Last post about TCRs!
Identify the cell surface molecules on T-cells and APC
There are a lot of cell surface molecules that you're going to need to know about, because the TCR can't initiate intracellular signalling all by itself. Instead, it needs help from some other proteins. This might be because while an MHC binds a peptide with high affinity, it binds to a TCR with relatively low affinity. Hence, we need other stuff to help hold things together!
Firstly, I'm going to give you an overview of the T-cell activation process, just to give you a framework for everything else that's going to follow. The first signal occurs when the TCR and MHC bind. Next co-stimulatory molecules on the TCR bind to molecules on the antigen-presenting cell (APC). Finally, the T-cell receives cytokine signalling, directing its differentiation into different kinds of effector cells.
The first thing that needs to happen is that the cells need to come into contact. This is helped by some of the cell-surface molecules. LFA-1 (on T-cell) binds to ICAM-1 (on APC) and CD2 (on T-cell) binds to LFA-3 (on APC) (and yes, you do need to know these pairings- just remember that the 1s go together). CD2, LFA-3 and ICAM-1 are all members of the Ig superfamily, but LFA-1 is an integrin instead (a molecule that facilitates cell-to-cell attachment and signal transduction).
Next up the TCR recognises a peptide bound to MHC. Since, as stated before, this is not a strong interaction, it is aided along by the ζ-chains in the TCR signalling complex, as well as by another little molecule called P56lck (sometimes just called P56 or lck for short). Also aiding the binding is the formation of an immunological synapse. This is basically a cluster of proteins: the TCR/MHC pair are in the middle and are surrounded by LFA-1/ICAM-1 and CD2/LFA-3 pairs. This helps to increase the avidity of the T-cell/APC interaction. The TCR/MHC pair in the middle are sometimes also known as the cSMAC (central supramolecular activating complex), whereas the other pairs are sometimes known as the pSMAC (peripheral supramolecular activating complex).
Finally some co-stimulatory receptors begin to kick in! CD22 on the APC binds to CD45R on the T-cell, which then goes off to activate signalling via P56lck (yup, it's a very versatile little guy). B7 (a.k.a. CD80) on the APC binds to CD28 on the T-cell, activating signalling via PKC (protein kinase C). This ultimately leads to effector activities, such as cytotoxic cells killing an infected cell or helper cells producing cytokines.
Explain the intracellular signalling molecules and signal transduction pathways
Now we get onto the intracellular stuff, which is kinda complex, but we'll get through it, I promise!
Firstly, just a refresher on the TCR signalling complex, which I mentioned in an earlier post. Recall that TCRs associate with CD3 proteins as well as with zeta-chains (which are homodimers). All of this is held together by opposing charges on the molecules. Another tidbit that you need to know is that the intracellular portions of CD3 and zeta-chains have ITAMs, short for "immunoreceptor tyrosine-based activation motifs," which have tyrosine residues that can be phosphorylated. Ultimately, it's this phosphorylation that kicks off the whole chain of events.
I've mentioned P56lck a few times (which I'll call Lck from now on because it's easier to type) and now I'm going to mention it again, because it is just that important. Lck is a tyrosine kinase that associates with CD4/CD8, but as mentioned above, it is activated by CD45R following binding to CD22. When activated, it phosphorylates ITAMs on the CD3 and zeta chains. Another protein, ZAP-70 (zeta-associated protein), can come in and "dock" to the new phosphate groups on the ITAMs. ZAP-70 can also be activated by Lck, and when active, ZAP-70 phosphorylates phospholipase Cγ (a.k.a. PLCγ). That's not the end though- we're pretty much only beginning!
The PLCγ signalling pathway is not unique to T-cells. In fact, I've mentioned it before in a PHAR2210 post about G-protein coupled receptors.
Phospholipase Cγ, once activated by ZAP-70, can cleave PIP2 (phosphatidylinositol-4,5-biphosphate) into IP3 (inositol triphosphate) and DAG (diacylglycerol). DAG remains in the membrane, while IP3 diffuses through the cytoplasm.
Now I'm going to split off and talk about the activation of the three main transcription factors in T-cell activation separately, as I find that works better for me.
Activation of NF-AT
IP3 is able to induce the release of Ca2+ ions from intracellular stores. Calcium can then bind a protein called calmodulin, which can then activate calcineurin phosphatase. Calcineurin phosphatase then dephosphorylates NF-AT (remember, phosphatases remove phosphate groups), which activates NF-AT.
An interesting thing about this pathway is that it can be blocked by an immunosuppressant called cyclosporine. Cyclosporine inhibits calcineurin phosphatase so that NF-AT cannot be activated. Since all three main transcription factors are ultimately required, this drug suppresses the immune system by blocking T-cell proliferation, and is thus useful in treating autoimmune diseases and preventing rejection following transplantation.
Activation of NFκB
Once again, this starts with IP3 inducing the release of Ca2+. Calcium sends protein kinase C (PKC) to diacylglycerol, which as you may recall is still hanging around in the membrane. This ultimately leads to activation of NFκB.
Activation of AP-1
This one's a bit different in that it's induced by CD28 on the T-cell binding to B7 (a.k.a. CD80) on the APC. This binding activates the MAPK cascade, as mentioned here (but we don't need to know it in so much detail for this course). This ultimately leads to transcription of AP-1.
So what happens after all three transcription factors have been activated? Well, activated transcription factors can bind to the promoter region for the IL-2 gene, inducing IL-2 transcription. IL-2 is an important cytokine for T-cell proliferation: as I said a little earlier, if transcription is blocked due to blocked production of NF-AT (via cyclosporine or otherwise), then T-cells cannot proliferate.
Last post on the T-cell receptor! The next Immunology post will cover humoral immunity, which is the last topic that will be covered on the next midterm.
Sunday, November 6, 2016
T-cell Receptor: Maturation
At the very end of my last post, I said that thymocyte development would be the topic of a later post. Well, this is the later post!
Firstly, a quick note about the thymus, just in case you don't know what it is. It's a primary lymphoid organ where T-cells are produced, and is located in the anterior mediastinum. As you get older, the thymus shrinks and thus produces fewer T-cells.
Just as with pretty much all aspects of the immune system, the importance of the thymus is highlighted in people who don't have one. People with DiGeorge's syndrome, and Nude mice (mice with a genetic mutation causing an absence of a thymus), lack T-cells and have reduced B-cell activation (as they are no longer receiving signals from T-helper cells). As an aside, there are also Scid mice ("Scid" stands for "severe combined immune deficiency") that lack RAG-1 enzymes, and thus don't have TCRs or BCRs.
Back to the thymus: like many other organs of the body, it has a cortex (outer bit) and a medulla (inner bit). Early thymocytes first enter through blood vessels of the medulla. As they mature, they move up through the cortex, and eventually back down and out through either veins or lymph vessels. Along the way they come into contact with cells such as medullary epithelial cells, cortical epithelial cells, Hassall's corpuscles, dendritic cells and macrophages. The first two types will be important in positive and negative selection, as you will see later. Hassall's corpuscles have an unknown function. As for the last two, hopefully you know what they are by now- if not, have a look through some of my earlier Immunology posts.
An important protein present on medullary epithelial cells is AIRE. AIRE stands for "AutoImmune REgulator." It induces the expression of many different proteins, including those specific for other tissues of the body. This allows the developing thymocyte to be able to meet some of those antigens before even leaving the thymus. If AIRE is defective, there's a much higher risk of immune destruction of other tissues, notably endocrine tissues. This causes a condition called Autoimmune Polyendocrinopathy-Candidiasis-Ectodermal Dystrophy, which conveniently goes by the acronym APECED so we don't have to waste our breath on that long name. Interestingly enough, Hassall's corpuscles appear to differentiate from cells that have lost their ability to express AIRE.
Now onto a bit about the development of the thymocytes themselves! Precursor cells are originally formed in the bone marrow, but then migrate to the thymus. TCR recombination then occurs, yielding either an αβ or a γδ cell. γδ cells can then move out straight away- as they don't recognise MHC molecules, there's no risk of them self-reacting, so there's no need for them to go through all of the processes to weed out self-reactive molecules. αβ cells, however, do need to stick around to continue developing and go through the selection process.
Another type of thymocyte that may be formed is the NK T-cell, which has some properties of T-cells and some of NK cells. Specifically, they express CD3, just like T-cells, and CD56 (a glycoprotein important for adhesion), just like NK cells. Their TCRs have an invariant α-chain and are able to interact with non-polymorphic CD1 molecules, which present lipid antigens. NK T-cells are pretty rare and only make up around 0.1% of peripheral blood T-cells, but their levels may be elevated in some autoimmune diseases as well as in cancers.
Another type of thymocyte that may be formed is the NK T-cell, which has some properties of T-cells and some of NK cells. Specifically, they express CD3, just like T-cells, and CD56 (a glycoprotein important for adhesion), just like NK cells. Their TCRs have an invariant α-chain and are able to interact with non-polymorphic CD1 molecules, which present lipid antigens. NK T-cells are pretty rare and only make up around 0.1% of peripheral blood T-cells, but their levels may be elevated in some autoimmune diseases as well as in cancers.
Describe developmental stages of T-cells in the thymus with regard to positive and negative selection
Positive selection refers to the signals that cause either a CD4 or a CD8 T-cell to develop, whereas negative selection refers to the removal of self-reactive T-cells. Aside from these processes, many cells die of neglect- there simply aren't enough survival signals to go around. It seems like a bit of a waste, but whatever.
As I mentioned earlier, epithelial cells in the cortex and medulla of the thymus are important in these processes. They express high levels of MHC-I and MHC-II bound to a range of different self-peptides, which basically sets up a test for double-positive T-cells. If the T-cells can't bind at all, they die of neglect. If they bind too strongly, they are given strong signals to undergo apoptosis (negative selection). If they bind "just right," then they are given signals to proceed to the single-positive stage of development (positive selection). Kinda like Goldilocks in a way- you don't want binding to be too strong or too weak, but "just right." Whether a cell becomes CD4+ or CD8+ depends on whether the double-positive T-cell binds to MHC-I or MHC-II: those that bind to MHC-I become CD8+ and those that bind to MHC-II become CD4+.
Negative selection is very helpful in reducing numbers of self-reactive T-cells. It is not perfect, however, because not all tissue antigens are expressed in the thymus. Thankfully there is also a mechanism called peripheral tolerance, allowing auto-reactive T-cells to become inactivated in the periphery. (Negative selection taking place in the thymus is known as "central tolerance.")
And that's it for T-cell development! Next up I'll talk about T-cell activation, which is a wild ride of signalling pathways. Hold onto your hat!
Positive selection refers to the signals that cause either a CD4 or a CD8 T-cell to develop, whereas negative selection refers to the removal of self-reactive T-cells. Aside from these processes, many cells die of neglect- there simply aren't enough survival signals to go around. It seems like a bit of a waste, but whatever.
As I mentioned earlier, epithelial cells in the cortex and medulla of the thymus are important in these processes. They express high levels of MHC-I and MHC-II bound to a range of different self-peptides, which basically sets up a test for double-positive T-cells. If the T-cells can't bind at all, they die of neglect. If they bind too strongly, they are given strong signals to undergo apoptosis (negative selection). If they bind "just right," then they are given signals to proceed to the single-positive stage of development (positive selection). Kinda like Goldilocks in a way- you don't want binding to be too strong or too weak, but "just right." Whether a cell becomes CD4+ or CD8+ depends on whether the double-positive T-cell binds to MHC-I or MHC-II: those that bind to MHC-I become CD8+ and those that bind to MHC-II become CD4+.
Negative selection is very helpful in reducing numbers of self-reactive T-cells. It is not perfect, however, because not all tissue antigens are expressed in the thymus. Thankfully there is also a mechanism called peripheral tolerance, allowing auto-reactive T-cells to become inactivated in the periphery. (Negative selection taking place in the thymus is known as "central tolerance.")
And that's it for T-cell development! Next up I'll talk about T-cell activation, which is a wild ride of signalling pathways. Hold onto your hat!
T-cell Receptor: Structure, Organisation and Genes
Back to blogging about Immunology!
Understand TCR binding to MHC complex
Understand the structure and formation of the TCR
TCRs (T-cell receptors), unlike BCRs, aren't antibodies. No offence to TCRs, but they're not as exciting as BCRs: rather than the Y-shape of antibodies, TCRs just have two small, straight chains (usually an α-chain and a β-chain), each containing Ig (immunoglobulin) domains. Each chain has a constant region and a variable region. Just like the BCR, the variable region of the TCR is where antigens bind.
Just as a refresher, MHC-I binds to TCRs on CD8 (cytotoxic) T-cells and MHC-II binds to TCRs on CD4 (helper) T-cells. In fact, CD8 and CD4 act as co-receptors that facilitate this: CD8 binds to α2 and α3 on MHC-I, whereas CD4 binds to β1 and β2 on MHC-II. CD4 is a monomer that has four domains in a long chain, whereas CD8 has two short chains, called amazeballs A and amazeballs B. (Just kidding. They're just called α and β.)
Anyway, back to TCRs. As I mentioned earlier, most TCRs have an α-chain and a β-chain, but some have a γ-chain and a δ-chain instead. These γδ TCRs are more common in early foetal development, but later on they are overtaken by the αβ variety. A T-cell can only have one kind of receptor (either αβ or γδ). Both kinds of TCRs develop in the thymus and associate with a co-receptor called CD3, but there are a lot of other major differences: T-cells expressing γδ generally do not have CD4 or CD8, and they don't interact with MHCs. Instead they are a bit more like PRRs in that they bind to ligands that are common across microbes, such as phospholipids and certain intact proteins. They are considered to be innate lymphocytes (probably because of this), but there's still a lot about them that we don't really know.
One last thing about γδ T-cells before I move on: when I said they don't have CD8, I kinda lied. Intraepithelial lymphocytes (iELs), which are γδ T-cells found in the gut, have a different form of CD8. Instead of an α-chain and a β-chain, the CD8s on iELs have two α-chains (and thus these receptors are known as CD8αα+). iELs still aren't considered CD8 T-cells, though, since they don't have the normal kind of CD8.
Now I'm going to talk about the TCR signalling complex! I'm going to talk about it in regards to the αβ T-cells, but I assume it probably works in a similar way in γδ T-cells. The TCR signalling complex consists of the TCR, as well as extracellular CD3 molecules and intracellular ζ (zeta) chains. CD3 molecules are comprised of three different proteins (γ, δ and ε) that can dimerise in different ways (γ/ε or δ/ε). CD3 molecules help out with the assembly, expression and stability of TCRs, whereas ζ-chains help out with the signalling.
Finally, a note on complementarity determining regions of TCRs, specifically αβ TCRs. This is a bit random, but I really didn't know where else to put this. The binding site of the TCR has complementarity determining regions (CDRs), imaginatively named CDR-1, CDR-2 and CDR-3. CDR-1 interacts with both the peptide and the MHC, CDR-2 interacts with the MHC only and CDR-3 interacts with the peptide only.
Understand the organisation of the TCR genes
The organisation of the T-cell receptor genes is somewhat similar to the organisation of the B-cell receptor genes, which I've gone over here.
Organisation of Genes
The α-chain, in some ways, is analogous to the light chain of the B-cell receptor in that it has leader, variable, joining and constant sequences, whereas the β-chain is more like the BCR heavy chain in that it also has diversity sequences. The β-chain genes are a bit unique, however, in that the D, J and C sequences are arranged in two separate "chunks": following the LV sequences, there's a D sequence, some J sequences and a C sequence, and then a second D sequence, more J sequences and a second C sequence.
The γ- and δ-chains have the same regions as the α- and β-chains (aside from the δ-chain lacking leader sequences), but there is less diversity (i.e. fewer variable, diversity and joining sequences) and the genes are arranged a little bit differently. In the γ-chain, which has L, V, J and C sequences, the LV sequences are followed by three joining sequences and a constant sequence, and then two more joining sequences and a constant sequence (like the "chunks" making up the β-chain genes). The δ-chain has the sequences more or less in order- three variable sequences, three diversity sequences, three joining sequences and a constant sequence- but the locus is rounded off by a final variable sequence at the end. Another important thing you need to know is that the δ-chain genes are located between the variable and joining segments of the α-chain locus, so once the VJ rearrangement is done in the α-chain, all of the δ-chain genes become unavailable.
Receptor Editing and Allelic Exclusion
Just like in BCRs, there are ways of ensuring that only one receptor is made, and that the receptor genes are productively arranged.
First, let's look at the β-chain. As I mentioned earlier, the β-chain genes are in two separate "chunks." Essentially, the first "chunk" gets rearranged first. If that's unsuccessful, then the second "chunk" is rearranged, deleting the locus of the first "chunk" in the process. (Presumably, if that's also unsuccessful, the cell dies.) To ensure that only one chain is made overall, β-chains are subject to allelic exclusion, a process I described in my post about B-cell development. (If you don't remember what that is, basically it's the process where only one chromosome is trialled at a time.)
Now let's look at the α-chain! α-chain troubleshooting is a little different. Essentially, if a rearrangement is non-productive, then a different VJ pair will join. If that's non-productive, then another VJ pair will join, and so on until either a productive rearrangement is made or the cell runs out of V and/or J segments. Unlike β-chains and BCRs, α-chains do not undergo allelic exclusion. Instead, they express TWO α-chains during development (one from each chromosome). Eventually one is selected.
Aside from these, there are a few more similarities and differences between TCR and BCR development that I need to go over. Firstly, TCRs, unlike BCRs, do not undergo somatic hypermutations. They do, however, have P- and N-nucleotide additions, particularly in CDR3 regions.
TCR and Thymocyte Development
Now it's time to see how this all fits in with the bigger picture of thymocyte development! (For the uninitiated: thymocytes are basically precursor T-cells, so-called because they grow in the thymus.)
Thymocytes first progress through four double-negative stages, so called because they lack CD4 and CD8. They then progress through the double-positive phase, where they have both CD4 and CD8. Eventually, they mature into single-positive cells expressing only CD4 or CD8.
That's not to say that other CD molecules aren't important! In some of the double-negative stages, thymocytes express CD44 and/or CD25. CD44 is a glycoprotein that plays roles in cell adhesions, whereas CD25 is part of the IL-2 receptor. Cells in the DN1 (double-negative 1) stage have only CD44, cells in DN2 have CD44 and CD25, cells in DN3 have low expression of CD44 and regular expression of CD25, and cells in DN4 lack both. Also, from the DN3 stage onwards, cells begin to express a "pre-TCR" which has a β-chain and a pre-Tα-chain (which I guess is kinda like the surrogate light chain in the early BCRs). The pre-TCR allows for the formation of a pre-TCR CD3 complex, which in turn allows for signalling.
So when does the β-chain actually start forming? Well, in the DN2 stage, the DJ rearrangement occurs, and in DN3, the VDJ rearrangement occurs. (Just like BCRs, the VDJ-C rearrangement isn't done in the DNA, but rather as a part of RNA processing.) When the cell enters the double-positive (DP) stage, the VJ rearrangement in the α-chain occurs, and cells begin to express a real α-chain which replaces the pre-α-chain.
I'm not going to go into too much more detail about thymocyte development here, as that's the topic of a later post. Last fun fact for this post is that a receptor called Notch commits new cells to the T-cell lineage. Now get out there and win those trivia games with that new fact!
Understand TCR binding to MHC complex
Understand the structure and formation of the TCR
TCRs (T-cell receptors), unlike BCRs, aren't antibodies. No offence to TCRs, but they're not as exciting as BCRs: rather than the Y-shape of antibodies, TCRs just have two small, straight chains (usually an α-chain and a β-chain), each containing Ig (immunoglobulin) domains. Each chain has a constant region and a variable region. Just like the BCR, the variable region of the TCR is where antigens bind.
Just as a refresher, MHC-I binds to TCRs on CD8 (cytotoxic) T-cells and MHC-II binds to TCRs on CD4 (helper) T-cells. In fact, CD8 and CD4 act as co-receptors that facilitate this: CD8 binds to α2 and α3 on MHC-I, whereas CD4 binds to β1 and β2 on MHC-II. CD4 is a monomer that has four domains in a long chain, whereas CD8 has two short chains, called amazeballs A and amazeballs B. (Just kidding. They're just called α and β.)
Anyway, back to TCRs. As I mentioned earlier, most TCRs have an α-chain and a β-chain, but some have a γ-chain and a δ-chain instead. These γδ TCRs are more common in early foetal development, but later on they are overtaken by the αβ variety. A T-cell can only have one kind of receptor (either αβ or γδ). Both kinds of TCRs develop in the thymus and associate with a co-receptor called CD3, but there are a lot of other major differences: T-cells expressing γδ generally do not have CD4 or CD8, and they don't interact with MHCs. Instead they are a bit more like PRRs in that they bind to ligands that are common across microbes, such as phospholipids and certain intact proteins. They are considered to be innate lymphocytes (probably because of this), but there's still a lot about them that we don't really know.
One last thing about γδ T-cells before I move on: when I said they don't have CD8, I kinda lied. Intraepithelial lymphocytes (iELs), which are γδ T-cells found in the gut, have a different form of CD8. Instead of an α-chain and a β-chain, the CD8s on iELs have two α-chains (and thus these receptors are known as CD8αα+). iELs still aren't considered CD8 T-cells, though, since they don't have the normal kind of CD8.
Now I'm going to talk about the TCR signalling complex! I'm going to talk about it in regards to the αβ T-cells, but I assume it probably works in a similar way in γδ T-cells. The TCR signalling complex consists of the TCR, as well as extracellular CD3 molecules and intracellular ζ (zeta) chains. CD3 molecules are comprised of three different proteins (γ, δ and ε) that can dimerise in different ways (γ/ε or δ/ε). CD3 molecules help out with the assembly, expression and stability of TCRs, whereas ζ-chains help out with the signalling.
Finally, a note on complementarity determining regions of TCRs, specifically αβ TCRs. This is a bit random, but I really didn't know where else to put this. The binding site of the TCR has complementarity determining regions (CDRs), imaginatively named CDR-1, CDR-2 and CDR-3. CDR-1 interacts with both the peptide and the MHC, CDR-2 interacts with the MHC only and CDR-3 interacts with the peptide only.
Understand the organisation of the TCR genes
The organisation of the T-cell receptor genes is somewhat similar to the organisation of the B-cell receptor genes, which I've gone over here.
Organisation of Genes
The α-chain, in some ways, is analogous to the light chain of the B-cell receptor in that it has leader, variable, joining and constant sequences, whereas the β-chain is more like the BCR heavy chain in that it also has diversity sequences. The β-chain genes are a bit unique, however, in that the D, J and C sequences are arranged in two separate "chunks": following the LV sequences, there's a D sequence, some J sequences and a C sequence, and then a second D sequence, more J sequences and a second C sequence.
The γ- and δ-chains have the same regions as the α- and β-chains (aside from the δ-chain lacking leader sequences), but there is less diversity (i.e. fewer variable, diversity and joining sequences) and the genes are arranged a little bit differently. In the γ-chain, which has L, V, J and C sequences, the LV sequences are followed by three joining sequences and a constant sequence, and then two more joining sequences and a constant sequence (like the "chunks" making up the β-chain genes). The δ-chain has the sequences more or less in order- three variable sequences, three diversity sequences, three joining sequences and a constant sequence- but the locus is rounded off by a final variable sequence at the end. Another important thing you need to know is that the δ-chain genes are located between the variable and joining segments of the α-chain locus, so once the VJ rearrangement is done in the α-chain, all of the δ-chain genes become unavailable.
Receptor Editing and Allelic Exclusion
Just like in BCRs, there are ways of ensuring that only one receptor is made, and that the receptor genes are productively arranged.
First, let's look at the β-chain. As I mentioned earlier, the β-chain genes are in two separate "chunks." Essentially, the first "chunk" gets rearranged first. If that's unsuccessful, then the second "chunk" is rearranged, deleting the locus of the first "chunk" in the process. (Presumably, if that's also unsuccessful, the cell dies.) To ensure that only one chain is made overall, β-chains are subject to allelic exclusion, a process I described in my post about B-cell development. (If you don't remember what that is, basically it's the process where only one chromosome is trialled at a time.)
Now let's look at the α-chain! α-chain troubleshooting is a little different. Essentially, if a rearrangement is non-productive, then a different VJ pair will join. If that's non-productive, then another VJ pair will join, and so on until either a productive rearrangement is made or the cell runs out of V and/or J segments. Unlike β-chains and BCRs, α-chains do not undergo allelic exclusion. Instead, they express TWO α-chains during development (one from each chromosome). Eventually one is selected.
Aside from these, there are a few more similarities and differences between TCR and BCR development that I need to go over. Firstly, TCRs, unlike BCRs, do not undergo somatic hypermutations. They do, however, have P- and N-nucleotide additions, particularly in CDR3 regions.
TCR and Thymocyte Development
Now it's time to see how this all fits in with the bigger picture of thymocyte development! (For the uninitiated: thymocytes are basically precursor T-cells, so-called because they grow in the thymus.)
Thymocytes first progress through four double-negative stages, so called because they lack CD4 and CD8. They then progress through the double-positive phase, where they have both CD4 and CD8. Eventually, they mature into single-positive cells expressing only CD4 or CD8.
That's not to say that other CD molecules aren't important! In some of the double-negative stages, thymocytes express CD44 and/or CD25. CD44 is a glycoprotein that plays roles in cell adhesions, whereas CD25 is part of the IL-2 receptor. Cells in the DN1 (double-negative 1) stage have only CD44, cells in DN2 have CD44 and CD25, cells in DN3 have low expression of CD44 and regular expression of CD25, and cells in DN4 lack both. Also, from the DN3 stage onwards, cells begin to express a "pre-TCR" which has a β-chain and a pre-Tα-chain (which I guess is kinda like the surrogate light chain in the early BCRs). The pre-TCR allows for the formation of a pre-TCR CD3 complex, which in turn allows for signalling.
So when does the β-chain actually start forming? Well, in the DN2 stage, the DJ rearrangement occurs, and in DN3, the VDJ rearrangement occurs. (Just like BCRs, the VDJ-C rearrangement isn't done in the DNA, but rather as a part of RNA processing.) When the cell enters the double-positive (DP) stage, the VJ rearrangement in the α-chain occurs, and cells begin to express a real α-chain which replaces the pre-α-chain.
I'm not going to go into too much more detail about thymocyte development here, as that's the topic of a later post. Last fun fact for this post is that a receptor called Notch commits new cells to the T-cell lineage. Now get out there and win those trivia games with that new fact!
Wednesday, November 2, 2016
Reproductive Cancers
Last post on endocrine pathophysiology! This post will cover prostate, cervical, uterine, ovarian and breast cancers. (Yeah, breasts aren't technically a part of the reproductive system, but it affects so many people. Also unfortunately we ran out of time to cover testicular cancer, so guys kinda get neglected a bit >_>)
Prostate Cancer
There are two somewhat related conditions affecting the prostate that you should know: benign prostatic hyperplasia (BPH) and prostate cancer. Benign prostatic hyperplasia is, as the name states, benign. The prostate enlarges from the centre out, forming nodules around the urethra that can block the flow of urine, but these nodules do not progress to cancer. Prostate cancer, on the other hand, is cancer (!). It is the second most common cancer in men (the most common being lung cancer). In advanced stages, it can metastasise to the lymph nodes, liver, lung, bone and adrenal glands.
Symptoms of BPH are mainly related to urinary retention. If untreated, urinary retention can progress to cystitis (inflammation of the bladder), bladder stones and kidney damage. BPH can be treated with medications such as anti-androgen drugs (androgen causes the prostate to grow, so depriving it of androgens causes prostate shrinkage) and α-adrenergic blockers which help to relax the bladder neck. Sometimes surgery may have to be performed, but this is relatively infrequent.
Prostate cancer, despite having similar symptoms to BPH, is obviously a bit nastier, considering that it can metastasise. It's unknown why prostate cancer develops, but age and genetics may have a role. Prostate cancer can be detected by testing for prostate-specific antigen (PSA), though as PSA levels are also elevated in BPH and infection, this needs to be taken in consideration along with a digital rectal exam. To definitively confirm a diagnosis of prostate cancer, a biopsy can be taken, and the cancer can be graded on the Gleason score according to how bad it is.
How can prostate cancer be treated? If it isn't too bad (low Gleason score), just keeping an eye out for further issues might be enough. Otherwise, the prostate can be destroyed by surgery or radiation, including brachytherapy, which is essentially the insertion of radioactive implants into the prostate. GnRH agonists that desensitise GnRH receptors, as well as androgen antagonists, may also be helpful in shrinking the size of the prostate. Sometimes this might be done before surgical removal.
Cervical Cancer
Cervical cancer tends to develop at a relatively young age- around 35 years old for early stage disease (in situ carcinoma). Prior to this early stage, there is dysplasia of the squamous cells at the external os, which can be picked up on a routine Pap smear. Symptoms do not appear until much later. It takes 5-10 years for cervical cancer to become invasive, and even then, it's only at the later stages of invasive cancer that you start to see spotting and watery discharge, and maybe anaemia and weight loss in more severe cases. If detected early, however, five-year survival is almost 100%, which is why pap smears are so important.
Cervical cancer is linked to sexually transmitted infections such as HPV (human papilloma virus), and thus the risk increases the more sexual partners you have. Some strains of HPV can be prevented with anti-vaxers' favourite vaccine *cough.* (The HPV vaccines on the market are Gardasil and Cervarix, but Gardasil's a lot more commonly used as it protects against 4 strains as opposed to Cervarix's 2 strains. I've heard that they're developing a new vaccine against 9 strains of HPV, though.) Although five-year survival rates are pretty damn good, do bear in mind that a positive pap smear can be scary and stressful, and if it develops into cancer, you may have to go through all of the surgery and radiation and all that.
Uterine Cancer
Carcinoma of the uterus tends to develop at an older age: around 55-65 years of age. Unfortunately, there is no screening test for this, so most women with the condition only find out when they get unexpected vaginal bleeding (which is pretty damn unexpected given that most women this age have gone through menopause). If uterine cancer is suspected, it can be confirmed with a biopsy of the endometrium.
In women that have gone through menopause, fat cells still continue to produce oestrogen. There is, however, no opposition to this oestrogen, so the oestrogen continues to stimulate the endometrium. This may lead to hyperplasia (growth of extra cells) and then dysplasia. (You can review this earlier post if you don't understand what the terms mean.) Also bear in mind that postmenopausal women obviously aren't menstruating, so they don't get a chance to get rid of these dysplastic cells.
Treatment of uterine cancer involves the main staples: surgery (hysterectomy in this case) and radiation. Chemotherapy may also be warranted if the cancer has spread to the lymph nodes. If the cancer is confined to the uterus, however, survival rates are pretty good: 90% after five years.
Ovarian Cancer
Ovarian cancer is much rarer, and thank goodness for that because prognosis is so poor (five-year survival of only around 20%). It mainly affects peri- and post-menopausal women. At early stages it is asymptomatic, but later on it can cause bladder and bowel problems.
Unfortunately, ovarian cancer cannot be tested for, but there are some risk factors to keep in mind. A personal or family history of breast, ovarian, endometrial, prostate or colon cancer can increase risk, as can carrying mutations in the BRCA1 or BRCA2 genes (genes that regulate the cell cycle, DNA repair and apoptosis). It seems that risk is also increased by ovulation, as oral contraceptive users have a lower risk of ovarian cancer, but that has still not been determined.
In women that have several risk factors (personal or family history, gene mutations, breast cancer before age 50), a prophylactic oophorectomy (removal of the ovaries) may be performed. Obviously hardly anyone knows if they have a gene mutation or not, and given that the prevalence of mutations is only around 1 in 800 for the general population, people are rarely tested. Ashkenazi Jews may want to consider testing, however, as BRCA1/2 gene mutations are much higher among them: around 1 in 50 carry a mutation.
Treatment for ovarian cancer involves all the usual stuff: surgery, radiation and chemotherapy. Palliative care was also mentioned in the lecture, probably because of the high mortality rate.
Breast Cancer
Breast cancer is pretty common. Chances are, you know someone, or know someone who knows someone, who's had breast cancer. The lifetime risk for most women is 1 in 9, unless they have mutations in the BRCA1/BRCA2 genes, in which case their lifetime risk is a whopping 1 in 2. Women with mutations in these genes are also more likely to develop breast cancer earlier than those without the mutation. Other risk factors for breast cancer include a family history of breast cancer and delayed childbirth. Some women with a very high risk of breast cancer (i.e. strong family history and BRCA mutations) may decide to have a prophylactic mastectomy.
As you are probably aware, mammograms are pretty useful for diagnosing breast cancer. Biopsies can also give a more definitive diagnosis. Treatments involve the standard surgery, radiation and chemotherapy, but if the cancer, like 80% of breast cancers, is oestrogen-receptor positive, then there are other drugs that can help. One of the more commonly-used drugs is Tamoxifen, which is an oestrogen antagonist, but aromatase inhibitors can also help.
And that's it! Good luck on the test this Thursday!
Prostate Cancer
There are two somewhat related conditions affecting the prostate that you should know: benign prostatic hyperplasia (BPH) and prostate cancer. Benign prostatic hyperplasia is, as the name states, benign. The prostate enlarges from the centre out, forming nodules around the urethra that can block the flow of urine, but these nodules do not progress to cancer. Prostate cancer, on the other hand, is cancer (!). It is the second most common cancer in men (the most common being lung cancer). In advanced stages, it can metastasise to the lymph nodes, liver, lung, bone and adrenal glands.
Symptoms of BPH are mainly related to urinary retention. If untreated, urinary retention can progress to cystitis (inflammation of the bladder), bladder stones and kidney damage. BPH can be treated with medications such as anti-androgen drugs (androgen causes the prostate to grow, so depriving it of androgens causes prostate shrinkage) and α-adrenergic blockers which help to relax the bladder neck. Sometimes surgery may have to be performed, but this is relatively infrequent.
Prostate cancer, despite having similar symptoms to BPH, is obviously a bit nastier, considering that it can metastasise. It's unknown why prostate cancer develops, but age and genetics may have a role. Prostate cancer can be detected by testing for prostate-specific antigen (PSA), though as PSA levels are also elevated in BPH and infection, this needs to be taken in consideration along with a digital rectal exam. To definitively confirm a diagnosis of prostate cancer, a biopsy can be taken, and the cancer can be graded on the Gleason score according to how bad it is.
How can prostate cancer be treated? If it isn't too bad (low Gleason score), just keeping an eye out for further issues might be enough. Otherwise, the prostate can be destroyed by surgery or radiation, including brachytherapy, which is essentially the insertion of radioactive implants into the prostate. GnRH agonists that desensitise GnRH receptors, as well as androgen antagonists, may also be helpful in shrinking the size of the prostate. Sometimes this might be done before surgical removal.
Cervical Cancer
Cervical cancer tends to develop at a relatively young age- around 35 years old for early stage disease (in situ carcinoma). Prior to this early stage, there is dysplasia of the squamous cells at the external os, which can be picked up on a routine Pap smear. Symptoms do not appear until much later. It takes 5-10 years for cervical cancer to become invasive, and even then, it's only at the later stages of invasive cancer that you start to see spotting and watery discharge, and maybe anaemia and weight loss in more severe cases. If detected early, however, five-year survival is almost 100%, which is why pap smears are so important.
Cervical cancer is linked to sexually transmitted infections such as HPV (human papilloma virus), and thus the risk increases the more sexual partners you have. Some strains of HPV can be prevented with anti-vaxers' favourite vaccine *cough.* (The HPV vaccines on the market are Gardasil and Cervarix, but Gardasil's a lot more commonly used as it protects against 4 strains as opposed to Cervarix's 2 strains. I've heard that they're developing a new vaccine against 9 strains of HPV, though.) Although five-year survival rates are pretty damn good, do bear in mind that a positive pap smear can be scary and stressful, and if it develops into cancer, you may have to go through all of the surgery and radiation and all that.
Uterine Cancer
Carcinoma of the uterus tends to develop at an older age: around 55-65 years of age. Unfortunately, there is no screening test for this, so most women with the condition only find out when they get unexpected vaginal bleeding (which is pretty damn unexpected given that most women this age have gone through menopause). If uterine cancer is suspected, it can be confirmed with a biopsy of the endometrium.
In women that have gone through menopause, fat cells still continue to produce oestrogen. There is, however, no opposition to this oestrogen, so the oestrogen continues to stimulate the endometrium. This may lead to hyperplasia (growth of extra cells) and then dysplasia. (You can review this earlier post if you don't understand what the terms mean.) Also bear in mind that postmenopausal women obviously aren't menstruating, so they don't get a chance to get rid of these dysplastic cells.
Treatment of uterine cancer involves the main staples: surgery (hysterectomy in this case) and radiation. Chemotherapy may also be warranted if the cancer has spread to the lymph nodes. If the cancer is confined to the uterus, however, survival rates are pretty good: 90% after five years.
Ovarian Cancer
Ovarian cancer is much rarer, and thank goodness for that because prognosis is so poor (five-year survival of only around 20%). It mainly affects peri- and post-menopausal women. At early stages it is asymptomatic, but later on it can cause bladder and bowel problems.
Unfortunately, ovarian cancer cannot be tested for, but there are some risk factors to keep in mind. A personal or family history of breast, ovarian, endometrial, prostate or colon cancer can increase risk, as can carrying mutations in the BRCA1 or BRCA2 genes (genes that regulate the cell cycle, DNA repair and apoptosis). It seems that risk is also increased by ovulation, as oral contraceptive users have a lower risk of ovarian cancer, but that has still not been determined.
In women that have several risk factors (personal or family history, gene mutations, breast cancer before age 50), a prophylactic oophorectomy (removal of the ovaries) may be performed. Obviously hardly anyone knows if they have a gene mutation or not, and given that the prevalence of mutations is only around 1 in 800 for the general population, people are rarely tested. Ashkenazi Jews may want to consider testing, however, as BRCA1/2 gene mutations are much higher among them: around 1 in 50 carry a mutation.
Treatment for ovarian cancer involves all the usual stuff: surgery, radiation and chemotherapy. Palliative care was also mentioned in the lecture, probably because of the high mortality rate.
Breast Cancer
Breast cancer is pretty common. Chances are, you know someone, or know someone who knows someone, who's had breast cancer. The lifetime risk for most women is 1 in 9, unless they have mutations in the BRCA1/BRCA2 genes, in which case their lifetime risk is a whopping 1 in 2. Women with mutations in these genes are also more likely to develop breast cancer earlier than those without the mutation. Other risk factors for breast cancer include a family history of breast cancer and delayed childbirth. Some women with a very high risk of breast cancer (i.e. strong family history and BRCA mutations) may decide to have a prophylactic mastectomy.
As you are probably aware, mammograms are pretty useful for diagnosing breast cancer. Biopsies can also give a more definitive diagnosis. Treatments involve the standard surgery, radiation and chemotherapy, but if the cancer, like 80% of breast cancers, is oestrogen-receptor positive, then there are other drugs that can help. One of the more commonly-used drugs is Tamoxifen, which is an oestrogen antagonist, but aromatase inhibitors can also help.
And that's it! Good luck on the test this Thursday!
Tuesday, November 1, 2016
Infertility
Second last post on endocrine pathophysiology!
Appreciate that the cause of infertility can be male, female or both and that our understanding of male infertility (unlike female infertility) is limited
Infertility, defined as the lack of conception after 1 year of frequent, unprotected intercourse, is actually a relatively common problem, affecting around 10-15% of couples. Around 20% of infertility is due to unknown causes, but of those that are known, around 40% is due to female factors, 40% due to male factors and 20% due to factors from both partners.
To understand infertility, it might first help to understand the workings of the reproductive system. Here are some posts that might help:
Semen analyses are sometimes used to diagnose infertility. Volume and viscosity of the semen, as well as density, motility and morphology of the sperm within, are examined to see if they fall into the normal range or not.
Since we don't know much about male infertility, we don't have many ways to treat it. Aside from encouraging patients to live a healthy lifestyle and crossing our fingers and hoping for the best, there's not really a lot we can do. There are, however, some technologies that we can use, such as intrauterine insemination of concentrated sperm (getting the semen, concentrating it and administering it into the uterus), IVF and intracytoplasmic sperm injection (ICSE- it's basically like IVF except you're taking a single sperm and injecting it straight into the egg).
Know the various causes of secondary amenorrhoea and be able to differentiate between ovulatory and structural causes
Be aware that female fertility declines long before menopause
Amenorrhoea, lack of menstruation, often goes hand in hand with anovulation (lack of ovulation) and hence female infertility. (However, not all amenorrhoea is anovulatory, as you shall soon see.) There are structural causes as well as immunologic ones (sometimes antibodies are formed against sperm or against the growing foetus). As mentioned above, fertility declines with age, especially from around age 35 onwards. This could be due to a variety of factors, such as older oocytes being "suboptimal" (more likely to have chromosome abnormalities, defective spindles, etc.), or simply from an increased likelihood of developing disorders within the reproductive tract.
Amenorrhoea can be divided into primary or secondary amenorrhoea. This division is a bit different from divisions of other endocrine disorders. In this case, primary amenorrhoea means that the patient has never had a menstrual period, whereas secondary amenorrhoea means that they used to have menstrual periods, but then stopped for some reason. Primary amenorrhoea might be caused by genetic disorders such as Turner syndrome (where the patient only has a single X chromosome), or by congenital disorders. Secondary amenorrhoea might be caused by CNS or pituitary tumours such as prolactinomas (prolactin has an inhibitory effect), inhibition of GnRH by stress, excessive exercise or otherwise, or by some kind of obstruction of the outflow tract. When obstruction is the issue, ovulation happens fine- it's just that the uterine lining can't get out because of the obstructions. Important obstructions to know about are leiomyoma (benign tumours of the myometrium) and Ashermann's syndrome (scarring of the uterine lining). Another issue may be blocked fallopian tubes, which usually occurs as a result of pelvic inflammatory disease.
Treatment of secondary amenorrhoea depends on the cause. In the case of leiomyomas and other tumours obstructing menstrual flow, surgical removal of the offending structure is often warranted. In the case of blocked fallopian tubes, surgical reanastomosis (cutting out the blocked bits and rejoining the good bits) may help. Some other medications may also be helpful: bromocriptine stops prolactin from exerting its inhibitory effects, as mentioned earlier, clomiphene can stimulate gonadotropin release by blocking negative feedback via oestrogen, and exogenous gonadotropins can also help. If the patient isn't worried about whether they can conceive or not, an oral contraceptive can be given to help maintain bone health (oestrogen is protective against osteoporosis).
Endometriosis
Endometriosis is another common problem that may affect fertility. Endometriosis is a condition where there is ectopic endometrium- that is, endometrium growing where it shouldn't be. This causes dysmenorrhoea (pain during menses) and dyspareunia (pain during intercourse). This can be treated by removing the stimulus for growth of the endometrium- that is, by preventing ovulation from occurring. This can be done by giving a GnRH agonist (sounds counter-intuitive, but this actually desensitises the GnRH receptor) or by giving an oral contraceptive. This, however, results in infertility. Sometimes the ectopic endometrium may be removed surgically.
Polycystic Ovary Syndrome (PCOS)
In PCOS, many follicles develop, appearing as a "string of pearls" on ultrasounds and other forms of imaging. Hardly any of these follicles develop fully, however, resulting in oligo-ovulation (few ovulations) or no ovulation. LH, FSH and androgen levels may all be elevated, and patients with the condition may develop insulin resistance (acanthosis nigricans). Due to the hyperandrogenism, patients with PCOS often have male-pattern body hair (so chest hair, beards etc.). It's not entirely sure what causes this, but a majority of patients with the syndrome (60%) are obese, so weight may be a factor.
Treatment for PCOS mainly consists of weight loss and a few different medications that may help with the symptoms. Even just a 5% decrease in body weight can help menstrual cycles return to normal. Clomiphene and aromatase inhibitors can stimulate FSH and thus ovulation, metformin can help with the diabetes as well as weight loss and menstrual cyclicity, and exogenous gonadotropins can also help stimulate ovulation. Alternatively oral contraceptives can be given to treat the hirsutism (excess body hair), but obviously this means that the patient will be unable to conceive. Oral contraceptives increase levels of sex-hormone binding protein (SHBG), which binds to androgen and stops it from causing excess hair growth.
Just one more post to go on this topic!
Appreciate that the cause of infertility can be male, female or both and that our understanding of male infertility (unlike female infertility) is limited
Infertility, defined as the lack of conception after 1 year of frequent, unprotected intercourse, is actually a relatively common problem, affecting around 10-15% of couples. Around 20% of infertility is due to unknown causes, but of those that are known, around 40% is due to female factors, 40% due to male factors and 20% due to factors from both partners.
To understand infertility, it might first help to understand the workings of the reproductive system. Here are some posts that might help:
- Endocrinology of Reproduction part 1
- Endocrinology of Reproduction part 2
- Endocrinology of Reproduction part 3
Now onto the pathological stuff! Let's look at male infertility first, even though less is known about that.
There are structural causes for male fertility, as well as some possible environmental ones. Structural causes include a complete lack of the vas deferens, which might happen in some patients with cystic fibrosis. Some patients have varicose veins (varicocoele) in the spermatic cord, which causes pooling of blood and an increase in temperature in that area. (As you should probably know, sperm need to be at a slightly lower temperature in order to develop.) Undescended testes are also a problem.
Possible environmental causes include excessive heat and some chemical toxins, including drugs. Anabolic androgenic steroids can increase negative feedback on the pituitary and hypothalamus, resulting in hypogonadotropic-hypogonadism (i.e. a decline in gonadotropins leading to smaller gonads). Another drug that may cause infertility is an alopaecia (baldness) treatment called finasteride, which inhibits 5α-reductase (an enzyme that converts testosterone into dihydrotestosterone).
Semen analyses are sometimes used to diagnose infertility. Volume and viscosity of the semen, as well as density, motility and morphology of the sperm within, are examined to see if they fall into the normal range or not.
Since we don't know much about male infertility, we don't have many ways to treat it. Aside from encouraging patients to live a healthy lifestyle and crossing our fingers and hoping for the best, there's not really a lot we can do. There are, however, some technologies that we can use, such as intrauterine insemination of concentrated sperm (getting the semen, concentrating it and administering it into the uterus), IVF and intracytoplasmic sperm injection (ICSE- it's basically like IVF except you're taking a single sperm and injecting it straight into the egg).
Know the various causes of secondary amenorrhoea and be able to differentiate between ovulatory and structural causes
Be aware that female fertility declines long before menopause
Amenorrhoea, lack of menstruation, often goes hand in hand with anovulation (lack of ovulation) and hence female infertility. (However, not all amenorrhoea is anovulatory, as you shall soon see.) There are structural causes as well as immunologic ones (sometimes antibodies are formed against sperm or against the growing foetus). As mentioned above, fertility declines with age, especially from around age 35 onwards. This could be due to a variety of factors, such as older oocytes being "suboptimal" (more likely to have chromosome abnormalities, defective spindles, etc.), or simply from an increased likelihood of developing disorders within the reproductive tract.
Amenorrhoea can be divided into primary or secondary amenorrhoea. This division is a bit different from divisions of other endocrine disorders. In this case, primary amenorrhoea means that the patient has never had a menstrual period, whereas secondary amenorrhoea means that they used to have menstrual periods, but then stopped for some reason. Primary amenorrhoea might be caused by genetic disorders such as Turner syndrome (where the patient only has a single X chromosome), or by congenital disorders. Secondary amenorrhoea might be caused by CNS or pituitary tumours such as prolactinomas (prolactin has an inhibitory effect), inhibition of GnRH by stress, excessive exercise or otherwise, or by some kind of obstruction of the outflow tract. When obstruction is the issue, ovulation happens fine- it's just that the uterine lining can't get out because of the obstructions. Important obstructions to know about are leiomyoma (benign tumours of the myometrium) and Ashermann's syndrome (scarring of the uterine lining). Another issue may be blocked fallopian tubes, which usually occurs as a result of pelvic inflammatory disease.
Treatment of secondary amenorrhoea depends on the cause. In the case of leiomyomas and other tumours obstructing menstrual flow, surgical removal of the offending structure is often warranted. In the case of blocked fallopian tubes, surgical reanastomosis (cutting out the blocked bits and rejoining the good bits) may help. Some other medications may also be helpful: bromocriptine stops prolactin from exerting its inhibitory effects, as mentioned earlier, clomiphene can stimulate gonadotropin release by blocking negative feedback via oestrogen, and exogenous gonadotropins can also help. If the patient isn't worried about whether they can conceive or not, an oral contraceptive can be given to help maintain bone health (oestrogen is protective against osteoporosis).
Endometriosis
Endometriosis is another common problem that may affect fertility. Endometriosis is a condition where there is ectopic endometrium- that is, endometrium growing where it shouldn't be. This causes dysmenorrhoea (pain during menses) and dyspareunia (pain during intercourse). This can be treated by removing the stimulus for growth of the endometrium- that is, by preventing ovulation from occurring. This can be done by giving a GnRH agonist (sounds counter-intuitive, but this actually desensitises the GnRH receptor) or by giving an oral contraceptive. This, however, results in infertility. Sometimes the ectopic endometrium may be removed surgically.
Polycystic Ovary Syndrome (PCOS)
In PCOS, many follicles develop, appearing as a "string of pearls" on ultrasounds and other forms of imaging. Hardly any of these follicles develop fully, however, resulting in oligo-ovulation (few ovulations) or no ovulation. LH, FSH and androgen levels may all be elevated, and patients with the condition may develop insulin resistance (acanthosis nigricans). Due to the hyperandrogenism, patients with PCOS often have male-pattern body hair (so chest hair, beards etc.). It's not entirely sure what causes this, but a majority of patients with the syndrome (60%) are obese, so weight may be a factor.
Treatment for PCOS mainly consists of weight loss and a few different medications that may help with the symptoms. Even just a 5% decrease in body weight can help menstrual cycles return to normal. Clomiphene and aromatase inhibitors can stimulate FSH and thus ovulation, metformin can help with the diabetes as well as weight loss and menstrual cyclicity, and exogenous gonadotropins can also help stimulate ovulation. Alternatively oral contraceptives can be given to treat the hirsutism (excess body hair), but obviously this means that the patient will be unable to conceive. Oral contraceptives increase levels of sex-hormone binding protein (SHBG), which binds to androgen and stops it from causing excess hair growth.
Just one more post to go on this topic!
Pituitary - Endocrine Axis Pathology
New lecture, new organ! This time we're focusing on the thyroid, which I mentioned briefly a couple of posts ago.
Recognise the components of the Hypothalamic-Pituitary-Thyroid and -Adrenal Axes
I feel like I've already written about these before, but oh well.
Hypothalamic-Pituitary-Thyroid Axis: The hypothalamus releases TRH (thyrotropin-releasing hormone), which stimulates the pituitary to release TSH (thyroid-stimulating hormone), which stimulates the thyroid gland to release T3 and T4.
Hypothalamic-Pituitary Adrenal Axis: The hypothalamus releases CRH (corticotropin-releasing hormone), which stimulates the pituitary to release ACTH (adrenocorticotropic hormone), which stimulates the adrenal cortex to release cortisol.
Know the clinical signs/symptoms of thyroid and adrenal diseases
Incorporate understanding of endocrine feedback control in differentiating between primary and secondary disease
Hypothyroidism
Hypothyroidism, or a deficiency of thyroid hormone, is relatively common, affecting around 5% of adults. It can be primary (originating from the thyroid gland) or secondary (originating elsewhere) and can be treated by simply replacing the missing hormones with Synthroid.
Some of the main causes of hypothyroidism include autoimmune destruction of the thyroid, as happens in Hashimoto's disease. Thyroiditis (inflammation of the thyroid) initially causes hyperthyroidism, but can lead to hypothyroidism later on. Some hypothyroidism is congenital (i.e. the thyroid gland doesn't develop). Other exogenous factors, such as iodine deficiency or aggressive treatments (surgery and radiation) for other thyroid diseases, may also cause hypothyroidism to develop.
Now for a little bit more on congenital hypothyroidism! One of the main causes of this is an iodine deficiency, so it is more prevalent in iodine-deficient areas. If congenital hypothyroidism is not treated by giving extra thyroxine (T4) and/or iodine, cretinism, a condition characterised by mental retardation and growth restriction, may also develop. This is a bit of a double-whammy, since many iodine-deficient areas are poorer countries that are probably also unable to give these children the support they need. Nowadays neonatal screening, testing for TSH and T4, can help to detect hypothyroidism. (I've mentioned how primary and secondary hypo- and hyperthyroidism can be differentiated by these tests in an earlier post.)
A reduction in thyroid hormones results in reduced metabolism. This results in symptoms such as cold intolerance, slow heart rate, lethargy, decreased appetite and weight gain. Primary hypothyroidism can also result in goitre (enlarged thyroid), which sounds counter-intuitive until you consider negative feedback: a reduction in thyroid hormones means a reduction in negative feedback on TSH, which continues to stimulate the thyroid. TSH is also responsible for growth of the thyroid, so goitre develops.
Hyperthyroidism
Hyperthyroidism is an excess of thyroid hormones. It can be caused by Graves disease, thyroid nodules (adenomas that produce thyroid hormone), through overmedicating hypothyroidism or, more rarely, through adenomas that secrete TSH. Graves Disease is an autoimmune disease that is kind of unique because it stimulates the thyroid rather than destroys it. In Graves Disease, there are antibodies called LATS (long-acting thyroid stimulators) that can stimulate TSH receptors on the thyroid gland, leading to excess secretion of thyroid hormone and goitre.
The symptoms of hyperthyroidism are basically the opposite of those of hypothyroidism, with the exception of goitre (both primary hypothyroidism AND both kinds of hyperthyroidism have goitre). Another common sign is exophthalmos, which is basically a fancy way of saying "bulging eyes." Other symptoms are related to increased metabolism: increased weight loss without loss of appetite, fatigue, muscle weakness, tachycardia, nervousness or irritability, heat intolerance and a higher risk of osteoporosis.
Hyperthyroidism can be helped with some medications. β-blockers can help with some of the symptoms. Anti-thyroid medications can also help by interfering with thyroperoxidase (TPO), which essentially catalyses the formation of thyroid hormone from iodine and tyrosine (I think that's how it works, anyway). If that fails, getting rid of the gland might be required. Radioactive iodine targets the thyroid gland. This usually produces hypothyroidism, but that can be treated with exogenous thyroxine (T4). Surgery can be used too, but it's a last resort, saved more for cases where there's cancer or really bad goitre.
Cushing's Syndrome
Now we're moving onto issues with the adrenal glands! Cushing's syndrome, as mentioned in my post for PHYL2001, is caused by excess glucocorticoids. This might be due to an ACTH-secreting tumour from the pituitary or otherwise (yep, sometimes there might be new growths that can secrete ACTH), glucocorticoid-secreting adrenal tumours, or glucocorticoid therapy. Symptoms of Cushing's Syndrome include central/truncal obesity (basically obesity around the stomach etc.), a "moon face," stria (stretch marks), increased hair growth, osteoporosis, insulin resistance (cortisol is gluconeogenic like glucagon, so it makes too much glucose for the body's insulin stores to handle) and delayed healing and increased infection (due to the immune suppression caused by glucocorticoids). The stress response may also be decreased due to desensitisation to glucocorticoids.
Adrenal Insufficiency
Primary adrenal insufficiency (Addison's Disease) is basically a problem with the adrenal gland, resulting in decreased production of all adrenocortical hormones (i.e. glucocorticoids, mineralocorticoids and androgens). This might be caused by autoimmune disease, tumours or infection. Symptoms include weight loss, loss of appetite, weakness, fatigue, hypotension (due to salt loss caused by excess aldosterone), body hair loss and hypoglycaemia.
Secondary adrenal insufficiency, in contrast, is a deficiency in ACTH secretion. This could be caused by a problem in the pituitary or in the hypothalamus or by suddenly stopping glucocorticoid therapy (you need to taper off to give the pituitary gland more time to restore its supply of ACTH). Since secondary adrenal insufficiency is only a deficiency in ACTH, secretion of aldosterone and androgens are normal.
How can these conditions be definitively diagnosed via labwork? Remember our negative feedback loops and the logic there: low cortisol but high ACTH suggests a primary condition, whereas low cortisol and low ACTH suggest a secondary condition. Interestingly enough though, in the ACTH stimulation test, where the patient is given an injection of ACTH, all patients with adrenal insufficiency do not have an increase in cortisol, regardless of whether their condition is primary or secondary. This is because, in secondary adrenal insufficiency, ACTH has been suppressed for so long that a single injection doesn't really do a lot.
To really differentiate the two, you need to perform the CRH stimulation test, which stimulates release of ACTH. If ACTH increases straight away, then you have primary adrenal insufficiency/Addison's. (Remember, in Addison's, the adrenals are the problem, not anything else.) If there is no change at all, then there is secondary adrenal insufficiency caused by a defect in the pituitary gland. Finally, if there is a change, but it is delayed, then there is secondary adrenal insufficiency caused by a defect in the hypothalamus: the pituitary is perfectly capable of producing ACTH, but it just hasn't received the stimulation to do so in a long time.
Recognise the components of the Hypothalamic-Pituitary-Thyroid and -Adrenal Axes
I feel like I've already written about these before, but oh well.
Hypothalamic-Pituitary-Thyroid Axis: The hypothalamus releases TRH (thyrotropin-releasing hormone), which stimulates the pituitary to release TSH (thyroid-stimulating hormone), which stimulates the thyroid gland to release T3 and T4.
Hypothalamic-Pituitary Adrenal Axis: The hypothalamus releases CRH (corticotropin-releasing hormone), which stimulates the pituitary to release ACTH (adrenocorticotropic hormone), which stimulates the adrenal cortex to release cortisol.
Know the clinical signs/symptoms of thyroid and adrenal diseases
Incorporate understanding of endocrine feedback control in differentiating between primary and secondary disease
Hypothyroidism
Hypothyroidism, or a deficiency of thyroid hormone, is relatively common, affecting around 5% of adults. It can be primary (originating from the thyroid gland) or secondary (originating elsewhere) and can be treated by simply replacing the missing hormones with Synthroid.
Some of the main causes of hypothyroidism include autoimmune destruction of the thyroid, as happens in Hashimoto's disease. Thyroiditis (inflammation of the thyroid) initially causes hyperthyroidism, but can lead to hypothyroidism later on. Some hypothyroidism is congenital (i.e. the thyroid gland doesn't develop). Other exogenous factors, such as iodine deficiency or aggressive treatments (surgery and radiation) for other thyroid diseases, may also cause hypothyroidism to develop.
Now for a little bit more on congenital hypothyroidism! One of the main causes of this is an iodine deficiency, so it is more prevalent in iodine-deficient areas. If congenital hypothyroidism is not treated by giving extra thyroxine (T4) and/or iodine, cretinism, a condition characterised by mental retardation and growth restriction, may also develop. This is a bit of a double-whammy, since many iodine-deficient areas are poorer countries that are probably also unable to give these children the support they need. Nowadays neonatal screening, testing for TSH and T4, can help to detect hypothyroidism. (I've mentioned how primary and secondary hypo- and hyperthyroidism can be differentiated by these tests in an earlier post.)
A reduction in thyroid hormones results in reduced metabolism. This results in symptoms such as cold intolerance, slow heart rate, lethargy, decreased appetite and weight gain. Primary hypothyroidism can also result in goitre (enlarged thyroid), which sounds counter-intuitive until you consider negative feedback: a reduction in thyroid hormones means a reduction in negative feedback on TSH, which continues to stimulate the thyroid. TSH is also responsible for growth of the thyroid, so goitre develops.
Hyperthyroidism
Hyperthyroidism is an excess of thyroid hormones. It can be caused by Graves disease, thyroid nodules (adenomas that produce thyroid hormone), through overmedicating hypothyroidism or, more rarely, through adenomas that secrete TSH. Graves Disease is an autoimmune disease that is kind of unique because it stimulates the thyroid rather than destroys it. In Graves Disease, there are antibodies called LATS (long-acting thyroid stimulators) that can stimulate TSH receptors on the thyroid gland, leading to excess secretion of thyroid hormone and goitre.
The symptoms of hyperthyroidism are basically the opposite of those of hypothyroidism, with the exception of goitre (both primary hypothyroidism AND both kinds of hyperthyroidism have goitre). Another common sign is exophthalmos, which is basically a fancy way of saying "bulging eyes." Other symptoms are related to increased metabolism: increased weight loss without loss of appetite, fatigue, muscle weakness, tachycardia, nervousness or irritability, heat intolerance and a higher risk of osteoporosis.
Hyperthyroidism can be helped with some medications. β-blockers can help with some of the symptoms. Anti-thyroid medications can also help by interfering with thyroperoxidase (TPO), which essentially catalyses the formation of thyroid hormone from iodine and tyrosine (I think that's how it works, anyway). If that fails, getting rid of the gland might be required. Radioactive iodine targets the thyroid gland. This usually produces hypothyroidism, but that can be treated with exogenous thyroxine (T4). Surgery can be used too, but it's a last resort, saved more for cases where there's cancer or really bad goitre.
Cushing's Syndrome
Now we're moving onto issues with the adrenal glands! Cushing's syndrome, as mentioned in my post for PHYL2001, is caused by excess glucocorticoids. This might be due to an ACTH-secreting tumour from the pituitary or otherwise (yep, sometimes there might be new growths that can secrete ACTH), glucocorticoid-secreting adrenal tumours, or glucocorticoid therapy. Symptoms of Cushing's Syndrome include central/truncal obesity (basically obesity around the stomach etc.), a "moon face," stria (stretch marks), increased hair growth, osteoporosis, insulin resistance (cortisol is gluconeogenic like glucagon, so it makes too much glucose for the body's insulin stores to handle) and delayed healing and increased infection (due to the immune suppression caused by glucocorticoids). The stress response may also be decreased due to desensitisation to glucocorticoids.
Adrenal Insufficiency
Primary adrenal insufficiency (Addison's Disease) is basically a problem with the adrenal gland, resulting in decreased production of all adrenocortical hormones (i.e. glucocorticoids, mineralocorticoids and androgens). This might be caused by autoimmune disease, tumours or infection. Symptoms include weight loss, loss of appetite, weakness, fatigue, hypotension (due to salt loss caused by excess aldosterone), body hair loss and hypoglycaemia.
Secondary adrenal insufficiency, in contrast, is a deficiency in ACTH secretion. This could be caused by a problem in the pituitary or in the hypothalamus or by suddenly stopping glucocorticoid therapy (you need to taper off to give the pituitary gland more time to restore its supply of ACTH). Since secondary adrenal insufficiency is only a deficiency in ACTH, secretion of aldosterone and androgens are normal.
How can these conditions be definitively diagnosed via labwork? Remember our negative feedback loops and the logic there: low cortisol but high ACTH suggests a primary condition, whereas low cortisol and low ACTH suggest a secondary condition. Interestingly enough though, in the ACTH stimulation test, where the patient is given an injection of ACTH, all patients with adrenal insufficiency do not have an increase in cortisol, regardless of whether their condition is primary or secondary. This is because, in secondary adrenal insufficiency, ACTH has been suppressed for so long that a single injection doesn't really do a lot.
To really differentiate the two, you need to perform the CRH stimulation test, which stimulates release of ACTH. If ACTH increases straight away, then you have primary adrenal insufficiency/Addison's. (Remember, in Addison's, the adrenals are the problem, not anything else.) If there is no change at all, then there is secondary adrenal insufficiency caused by a defect in the pituitary gland. Finally, if there is a change, but it is delayed, then there is secondary adrenal insufficiency caused by a defect in the hypothalamus: the pituitary is perfectly capable of producing ACTH, but it just hasn't received the stimulation to do so in a long time.
Diabetes Mellitus
Now onto another disease of the endocrine system: Diabetes!
Please note: Just like everything else on this site, this post should not be taken as medical advice. If you actually have diabetes, or suspect you might, listen to your doctor first and foremost, not a random second-year undergrad on the Internet.
Understand differences between type 1 and type 2 diabetes mellitus
Diabetes, as you probably know, is a condition in which not enough insulin is produced. That isn't to say that no insulin is produced, just that not enough insulin is produced.
So what is insulin exactly? Insulin, produced by the β-cells of the pancreas, is released when glucose levels rise (usually following a meal). It increases glycolysis (glucose oxidation), glycogenesis (synthesis of glycogen from glucose) and lipogenesis (synthesis of fatty acids from glucose), as well as active uptake of glucose by cells other than liver cells. Insulin also increases glucose uptake in the liver, but in a roundabout fashion: glycogenesis decreases the concentration of glucose inside liver cells, so glucose can enter by going down a concentration gradient. All of these processes work to decrease plasma glucose so that the β-cells cease to be activated.
There is an opposing hormone called glucagon, which is produced by the α-cells of the pancreas. Glucagon stimulates glycogenolysis (breakdown of glycogen into glucose), gluconeogenesis (formation of glucose from other sources, such as amino acids and lipids) and ketogenesis (breakdown of fatty acids into ketones). Glucagon, however, is usually only produced when there is a substantial drop in blood glucose levels, such as after fasting for a while.
So anyway, back to diabetes. As I said, it's a condition in which inadequate insulin is produced. In Type 1 diabetes, β-cells are destroyed by autoimmune processes, and thus little or no insulin is produced by cells of the body. It is sometimes known as "juvenile onset diabetes" as most patients with the condition develop it early on in life. In type 2 diabetes, patients have normal or elevated levels of insulin, but the cells are insensitive to it for some reason. Most patients with type 2 diabetes develop it in adulthood, but it can also occur in children. Both types may have underlying genetic components.
So what's so bad about not having enough insulin? Well, without insulin, blood glucose levels are higher than normal. This causes more glucose to be secreted into the urine. As water follows by osmosis, more urine is produced (polyuria). To make up for the water deficit, diabetic patients often have to drink a lot (polydipsia). Fun fact: diabetes mellitus is Greek for "sweet flow," referring to the sweet taste of urine. (Yup, before we had better tools, doctors actually had to taste their patients' urine to test for diabetes. Good thing we've moved beyond that!) Patients may also be hungry (polyphasia) as less glucose is entering their cells.
Type 1 and Type 2 diabetes have different treatments. In Type 1, since the symptoms result from a complete lack of insulin, the solution is to provide exogenous insulin. As I'm sure you're aware, many patients give themselves insulin via subcutaneous injection, but there are also continuous infusion pumps as well. Glucose levels also have to be monitored so that they know how much insulin to take etc. Unfortunately there is no known cure for type 1 diabetes.
Type 2 diabetes, on the other hand, seems to be more of a result of lifestyle factors such as poor diet and exercise (though the mechanism is not yet well understood), and thus these areas are targeted in treatment. A diet for a type 2 diabetic may include a lot of complex carbohydrates, fibre and protein, in order to reduce the demand for insulin. Exercise also increases uptake of glucose by skeletal muscles so that there's less in the circulation.
Oral hypoglycaemic drugs, which reduce glucose levels, may also help type 2 diabetics. These include sulfonylureas, which stimulate the β-cells of the pancreas to release insulin; biguanides, which increase sensitivity to insulin and reduce glucose production and absorption; and α-glucosidase inhibitors, which reduce glucose absorption by inhibiting digestion of disaccharides to monosaccharides.
Bariatric surgery can also help some type 2 diabetics, partly because it helps in losing weight, and even a 5% weight loss can help to normalise glucose levels. Sometimes, diabetes can resolve following bariatric surgery even before any weight loss occurs!
Understand how to differentiate between insulin shock and ketoacidosis in the unconscious diabetic
Insulin shock and ketoacidosis are two acute complications of diabetes. Insulin shock is caused by too much insulin, whereas ketoacidosis is caused by too little insulin.
Insulin shock is caused by too much insulin for the situation. For example, a type 1 diabetic may take insulin and then not eat, or exercise excessively, or throw up. This results in too much insulin for the amount of glucose actually circulating in the blood, and in turn results in lowered blood glucose levels within only a few hours. This depresses the central nervous system (CNS) as neurons need glucose to function, resulting in symptoms such as inability to concentrate, slurred speech, lack of coordination and staggering- all of which may be mistaken for alcohol intoxication. In order to try and compensate, the sympathetic nervous system (SNS) is activated to suppress insulin in an attempt to restore glucose levels, but this may not be sufficient. SNS activation results in other lovely symptoms like sweating, tachycardia (elevated heart rate), pallor (pale skin due to vasoconstriction), tremors and anxiety.
So how can insulin shock be treated? Treatment is relatively straightforward, and mainly consists of raising blood glucose levels. If the patient is conscious, they can eat or drink something sugary, like fruit juice or sugar. If the patient is unconscious they should not be given anything by mouth, but they can be given glucose intravenously.
Diabetic ketoacidosis has the opposite cause: inadequate insulin over the course of several days. Aside from forgetting to take insulin, this complication may develop due to infection, stress or binging on food or alcohol. In contrast to insulin shock, diabetic ketoacidosis is characterised by hyperglycaemia rather than hypoglycaemia. Also, since the glucose isn't getting into the cells, lipids may be broken down to provide energy, resulting in the formation of acidic ketones (hence "ketoacdosis").
Ketoacidosis has some of the symptoms of hyperglycaemia experienced by untreated diabetics: lots of sugary urine is formed, which leads to dehydration, which in turn leads to thirst, warm dry skin, low blood pressure and also oligouria (reduced urine production). There are also symptoms relating to acidosis, such as rapid respirations (gotta try and blow off that CO2), fruity breath (the ketones have a fruity smell) and lethargy. Finally there are symptoms related to electrolyte imbalance, such as abdominal cramping, vomiting and lethargy.
Since ketoacidosis is caused by a lack of insulin, the treatment here is to administer insulin. The other symptoms should also be taken care of: the patient should be rehydrated, have their electrolytes replaced and acidosis treated with bicarbonate.
Now how do you tell the difference? That's pretty important- you don't want to be giving glucose to someone who has too much glucose or insulin to someone who has too much insulin. One giveaway sign is fruity breath, as this is only present in ketoacidosis. Ketoacidosis also has several signs of dehydration, which aren't necessarily shared by patients with insulin shock. I am a bit shaky on this one so I don't want to say any more- even though I've explicitly stated that this post is not medical advice, I'd hate it if I said the wrong thing and someone tried to force their friend suffering from ketoacidosis to drink a shitload of orange juice.
Appreciate the causes and clinical significance of chronic complications
Aside from acute complications, diabetes also has an array of chronic complications, which are thought to be the result in metabolism changes due to inadequate insulin. Type 1 diabetics are more likely to experience these as they obviously spend more time living with the disease. Diabetics are at greater risk of heart disease, stroke, blindness, neural impairment, kidney disease, non-traumatic amputations and pregnancy complications. Not a great list.
As our cardiovascular lecturer stated, "diabetes is one of the enemies of the blood vessels." He wasn't kidding. Macrovascular (large vessels) complications include increased risk of heart attack and stroke, as well as poor circulation to the extremities (hands and feet). This results in poor healing and a greater likelihood of infection, which is why so many non-traumatic amputations are in diabetic patients (my grandmother was unfortunately one of them).
Aside from the large blood vessels, diabetes can also affect the smaller vessels. Capillaries supplying the retina can become thick and hard, which make them more likely to rupture, resulting in blindness. Sorbitol can also accumulate in the lens, resulting in cataracts. Vessels supplying the kidneys can likewise become damaged: the glomerular basement membrane can thicken, leading to increased permeability and an increased risk of kidney failure.
Neural complications (neuropathy) are a little bit more of a mystery. Symptoms experienced here are numbness and tingling, if peripheral nerves are affected, or incontinence and erectile dysfunction, if autonomic nerves are affected. The cause of diabetic neuropathy is a little more uncertain and may related to vascular problems, autoimmune problems, demyelination or something else.
Please note: Just like everything else on this site, this post should not be taken as medical advice. If you actually have diabetes, or suspect you might, listen to your doctor first and foremost, not a random second-year undergrad on the Internet.
Understand differences between type 1 and type 2 diabetes mellitus
Diabetes, as you probably know, is a condition in which not enough insulin is produced. That isn't to say that no insulin is produced, just that not enough insulin is produced.
So what is insulin exactly? Insulin, produced by the β-cells of the pancreas, is released when glucose levels rise (usually following a meal). It increases glycolysis (glucose oxidation), glycogenesis (synthesis of glycogen from glucose) and lipogenesis (synthesis of fatty acids from glucose), as well as active uptake of glucose by cells other than liver cells. Insulin also increases glucose uptake in the liver, but in a roundabout fashion: glycogenesis decreases the concentration of glucose inside liver cells, so glucose can enter by going down a concentration gradient. All of these processes work to decrease plasma glucose so that the β-cells cease to be activated.
There is an opposing hormone called glucagon, which is produced by the α-cells of the pancreas. Glucagon stimulates glycogenolysis (breakdown of glycogen into glucose), gluconeogenesis (formation of glucose from other sources, such as amino acids and lipids) and ketogenesis (breakdown of fatty acids into ketones). Glucagon, however, is usually only produced when there is a substantial drop in blood glucose levels, such as after fasting for a while.
So anyway, back to diabetes. As I said, it's a condition in which inadequate insulin is produced. In Type 1 diabetes, β-cells are destroyed by autoimmune processes, and thus little or no insulin is produced by cells of the body. It is sometimes known as "juvenile onset diabetes" as most patients with the condition develop it early on in life. In type 2 diabetes, patients have normal or elevated levels of insulin, but the cells are insensitive to it for some reason. Most patients with type 2 diabetes develop it in adulthood, but it can also occur in children. Both types may have underlying genetic components.
So what's so bad about not having enough insulin? Well, without insulin, blood glucose levels are higher than normal. This causes more glucose to be secreted into the urine. As water follows by osmosis, more urine is produced (polyuria). To make up for the water deficit, diabetic patients often have to drink a lot (polydipsia). Fun fact: diabetes mellitus is Greek for "sweet flow," referring to the sweet taste of urine. (Yup, before we had better tools, doctors actually had to taste their patients' urine to test for diabetes. Good thing we've moved beyond that!) Patients may also be hungry (polyphasia) as less glucose is entering their cells.
Type 1 and Type 2 diabetes have different treatments. In Type 1, since the symptoms result from a complete lack of insulin, the solution is to provide exogenous insulin. As I'm sure you're aware, many patients give themselves insulin via subcutaneous injection, but there are also continuous infusion pumps as well. Glucose levels also have to be monitored so that they know how much insulin to take etc. Unfortunately there is no known cure for type 1 diabetes.
Type 2 diabetes, on the other hand, seems to be more of a result of lifestyle factors such as poor diet and exercise (though the mechanism is not yet well understood), and thus these areas are targeted in treatment. A diet for a type 2 diabetic may include a lot of complex carbohydrates, fibre and protein, in order to reduce the demand for insulin. Exercise also increases uptake of glucose by skeletal muscles so that there's less in the circulation.
Oral hypoglycaemic drugs, which reduce glucose levels, may also help type 2 diabetics. These include sulfonylureas, which stimulate the β-cells of the pancreas to release insulin; biguanides, which increase sensitivity to insulin and reduce glucose production and absorption; and α-glucosidase inhibitors, which reduce glucose absorption by inhibiting digestion of disaccharides to monosaccharides.
Bariatric surgery can also help some type 2 diabetics, partly because it helps in losing weight, and even a 5% weight loss can help to normalise glucose levels. Sometimes, diabetes can resolve following bariatric surgery even before any weight loss occurs!
Understand how to differentiate between insulin shock and ketoacidosis in the unconscious diabetic
Insulin shock and ketoacidosis are two acute complications of diabetes. Insulin shock is caused by too much insulin, whereas ketoacidosis is caused by too little insulin.
Insulin shock is caused by too much insulin for the situation. For example, a type 1 diabetic may take insulin and then not eat, or exercise excessively, or throw up. This results in too much insulin for the amount of glucose actually circulating in the blood, and in turn results in lowered blood glucose levels within only a few hours. This depresses the central nervous system (CNS) as neurons need glucose to function, resulting in symptoms such as inability to concentrate, slurred speech, lack of coordination and staggering- all of which may be mistaken for alcohol intoxication. In order to try and compensate, the sympathetic nervous system (SNS) is activated to suppress insulin in an attempt to restore glucose levels, but this may not be sufficient. SNS activation results in other lovely symptoms like sweating, tachycardia (elevated heart rate), pallor (pale skin due to vasoconstriction), tremors and anxiety.
So how can insulin shock be treated? Treatment is relatively straightforward, and mainly consists of raising blood glucose levels. If the patient is conscious, they can eat or drink something sugary, like fruit juice or sugar. If the patient is unconscious they should not be given anything by mouth, but they can be given glucose intravenously.
Diabetic ketoacidosis has the opposite cause: inadequate insulin over the course of several days. Aside from forgetting to take insulin, this complication may develop due to infection, stress or binging on food or alcohol. In contrast to insulin shock, diabetic ketoacidosis is characterised by hyperglycaemia rather than hypoglycaemia. Also, since the glucose isn't getting into the cells, lipids may be broken down to provide energy, resulting in the formation of acidic ketones (hence "ketoacdosis").
Ketoacidosis has some of the symptoms of hyperglycaemia experienced by untreated diabetics: lots of sugary urine is formed, which leads to dehydration, which in turn leads to thirst, warm dry skin, low blood pressure and also oligouria (reduced urine production). There are also symptoms relating to acidosis, such as rapid respirations (gotta try and blow off that CO2), fruity breath (the ketones have a fruity smell) and lethargy. Finally there are symptoms related to electrolyte imbalance, such as abdominal cramping, vomiting and lethargy.
Since ketoacidosis is caused by a lack of insulin, the treatment here is to administer insulin. The other symptoms should also be taken care of: the patient should be rehydrated, have their electrolytes replaced and acidosis treated with bicarbonate.
Now how do you tell the difference? That's pretty important- you don't want to be giving glucose to someone who has too much glucose or insulin to someone who has too much insulin. One giveaway sign is fruity breath, as this is only present in ketoacidosis. Ketoacidosis also has several signs of dehydration, which aren't necessarily shared by patients with insulin shock. I am a bit shaky on this one so I don't want to say any more- even though I've explicitly stated that this post is not medical advice, I'd hate it if I said the wrong thing and someone tried to force their friend suffering from ketoacidosis to drink a shitload of orange juice.
Appreciate the causes and clinical significance of chronic complications
Aside from acute complications, diabetes also has an array of chronic complications, which are thought to be the result in metabolism changes due to inadequate insulin. Type 1 diabetics are more likely to experience these as they obviously spend more time living with the disease. Diabetics are at greater risk of heart disease, stroke, blindness, neural impairment, kidney disease, non-traumatic amputations and pregnancy complications. Not a great list.
As our cardiovascular lecturer stated, "diabetes is one of the enemies of the blood vessels." He wasn't kidding. Macrovascular (large vessels) complications include increased risk of heart attack and stroke, as well as poor circulation to the extremities (hands and feet). This results in poor healing and a greater likelihood of infection, which is why so many non-traumatic amputations are in diabetic patients (my grandmother was unfortunately one of them).
Aside from the large blood vessels, diabetes can also affect the smaller vessels. Capillaries supplying the retina can become thick and hard, which make them more likely to rupture, resulting in blindness. Sorbitol can also accumulate in the lens, resulting in cataracts. Vessels supplying the kidneys can likewise become damaged: the glomerular basement membrane can thicken, leading to increased permeability and an increased risk of kidney failure.
Neural complications (neuropathy) are a little bit more of a mystery. Symptoms experienced here are numbness and tingling, if peripheral nerves are affected, or incontinence and erectile dysfunction, if autonomic nerves are affected. The cause of diabetic neuropathy is a little more uncertain and may related to vascular problems, autoimmune problems, demyelination or something else.
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