the liver aids in digestion in the small intestine. It breaks down and absorbs fats, cholesterol, and occasionally some vitamins. Bile is produced by the liver and is stored in the gallbladder. The liver also absorbs and metabolizes bilirubin. Bilirubin is caused by the breakdown of hemoglobin in red cells. This can either be extravascular or intravascular hemolysis and can either be normal breakdown as red cells only live for 120 days before being recycled or it can be not normal. The iron that is released by the bilirubin is stored in the liver or the bone marrow that is used to make new red cells. Bilirubin is metabolized to its direct conjugated form where it is excreted by the urine and feces. The liver produces clotting factors. Vitamin K is necessary for some clotting factors to be produced and in order for vitamin K to be absorbed from the diet the liver needs to produce bile. Without the bile clotting factors would not be produced. The liver aids in filtering the blood. It filters and removes different waste material produced from the body as well as exogenous compounds like alcohol and other drugs. The liver also has a immunological function in that it contains Kupffer cells. These Kupffer cells are the macrophages of the liver and are part of the mononuclear phagocyte system that destroy any foreign antigen that enters the liver. The liver produces albumin which is arguably the most important protein in the body. Albumin is used as a transport protein and maintains colloid pressure in the blood vessels. Angiotensinogen is produced by the liver that is used in the angiotensinogen-Renin system in the kidneys that raises blood pressure by vasoconstriction.

Regeneration is a unique feature of the liver. Its important to the body is unmatched and it has evolved the ability of regeneration. Regeneration is the ability for the organ to regrow rapidly as long as it is kept healthy. During this process of regeneration the function of the liver is not compromised. If needed there are a number of compounds that can aid in the regeneration process like hepatocyte growth factor, insulin, epidermal growth factor, IL-6, and even norepinephrine.

Analysis of bilirubin is based on the reaction of bilirubin with a diazotized sulfanilic acid. Three fractions of bilirubin is measured. Conjugated, unconjugated, and delta bilirubin. Delta bilirubin is bilirubin bound to albumin. A fasting sample is preferred and hemolyzed samples should be avoided. Bilirubin is sensitive to light so care should be taken to shield the sample from the light.

Liver enzymes are relatively nonspecific indicators that can indicate tissue destruction in several organs. Alkaline phosphatase is a group of isoenzymes that are found on the membranes of cells in almost every tissue. Alkaline phosphatase can become elevated in many different conditions including bone diseases, puberty, and even in late pregnancy. One important feature of alkaline phosphatase is that the isoenzyme found in bone is the most heat labile. Differentiation in the laboratory includes heating the sample and then remeasuring the alkaline phosphatase and measuring the difference.

Gamma-glutamyltransferase (GGT) is a membrane enzyme that is important in glutathione metabolism. It transfers glutamate to the amino acid peptide chain. GGT is among one of the first enzymes to become elevated in acute liver diseases such as hepatitis. Its important to note that GGT is normal in patients with bone diseases making it one of the most clinically specific of all the liver enzymes. Lactate dehydrogenase is a cytosolic enzyme that interconverts pyruvate and lactate. There are five isoenzymes. Isoenzymes 4 and 5 are increased in viral or toxic hepatitis, biliary obstructions and cirrhosis. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) convert aspartate and alanine to oxaloacetate and pyruvate respectively. ALT is very specific for liver pathology. AST is found in liver tissues, but also present in heart and muscle tissue. The AST/ALT ratio is an important factor to look at. A ratio less than 1.0 indicates viral hepatitis. This is an increase in ALT greater than the increase in AST. An AST/ALT ratio greater than 1.0 usually means that the ALT is elevated to a lesser degree than the AST and this can be found in cirrhosis, bile duct obstruction, or metastatic cancer of the liver.

-Caleb

Viral Hepatitis

Viral hepatitis is acute or chronic symptomatic or even sometimes asymptomatic inflammation of the liver. Usually the infection is self-limiting and clears within 12 weeks, but in immunocompromised patients it can pose serious complications and development of systemic problems. All viral hepatitities can lead to liver cirrhosis if untreated. There are important serological markers involving different proteins of the virus that can tell us whether or not the infection is acute or chronic and whether or not the virus is actively replicating or not. The viruses replicate one week before detection and two weeks post-detectable levels. The most common types of hepatitis are A, B and C. Although Hep A and B are on the decline as vaccination campaigns have been more successful. Hep C is gradually declining, but as of recently there has been an increase in incidence. It should be noted that as of now there is no currently FDA approved vaccination for Hep C. There are some more less common Hep virus like E, and D, but the incidence is low and clinically not very relevant. One important distinction to point out is that a person much have Hep B to acquire Hep D. Hep D requires the viral envelope protein from Hep B to survive.

Hep A is a +ssRNA picornavirus. It is non-enveloped which means when it is shedding and replicating it causes lysis of the hepatocytes in the liver. The disease is spread by fecal/oral route and the virus is exceptionally hardy. It is very hard to inactivate and can survive in water or on surfaces for an extended period of time. The incubation period is 20-40 days and the disease itself is mild in nature. Clinical presentation includes variable prodromal symptoms usually fever, malaise, weakness, nausea, loss of appetite, and myalgia. Jaundice may or may not be present. The virus usually presents as asymptomatic, especially at a younger age as the immune system is able to hold it in check. Symptoms can actually be a good thing as it means that the immune system is recognizing the virus and trying to rid of it. Risk groups include those who have direct contact with persons who have Hep A such as a healthcare worker, travelers to endemic countries are at high risk even when good hygiene and sanitation measures are being applied. Less commonly users of injection and non-injection drugs, and people with clotting factor disorders. Diagnostic workout includes serologically workup and liver enzyme panel as well as bilirubin levels.

Hep B is a dsDNA-RT enveloped hepadnavirus. The Hep B genome is unique in that it virally replicates using an RNA intermediate and uses its reverse transcriptase mechanism to complete its DNA replication making the life cycle very complex. Transmission is through body fluids or sexually and is considered a sexually transmitted disease (STD). Activities involving percutaneous or mucosal contact such as heterosexual contact, injection drug-use with sharing of needles, birth to an infected mother or contact with blood or sores of an infected person. Medical professionals should take care to avoid any needle sticks or other exposures to those infected. Its estimated that 400 million people worldwide are infected with Hep B. The clinical presentation often presents with very generalized symptoms similar to Hep A with the addition of joint pain, jaundice, dark urine or clay-colored bowel movements. Chronic Hep B infection is not commonly talked about as Hep C is primarily dubbed as the chronic hepatitis infection, but 5% of adults become chronically infected with Hep B. They can live asymptomatically or they can display a spectrum of disease ranging from chronic hepatitis flares to cirrhosis or hepatocellular carcinoma.

The Hep B diagnosis is largely reliant on serology. The Hep B surface antigen (HBsAg) is a protein on the surface of HBV. It can be detected in high levels in the serum during acute or chronic HBV infection. It should be noted that individuals typically lose the expression of the HBsAg after 12 weeks when chronically infected. The presence of HBsAg means that person is infectious. Hep B surface antibody (Anti-HBs) present means that the person is recovering from an infection and that they now have immunity to the HBV. Anti-HBs also is developed when an individual is vaccinated against Hep B. IgM antibody to Hep B core antigen (IgM-Anti-HBc) indicates that an individual has an acute Hep B infection or has had an infection within the last 6 months. IgG-Anti-HBc indicates previous infection with Hep B and immunity towards the virus. The core antibody persists for life. Its important to note that when you run labs looking for hepatitis if the Anti-HBs antibody is present, but the Anti-HBc antibody is NOT present this indicates the individual has been vaccinated, not previously infected. The core antibody will not develop during vaccination. The Hep B (e) antigen is a secreted product of the nucleocapsid of HBV that is found in the serum during actively replicating infection. This indicates that the individual has an incredibly high viral burden. Anti-HBe antibody produced is an indicator of seroconversion and is used as a predictor of clearance of the Hep B virus for individuals undergoing treatment. Acute Hep B is usually not treated and the individual receives supportive therapy if needed. Chronic Hep B is treated using interferon or five different antiviral nucleoside analogs. The treatment is not curative, and only has a 20-50% response rate, but improves prognostic markers. Hep B is HIGHLY infective, 50-100x more infectious than HIV and 10x more infectious as HCV.

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Hep C is a +ssRNA enveloped flavivirus. Typical transmission is through exposure to infectious blood. This can either be through injection drug use of shared needles or through recipient of donated blood, or organs, or neonatal birth to an HCV infected mother. Sexual transmission can still occur, but not at the rate that Hep B is transmitted. Acute infection usually is asymptomatic or presents with only mild symptoms similar to that of HAV and HBV. The incubation period is 4-12 weeks. Chronic HCV is generally asymptomatic while some individuals present with mild chronic liver disease and others with cirrhosis or hepatocellular carcinoma. 15-25% of individuals who develop Hep C will be able to clear the disease. Of the 75-85% that develop chronic HCV 60-70% will develop chronic liver disease, 5-20% will develop cirrhosis, and 1-5% will develop HCC. Hep D diagnosis is dependent on screening tests for the HCV antibody. These screening methods include enzyme immunoassay (EIA) or enhanced chemiluminescence immunoassay (CIA). There are PCR tests that detect the HCV RNA and also that quantify the viral RNA to determine the disease burden. A diagnosis based solely on elevation of liver enzymes AST, ALT is not acceptable. There is no currently accepted vaccine, but there is research ongoing. Previous infection does not grant immunity for subsequent infections like one would think likely due to high rte of viral mutation. There are 3 characteristic classes of drugs for treatment of Hep C and one novel advancement of one. HCV protease, polymerase inhibitors and interferon are most commonly used. A new novel treatment called direct acting antivirals (DAA) is a combination therapy that is shown to be highly effective at suppressing viral replication and can actually result in a cure in as short as 12 weeks of treatment. The cure rate is 95%. This novel treatment protocol is showing unprecedented success, but it comes as cost. A cost that no insurance company wants to pay for and that most people can’t afford.

Chronic HBV and HCV are associated with an increased incidence of HCC. This is due to the continuous cycles of viral replication, the immune-mediated killing of the hepatocytes and inflammation. Inflammation induces oxidative damage and altered cellular metabolism. This creates an unhealthy environment in the liver.

-Caleb