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.

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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

Overview of the Immune System; Part One

The overall function of the immune system is to prevent or limit infection. It is essential for survival. Multiple organ systems, cells, and proteins are involved in the immune response. It is the most complex system that the human body has. The immune system is differentiated into two directions. Innate or non-specific immunity or Acquired (specific) immunity.

The Innate immune system consists of many components. The skin acts as a mechanical barrier and is typically the first line of defense against foreign substances. Mucous membranes consist of the bodies normal microbiota which compete with invading microbes. The mucous membranes are also lined with mucous and cilia which act in an elevator type motion to push foreign substances away. Physiological barriers such as temperature, pH and the complement system. The more acidic environment that a lower pH offers disrupts bacterial growth. Antimicrobial proteins and peptides are present in different epithelial locations in the body. Lysozymes are present in the tears and saliva and cleave the peptidoglycan cell wall present in bacteria. Secretory phospholipase A2 is present in the gut and can enter the bacterial cell and hydrolyze lipids in the cell membrane. Lectins target gram positive bacteria and forms pores in the membranes. Defensins integrate into the lipid and form pores which causes loss of membrane integrity. These defensins are present in PMNs (neutrophils) and lamellar bodies in the gut. Cathelicidins are present in neutrophils and macrophages in the lungs and intestines and distrupt membranes. Histatins are constitutively produced by the glands in the oral cavity and are active against pathogenic fungi.  Inflammation plays a huge role in the Innate immune system. Inflammation induces vasodilation and increase in capillary permeability causing an influx of immune cells like PMNs and macrophages. Inflammation can be observed by the four cardinal signs; rumor (redness), tumor (swelling), color (heat), and dolor (pain). The innate immune response is a rapid response.

Innate Immunity

The complement system recognizes features of microbial surfaces and marks them for destruction by coating them with C3b. There are three distinct pathways; the classical pathway, the lectin pathway, and the alternative pathway. All pathways generate a C3 convertase which cleaves C3, leaving C3b bound to the microbial surface and releasing C3a. In the classical pathway the activated C1s cleaves C4 to C4a and C4b which binds to the microbial surface. C4b then binds C2, which is cleaved by C1s to C2a and C2b forming the C4b2b complex. C4b2b on the microbial surface is an active C3 convertase which cleaves C3 to C3a and C3b. This results in opsonization of the bacterial surface by C3b. The C4b2b3b complex is an active C5 convertase leading to the development of the membrane-attack complex. Each complement component (C4a/b, C2a/b, C3a/b) have different functions, but that is another discussion for another time. The lectin pathway of complement activation is when mannose-binding lectin (MBL) and ficolins recognize and bind to carbohydrates on the pathogen surface. Ficolins are similar to MBLs, but have a different carbohydrate binding domain. MBLs bind with high affinity to mannose and fucose residues. Conversely ficolins bind oligosaccharides containing acetylated sugars. When MBL binds to a pathogen surface MBL-associated serine protease (MASP)-2 is activated and cleaves C4 and C2 similar to the classical pathway. The alternative pathway is an amplification loop for C3b formation that is accelerated by properdin (factor P) in the presence of pathogens. Properdin stabilizes the C3bBb complex. C3 undergoes spontaneous hydrolysis to C3(H20) which binds to factor B, allowing it to be cleaved by factor D into Ba and Bb. The C3(H20)Bb complex is essentially a C3 convertase which cleaves more C3 into C3a and C3b. C3b molecules result in opsonization of bacterial surfaces. Its important to recognize that all pathways lead to generation of a C5 convertase. C4b2a4b in the classical pathway, C4b2a3b in the lectin pathway, and C3b2Bb in the alternative pathway. C5 is cleaved into C5a/b that initiates the assembly of the terminal complement components. These are the terminal complement components that form the membrane-attack complex.

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The membrane attack complex consists of an assembly of C6, C7, and C8. This complex undergoes a conformational change that results in polymerization of C9 which generates a large pore in the cell membrane. Host cells contain CD59 which prevents the assembly of the C9 molecules preventing the formation of the membrane-attack complex.

C3a, C4a, and C5a are unique in that these complement components are called anaphylatoxics. They initiate a local inflammatory response when systemic injection of these molecules occurs. They induce smooth muscle cell contraction and increased vascular permeability. They induce adhesion molecules and activate mast cells that invade and populate submucosal tissues to release inflammatory mediators such as histamine and TNF-a.

The Acquired or adaptive immune system is all about specificity. The Humoral branch of the acquired immune system is executed by the B lymphocytes that produce antibodies to specific antigens. The cell-mediated branch consists of antigen presenting cells (APC) such as the dendritic cells processing foreign substances and presenting proteins of those substances as antigens through the major histocompatibility complex (MHC) to CD8 T lymphocytes. These are cytotoxic T-cells that kill these foreign antigens. The acquired immune response is a slow response because it takes the body time to produce antibodies. An important aspect of the adaptive response is memory. Once antibodies have been produced to an antigen, these responses last and the time it takes to produce an antibody on subsequent exposures is rapidly decreased.

These two different systems work in conjunction to produce an adequate and sustained response. When foreign antigens are processed and expressed on the surface of APCs as MHC peptides, pro-inflammatory cytokines such as IL-12p70, IL-18, and IFN-a are secreted. These attract NK cells which primarily attack viruses as well as PMNs and macrophages that phagocytize these antigen peptides to destroy them. Adaptive immunity is also started with dendritic cells that also undergo antigen uptake and processing. This is also called the maturation signal. This signal is augmented by IFN-y and TNF-a secreted by macrophages and NK cells. These dendritic cells either present the antigen to B lymphocytes which are the antibody producers or they present the antigen to CD4/CD8 T-cell lymphocytes.

There are multiple classes of antibodies. IgD is typically expressed on B-cell lymphocytes during differentiation with IgM. IgD is also present in the serum in low concentrations. IgM is a pentamer and the largest immunoglobulin. It is the first antibody that is produced in the immune response. IgA is in high concentration in the mucosal linings, saliva, and tears. Typically part of first line defenses. IgG is present in high concentrations in the serum. IgG is unique in that it can cross the placenta. IgE is involved in allergic reactions. It binds to mast cells and basophils causing degranulation.

-Caleb