Direct Bilirubin - Health Encyclopedia - University of
Direct Bilirubin - Health Encyclopedia - University of
What causes high conjugated bilirubin? - TreeHozz.com
conjugated bilirubin - General Practice Notebook
Conjugated bilirubin: a better indicator of impaired
Conjugated & unconjugated bilirubin, causes & treatment of
Newborn Direct or Conjugated Bilirubin Measurements As a
Direct Bilirubin - Family Practice Notebook
Direktes Bilirubin - DocCheck Flexikon
Difference Between Conjugated and Unconjugated Bilirubin
Lab Test: Bilirubin, Conjugated, Direct Level (Blood)
conjugated bilirubin direct
conjugated bilirubin direct - win
I've completely lost my appetite
Hello everyone. My information : -Age : 22 -Gender: Male -Height: 5'4 (165cm) -Weight: 132lbs (60kg) -Race: Caucasian I don't drink alcohol or smoke at all. So here's my story. Since I was a child I always had appetite problems, almost couldn't feel hunger at all. When I eat a small meal I always get full easily and feel nausea. I'm really underweight if you can notice from my info, couldn't gain weight at all. Recently I went to a gastroenterologist to talk about all the symptoms I'm having which are : -Early satiety -Permanent loss of appetite -Very small stomach capacity -Nausea -Can't feel hungry -Acid reflux -Bloating -Very slow digestion -Sensitive gag reflex -Shortness of breath -Very slow emptying of the stomach -Difficult to breathe -Impossible to gain weight -Permanent chest pain -Frequent burping -Regurgitation of food -Difficulty swallowing -Feeling of vomiting after eating -Unintentional weight loss After talking to my doctor, he ordered for me to make a full blood test. After the results came in, they showed I have a really serious problem in my liver. These were the results for my liver: -Gamma G.T. was 86 U/L but normal range is (<55) -Total bilirubin was 13.2 mg/L ( 3.0-12.0) -Free bilirubin(indirect) was 10.6 mg/L (<10.0) -Conjugated bilirubin (direct) was 2.6 mg/L (<2.0) I really didn't expect to have a liver problem because I don't drink alcohol at all. However, I have been taking antithyroid medication for 3 months to cure my hyperthyroidism and also have been taking cyproheptadine for 1 year to boost my appetite. My most probable answer is that these meds messed up my liver because I don't see other possible answers. The only problem is, before taking these meds I already had the permanent loss of appetite and all the symptoms listed above. My doctor also diagnosed me with a bloating problem in my stomach but that's not enough to cause all of the symptoms. Also, this is the first time I do a specific blood test for the liver. I'm really depressed right now to a point where I can't eat almost nothing. I'm already scrawny with skin and bones and feel miserable. Everyday I feel sick. This week I have another appointment with the doctor to show him the results. I hope he gives me a treatment for my liver. What do you think of these symptoms, do you think a damaged liver can cause a permanent loss of appetite?
Why is the conjugated/direct bilirubin raised a little in a purely unconjugated icterus (i.e. hemolysis)?
I was talking about this with a resident today. The direct bilirubin is often raised by a small, clinically insignificant, amount (but enough to exceed the reference range) in hemolysis, jaundice of the newborn etc. We were discussing the pathofysiological mechanisms behind this phenomenon. At first, I thought it was simple: "More unconjugated bilirubin means the liver has a larger 'pool' of bilirubin it can conjugate, and conjugated bilirubin will rise as a bit as well". But a quick brush-up of bilirubin metabolism reminded me of the fact that conjugated bilirubin immediately gets excreted in the bile, and is not present in the blood in normal circumstances (modern testing has shown that there's virtually no conjugated bilirubin in the blood in normal circumstances. Any direct bilirubin under normal circumstances is actually a false positive for conjugated bilirubin). Does the raised unconjugated bilirubin create a kind of 'overflow' that forces some conjugated bilirubin back into the blood? I couldn't find any documentation on that. Can anyone point me to the correct mechanism? Or is it a measuring error? I've read that the older staining methods for direct/indirect bilirubin meant that direct bilirubin would get overestimated (because some unconjugated bilirubin will participate in the 'direct' reaction). Is this still a "problem" with more modern tests?
[Discussion] Hepatic Metabolism of Oral AAS, Hepatotoxicity, and Liver Support
I know this is a long write up, the first half is biochemistry and what happens on a cellular level. The second half is more pertaining to the average AAS user, including a deeper dive into liver functioning tests and liver support. I highly recommend at least reading the second half, especially the Liver Support section. Hepatotoxicity is a word that is frequently thrown around, everyone’s heard it, everyone thinks they know what it is, but once you ask something beyond surface level, you get a whole lot of conflicting answers. Let’s dive into it. Overview/Background/General Information/What the fuck actually happens? Drug Metabolism: The human body identifies almost all drugs as foreign substances and subjects them to various chemical processes to make them suitable for elimination. Drug metabolism is typically split into two phases: Phase 1 (oxidation via Cytochrome P450, reduction, and hydrolysis) tends to increase water solubility of the drug and can generate metabolites. Phase 2 further increases water solubility of the drug, inactivating metabolites, thus preparing it for excretion.
Aside: There has been a lot of questions regarding using high dose psoralens (from grapefruit juice/extract) to inhibit the activity of Cyp3A4 (and the Cyp450 family in general) or consuming large quantities of chargrilled meat to induce the activity Cyp450. DO NOT purposely do this in an attempt to increase the bioavailability of oral steroids. The Cyp450 family is incredibly important enzyme family that is involved in the metabolism (both activation and degradation depending) of statins, oral contraceptives, acetaminophen, anti-depressants, beta-blockers, antiarrhythmic agents, and many, many more. This can cause SEVERE adverse effects.
Example: Acetaminophen (Tylenol) is often seen as hepatotoxic, it is not. One of the metabolites, NAPQI, is. Under normal conditions, NAPQI is produced in incredibly minor amounts. Alcohol induces Cyp450 enzyme family, which increases the breakdown of Tylenol into NAPQI, causing intensive acute liver damage which can often be fatal in high doses. In short, don’t nurse your hangover with Tylenol, use Advil instead… or better of just don’t drink alcohol.
17α-Alkylated Anabolic Steroids. These AAS contain a methyl or ethyl group on the C17α position, allowing for oral activation. This modification allows the drug to survive hepatic metabolism, limiting the amount of steroid that is broken down, allowing for more drug to reach the bloodstream. Without this modification, the drug is completely broken down by the liver, never reaching systemic circulation. This initial process is called First Pass Metabolism. First pass metabolism: After a drug is swallowed, it is absorbed by the digestive system and enters the hepatic portal system. It is carried through the portal vein into the liver before it reaches the rest of the body. The liver metabolizes many drugs, sometimes to such an extent that only a small amount of active drug emerges from the liver to the rest of the circulatory system. This first pass through the liver may greatly reduce the bioavailability of the drug. Some oral steroids have a very low bioavailability due to first pass metabolism, thus injectable versions may be used to prevent the initial breakdown, effectively increase bioavailability and reducing liver stress.
Aside: There have been questions regarding sublingual administration of oral AAS in order to bypass first pass metabolism. In short, very few drugs can be properly absorbed sublingually, Nitroglycerin is a prime example. AAS, although can be manufactured for sublingual absorption it requires a specific method of delivery (sublingual tablets, strips, or sprays for example), which are difficult to obtain and manufacture; it’s not as simple as placing some powder under your tongue. Other drawbacks exist of sublingual administration such as tooth decay and difficulty in dose management.
Anavar: The exception to the rule: The oral bioavailability of oxandrolone is 97%. The drug is metabolized primarily by the kidneys and to a lesser extent by the liver. Oxandrolone is the only AAS that is not primarily or extensively metabolized by the liver, and this is thought to be related to its diminished hepatotoxicity relative to other AAS. For this reason, there is no reason to ever use injectable anavar (unless poking yourself that often is your kink, no judgement).
[aside: not all drugs are orally active, in fact the majority are inactive. For example, codeine (inactive) will be converted into the active form, Morphine, within the liver via Cyp450 enzymes]
In the case of oral AAS, hepatic metabolism can convert an active drug into its inactive form; C17α methylation prevents this. Why is this modification known to be hepatotoxic? The primary enzyme that normally breaks down hormonal steroids (such as endogenous DHEA, testosterone, estradiol, etc) is 17β-Hydroxysteroid dehydrogenase, 17β-HSD, (and to a minor extent the Cyp450 family) which can no longer break down the methylated drug, thus the liver finds an alternative route for metabolism. The actual specific process is still relatively unknown, but involves a variety of oxidation reactions, inducing an increase of free oxygen radicals within the hepatocytes (liver cells), causing cell death due to oxidative stress. There is another hypothesis which involves the presence of androgen receptors within the liver. The C17α methylated oral steroid, that is no longer properly broken down, will bind to these receptors, causing a drastic increase of androgenic activity within the liver, leading to hepatoxicity. In my opinion, it is a mixture of both. Many studies show a direct correlation between the androgenic effect of the oral steroid and the amount of hepatoxicity. The exact link between the two is yet to be determined. In general, the greater the affinity of C17α methylated oral steroid for the androgen receptor, the more hepatoxicity occurs.
Hepatotoxicity is an overlying term: the specifics related to AAS use are Cholestasis (blockage of biliary flow), Steatosis (accumulation of fatty lipids within the liver), Zonal Necrosis (hepatocyte death within a specific zone of the liver), and Peliosis Hepatitis (vascular lesions leading to liver enlargement).
Aside: Steatosis (fatty liver) has been an observed adverse effect of Nolvadex and Raloxifene
Cholestasis is a condition where bile cannot flow from the liver to the duodenum. It is the most common condition resulting from oral AAS use. In short, bile is continuously produced but cannot leave the liver, causing build up, backflow, and eventually hepatocyte death. Differential symptoms of cholestasis include but are not limited to pruritus (itchiness), jaundice (yellowing of the skin and whites of the eyes), pale stool, and dark urine. Liver Functioning Tests: What do they mean and why are they relevant? AST: Aspartate Transaminase: This alone is not a good indication of liver damage. AST is found in abundance within both cardiac and skeletal muscle. An elevated AST value can be caused by something as minor as weightlifting. ALT: Alanine Transaminase: ALT is found specifically within the liver and is released into the plasma when significant liver stress, including hepatocyte death, occurs. An elevated value is of concern.
Aside: general rule of thumb (not always true) if both elevated are elevated and if AST>ALT in a ratio of 2:1, suspect alcohol/drug induced damage. If both values are elevated and if ALT>AST in a ratio of 2:1, suspect viral hepatitis.
ALP: Alkaline Phosphatase: ALP is found within the hepatobiliary ducts. An elevated value is commonly indicative of obstruction and bile buildup, signifying cholestasis. GGT: Gamma-glutamyl Transferase: GGT is an enzyme that is found in many organs throughout the body, with the highest concentrations found in the liver. GGT is elevated in the blood in most diseases that cause damage to the liver or bile ducts. 5’-nucleotidase: The concentration of 5’-nucleotidase protein in the blood is often used as a liver function test in individuals that show signs of liver problems. ALP can be elevated due to both skeletal disorders and hepatic disorders. 5’-nucleosidase is elevated ONLY with hepatic stress, not skeletal, thus allowing for differentiation.
Putting it all together: Cholestasis can be suspected when there is an elevation of both 5'-nucleotidase and ALP enzymes. Normally GGT and ALP are anchored to membranes of hepatocytes and are released in small amounts in hepatocellular damage. In cholestasis, synthesis of these enzymes is induced, and they are made soluble. GGT is elevated because it leaks out from the bile duct cells due to pressure from inside bile ducts. As hepatocyte damage continues, ALT, AST, and unconjugated bilirubin will begin to rise. In short: Initial liver stress causes 5’-nucleiotidase and ALP to rise, shortly after GGT rises, then finally AST and ALT rise. Thus, with only AST and ALT values, it is difficult to determine the cause and extent of hepatic damage. Liver Support: NAC/TUDCA/Liv52 NAC: N-Acetyl Cystein NAC is a prodrug of L-cysteine, a precursor of the biological antioxidant glutathione which is able to reduce free radicals within the body. Free radicals, which as discussed above, are associated with causing extensive hepatocyte damage due to the oxidative breakdown of C17α methylated AAS. In addition to its antioxidant action, NAC acts as a vasodilator by facilitating the production and action of nitric oxide. This property is an important mechanism of action in the prophylaxis of contrast-induced nephropathy and the potentiation of nitrate-induced vasodilation.
Aside: NAC has been constantly used as an adjunct to multiple neurological disorders including Parkinson’s, Huntington’s, Multiple Sclerosis, Cerebral Ischemia, Alzheimer’s and MANY more due to the potent free radical trapping effect which prevent mitochondrial dysfunction.
Multiple studies have constantly showed NAC decreasing liver functioning tests and improving liver function and mitigating cholestasis. NAC had the ability to vastly improve markers of kidney function and was actually able to even double the rate of sodium excretion, indicating that NAC is may be useful in preventing water retention. In short, NAC has a vast number of benefits, including hepatoprotective (liver), nephroprotective (kidney), and neuroprotective (neural), and anti-inflammatory effects that have been constantly demonstrated thru literature. Moreover, NAC can and should be used for year-round support since the adverse effects are incredibly mild. There is absolutely NO reason to not be taking NAC.
TUDCA: Tauroursodeoxycholic acid TUDCA is a bile acid taurine conjugate form of UDCA. As discussed above, during cholestasis, bile builds up, creating backflow and inducing hepatocyte death thru apoptosis. Apoptosis, or programmed cell death, is largely influenced by the mitochondria. If the mitochondria are distressed, they release the molecule cytochrome C. Cytochrome C initiates enzymes called caspases to propagate a cascade of cellular mechanisms to cause apoptosis. TUDCA prevents apoptosis with its role in the BAX pathway. BAX, a molecule that is translocated to the mitochondria to release cytochrome C, initiates the cellular pathway of apoptosis. TUDCA prevents BAX from being transported to the mitochondria, effectively inhibiting hepatocyte death. Furthermore, TUDCA aids in the processing of toxic bile acids into less toxic forms, resulting in decreased liver stress, further preventing hepatocyte death. Moreover, TUDCA aids in the transport of bile from the liver into the duodenum, effectively unblocking the build up causing cholestasis. Finally, TUDCA has been proven to be an effective treatment for the necro-inflammatory effects of Hepatitis. Study after study has shown that TUDCA greatly improves liver enzyme values. Why do we recommend only using TUDCA with hepatotoxic oral steroids? The idea is that TUDCA induces liver damage when there is no hepatotoxicity present… but after reading the above, does that make sense? It does not. I could not find any literature showing that TUDCA induces liver toxicity. The recommendation instead is due to the negative effects of TUDCA on cholesterol values. TUDCA has been shown to greatly decrease HDL levels when taken for extended periods of time. The idea is, if you have a healthy functioning liver, there is no reason to take TUDCA for long periods of time since all you’re doing is decreasing HDL values. That being said, after doing the research and seeing the vast benefits of TUDCA (included bellow, not a comprehensive list), I am beginning to change my perspective on TUDCA use with only hepatotoxic oral AAS. In short, TUDCA prevents hepatocyte death, enhances hepatocyte function, exhibits anti-inflammatory effects on the liver, neutralizes toxic bile, and prevents bile build up that was caused by the alternative metabolism of C17α methylated AAS. ***THERE IS NO EVIDENCE THAT I HAVE COME ACROSS THAT SHOWS THAT TUDCA ITSELF INDUCES LIVER DAMAGE WHEN USED WITHOUT HEPATOTOXIC DRUGS**\* TUDCA has a variety of other benefits outside the liver, but I will not go into them this time. In short:
Increasing glucose-induced insulin release via the cAMP/PKA pathway, increasing insulin sensitivity.
Relieving endoplasmic reticulum (ER) stress. The ER makes sure proteins are folded properly.
Reducing programmed cell death (apoptosis) in healthy cells. TUDCA prevents the molecule BAX from reaching the mitochondria. BAX causes mitochondria to release cytochrome C, which causes enzymes (caspases) to initiate apoptosis.
Inactivating Bcl-2-associated death promoter (BAD), a molecule involved in apoptosis.
Removing toxic bile acids from the liver and preventing them from damaging liver cells
Exhibits neuroprotective effects via the inhibition of NF-kB
Preserve photoreceptor function and increases retinal health by increasing rd10
Liv52 Liv52 is an herbal liver support. There have been medical studies conducted on Liv.52 in recent years, many of which involve its ability to protect the liver from damage by alcohol or other toxins. Liv52 has been shown to exhibit antiperoxidative function, antioxidant effects, anti-inflammatory, diuretic effects and neutralization of toxic products within the liver. “The results demonstrated that the patients treated with Liv-52 for 6 months had significantly better child-pugh score, decreased ascites, decreased serum ALT and AST. We conclude that Liv-52 possess hepatoprotective effect in cirrhotic patients. This protective effect of Liv-52 can be attributed to the diuretic, anti-inflammatory, anti-oxidative, and immunomodulating properties of the component herbs.”
“Liv.52 enhanced the rate of absorption of ethanol and rapidly reduced acetaldehyde levels, which may explain its hepatoprotective effect on ethanol-induced liver damage.”
“Liv.52 administration reduced the deleterious effects of ethanol. The concentration of acetaldehyde in the amniotic fluid of ethanol-consuming animals was 0.727 microgram/ml. Liv.52 administration lowered it to 0.244 microgram/ml. The protective effect of Liv.52 could be due to the rapid elimination of acetaldehyde.”
That being said, there is conflicting research on Liv52. The studies either show hepatoprotective function or no effect, positive or negative. “There was no significant difference in clinical outcome and liver chemistry between the two groups at any time point. There were no reports of adverse effects attributable to the drug. Our results suggest that Liv.52 may not be useful in the management of patients with alcohol induced liver disease.”
In short, Liv52 can be used if you have the additional funds, it is not the end-all-be-all but can be used as an adjunct. It is an incredibly cheap drug thatmayimprove liver function and exhibit hepatoprotective effects. IT SHOULD IN NO WAY YOUR ONLY LIVER SUPPORT MEDICATION, but there is nothing wrong with using it.
Hey there. I've been struggling with some health issues off and on for years and haven't quite been able to pin anything down. One consistent issue I have is significantly elevated bilirubin. I've been diagnosed with Gilbert's which is not all that uncommon, but a recent test showed elevated direct bilirubin which Gilbert's isn't supposed to have an impact on. What are some other causes of elevated direct bilirubin? I do not smoke or drink alcohol if that helps
Hi all! I recently had my yearly check-up and my total bilirubin was 3.2 mg/dL. Since it was elevated, my doctor ordered another blood test last week to get a breakdown of the bilirubin (I'm assuming to see the direct/indirect bilirubin levels). I'm still waiting on the results of that blood test, but I was doing some reading about elevated bilirubin levels and I came across some info that said if bilirubin is present in the urine then the elevation is probably caused by direct (conjugated) bilirubin. That means the absence of bilirubin in the urine points to the total bilirubin being made up of indirect (unconjugated) bilirubin. It also said that the absence of urobilinogen points to direct bilirubin levels being high, while normal urobilinogen levels are a characteristic of high levels of indirect bilirubin. I was wondering if this was true for those of you who have been diagnosed with Gilbert Syndrome. My urine was negative for bilirubin and the urobilinogen was normal, so I'm leaning towards the breakdown probably showing mostly unconjugated bilirubin and being Gilbert Syndrome.
Ok so I (26, male) have had very strange chest pains since September 2019. Went to the hospital a couple times and my liver enzymes were always elevated. In February of 2020 I got a copy of the following letter: “Just a quick update regarding this patients results. Liver ultrasound scan has been normal, MCRP scan shows normal bile ducts. Liver screen, including extended auto-antibodies, is unremarkable. Gamma-GT is 17, and while bilirubin is slightly high at 27, conjugated bilirubin is normal at 9, suggesting a component of Gilbert’s syndrome. Alkaline phosphatase is 170, the pattern is suggestive of an extra hepatic source, likely bone. I am enclosing blood forms for Vitamin D and for ALP isoenzymes with Mr redacted’s copy of this letter for him to get done soon. We will see him back in our liver clinic in due course with the blood results.” Fast forward to July of 2020 and because of covid I’ve been laying low at home. I haven’t stepped outside a lot at all which worries me considering the vitamin D shout. Especially since there seems to be a direct link in the severity of the disease in those with a vitamin D deficiency. What’s worrying to me is the fact that I’ve been working the night shift for the past two years and have avoided a lot of sunlight during UVB hours (10am - 3pm). This, unbeknownst to me then, probably caused my mild depression. I ate a lot of junk food and lived a very sedentary lifestyle. Although I never looked fat at all so I guess that’s why I didn’t portion my meals. However ever since September 2019 I’ve been eating very clean and went from ~ 20% body fat in February to probably ~10% body fat. I also take around 7 ~ 10k steps every day. List of symptoms: chest pain, cold/tingling feet and hands. Smelly feet even if I wash them 3 times in a day. Eyes that become bloodshot after walking ~30 mins. Random dizziness etc. Lumps on my chest and lower back, feel sensitive to touch. Last one is probably the most concerning. But I’ve had chest x-rays and an MRI scan done so surely this should’ve been picked up? I wrote a lot, but all in all I’m lost. I’m too afraid to go to the GP or hospital because of covid. I’m trying my best to escape reality by keeping my mind occupied, but every now and then I’ll feel pain that snaps me back to reality.
Often in questions, it will say total bilirubin is 5 mg/dl and direct is 2.3 mg/dl is this a conjugated or unconjugated hyperbilirubinemia? This affects the thinking for my differential diagnosis Before I read it was about 30%+ of the total, and some people have said 50%+, and I looked it up but couldn't find it either. So I was wondering if anyone knows the precise definition?
12-yo girl has a 2-month history of intermittent jaundice. She has both unconjugated and conjugated bilirubinemia. Also - normal haptoglobin, AST, ALT levels. There is no evidence of injury/toxins. Which additional finding is most likely?
So, obviously I ruled out hemolysis immediately (hemolysis would have ↓ haptoglobin) Then I ruled out "decreased activity of UDP gluronysyltransferase" because of the direct bilirubinemia. That left me with: A. Ineffective erythropoiesis → didn't seem to be a likely cause of jaundice B. Increased alkaline phosphatase → I forget what this even means C. Gallstones I chose gallstones because I was thinking ↑ bilirubin would lead to gallstones. The answer ended up being "decreased activity of UDP gluconysyltransferase" because I guess since the jaundice was intermittent/mostly asymptomatic that automatically points you to Gilbert's syndrome? Just seems pretty bullshit to me. Anyway, can someone please explain the right answer and why it's not the 3 answers I was left with? Thanks.
27 year old male. white. 5'5 and 154 lbs. From Aus. Existing relevant medical issues: Hypothyroidism treated with levothyroxine. Gastritis treated with pantoprazole (that resolved already tho). For about two days I have been having abdominal pain on the right side, right under the ribcage, so approximately where the liver is supposed to be I'd say. This was following a night out with heavy drinking (I go out usually once a week, at most, but when I do, then I drink a lot.), which involved me throwing up when I came home. The day after that I was sent to the hospital by my physician because I'd been having chest pains and he wanted them to check my cardiac markers. So I went there and they ran a blood test (by that time I didn't have those chest pains anymore, neither have I since, this is just to let you know why I had a blood test done in the first place). The doctors at the hospital said everything was fine and then sent me home. Since then I've developed said abdominal pain in my right upper quadrant. That combined with the fact that some of the paramaters of my liver where elevated in the blood test (results below) has left me a bit worried. About the pain: It's kind of a dull pain that is most noticable when inhaling. I am also a little bit nauseas and I don't really have an appetite at all. First stool since then was somewhat pale and loose, second one was looking normal again. Urine also looked normal to me. Here are all the results that were above or under the normal range: Potassium in Plasma: 3.5 mmol/l (normal range: 3.6-5.0) Glucose: 103 mg/dl (nr: 70-100) Total Bilirubin: 1.50 mg/dl (nr: 0.2-1.2) Direct (conjugated) Bilirubin: 0.50 mg/dl (nr: <0.3) GOT (AST): 36.00 u/l (nr: 10-50) GPT (ALT): 24.00 u/l (nr: 10-50) I included AST and ALT even though they are within normal range because the ratio of AST/ALT is >1 and I've read that this indicates liver damage, associated especially with alcohol consumption. I don't know if that is relevant or not, but it seemed weird to me, especially since in an older bloodtest, taken about half a year back my AST was well below ALT and now it's the opposite. Everything else was within reference range and didn't get flagged in the screening, so I didn't include it. Please let me know if there are other markers you'd like me to add. I also want to point out that this was taken a day and a half after I got completely hammered and I was still feeling a little bit hungover, so maybe it's normal for liver markers to be out of whack right after something like that idk. Anyways, just a little worried about the pain in my right side coupled with those results, that's all. I guess it's probably just sore muscles from throwing up or something, but I'd feel better if you guys had a look at it and told me that I'm an idiot for even worrying about it.
Interesting (relatively rare) case I saw last week
Hi Meddit! (I'm a medical student, so please forgive me if this case is not particularly challenging for many of you. Hopefully it'll at least be interesting!) Patient is a 25 year old woman from South Africa, who is HIV positive. She was diagnosed in 2010, and is currently on ARVs (TDF/FTC/EFV). Her most recent CD4 count is 112. She also had pulmonary TB in 2009, and completed her 6/12 of treatment. She was admitted to a tertiary hospital in the area earlier in the year because "[her] eyes were yellow, and [she] got bags of blood and yellow liquid." She received "pills" there for two months, but then defaulted further appointments. Now her primary complaint is of a week's duration of fatigue, decreased effort tolerance and dizziness. She has had no orthopnea/PND. She also reports a three day history of cough - non-productive, no haemoptysis, no pain, no recent night sweats/loss of weight/loss of appetite. There is also a curious episode of transient, complete right arm weakness, lasting ± 1 day. Her urine has also been red, for "a while". No history of epistaxis, menorrhagia, easy bruising, melaena, nausea/vomiting/diarrhoea. Non-smoker, non-drinker, no use of illegal drugs. No other medication. No family history of similar problems. On exam: HR 116 bpm, RR 38 br pm, BP 110/60, T 38 degrees, finger-prick Hb 6.8 g/dL, sats 99% on FMO2, 85% off O2. Normal finger-prick glucose. Very pale conjunctivae and oral mucosa. ?slightly jaundiced. Not oedematous, not clubbed, no lymphadenopathy. No obvious petechiae/purpura/ecchymoses. Resp tachypnoeic, but not distressed. Trachea central. Dullness to percussion right lower zone. Coarse crackles right lower zone, with decreased air entry. CVS tachycardic, but otherwise completely normal. Abdo soft, non-tender. No hepatosplenomegaly. Normal bowel sounds. CNS GCS 15/15, normal cranial nerve exam, normal motor and sensation exam, normal cerebellar exam. Dipstix 4+ blood, 2+ protein So what do you guys think? That's as much information we had going in to it :) What are your differential diagnoses, and which investigations would you like/need to include/exclude those diagnoses? I'll post updates with investigations as we go! Update 1 sorry for the delay; time zones are real, yo! CBC (or full blood count as we call it here) - we might use different units, so I'll just comment increased, decreased etc. Hb 6.7 WCC 7.99 (4-10) Platelets 7 (ultra low) MCV 104.5 (increased) MCH 34.0 (increased) MCHC 32.7 (normal) RCCount 1.97 (decreased) Hct 0.205 (decreased) RCDW 19.2 (increased) Smear: 10% fragments, polychromasia, mild toxic granulation D-dimer positive ECG normal (except for sinus tachy) CXR: left upper lobe shows extensive fibrosis, likely from previous TB right lower lobe and inferior upper lobe show opacification with air-bronchograms. Not a ground glass appearance. Sodium 137 Potassium 3.7 Urea 6.5 Creatinine 63 (all normal) So where does that leave everyone? Update 2 Fantastic theories coming through, everyone! Sorry I'm not updating at shorter intervals - just got back from call. One person has suggested the correct diagnosis so far. Here is another batch of test results: LFTs Bilirubin total 13 µmol/l (0 — 21) Bilirubin conjugated 5 µmol/l (0 — 6) Total Protein 98 g/l (60 — 85) Albumin 40 g/l (35 — 52) ALP 118 U/l (40 — 120) GGT 30 U/l (0 — 35) ALT 11 U/l (5 — 40) AST 31 U/l (5 — 40) LDH 982 (100-190) INR 1.04 PTT normal Fibrinogen normal Direct Coombs negative Haptoglobin < 0.20 (0.30-2.00) ANA negative Anti-dsDNA negative C3 and C4 normal So get your final differentials in - answers tomorrow! Hope everyone has enjoyed this so far. Update 3 Answer time! The patient's diagnosis was secondary TTP, likely associated with HIV. I think Chayoss was the first person to suggest it, so hats off to him/her. For everyone who was a bit thrown by respiratory involvement (as I was initially), Hickam's Dictum is a reminder that it's not always a single condition causing all the patient's symptoms/signs. In this case, she also had a CAP. She was transferred to our local tertiary hospital, where she apparently did very well. It turns out that she was known to them, and had been admitted with TTP in April this year. She had not returned for her follow up appointments after 2/12. Her biggest issue going forward is probably going to be her HIV management her CD4 is low and her viral load is high, despite nearly four years of ARV treatment. Her adherence has not been perfect, and there is concern that she may need to be switched our second line ART regimen (lopinaviritonavir, lamivudine, efavirenz). I hope this was a fun exercise. I saw another interesting (less uncommon) case the week before, so if anyone is keen I can put that one up as well. Have a good weekend, Meddit.
What I don't understand is how non functional or a malfunction of UDPglucuronosyltransferase affects this type of treatment. Also, does this apply to Gilbert's syndrome These considerations demonstrate the need for alternative treatment strategies. Most hypobilirubinemic treatments, as described in chapters 1 and 2, stimulate the fecal excretion of bilirubin via the bile. Biliary bilirubin excretion, however, is highly inefficient in patients with Crigler-Najjar disease and, to a lesser extent, in patients with neonatal jaundice. This is due to an inactivated (Crigler-Najjar disease) or immature (neonatal jaundice) isoform of the enzyme UDPglucuronosyltransferase. This hepatic enzyme catalyzes the transfer of glucuronic acid to bilirubin, thus forming bilirubin monoglucuronoside or diglucuronoside. This so-called conjugated bilirubin is more water soluble, and can readily be excreted into the bile. Bilirubin, however, is not exclusively excreted via the bile, but may also enter the intestinal lumen via direct transmucosal excretion from the blood. The efficiency of this excretory pathway is decreased, however, by reabsorption of unconjugated bilirubin from the intestinal lumen. This reabsorption can be prevented by intestinal capture; the binding of intestinal unconjugated bilirubin to orally administered agents.
26 Male 5'8" 190lbs White 4 months upper right portion of rib cage. bipolar, ptsd from a tour in iraq a few years back. I'm titrating down off of depakote and starting topamax. My current Meds are Depakote 1500MG Lamictal 100MG Seroquel 600MG Propanol 100 MG and Topamax 100MG. I've been having some liver problems. After a sonogram I was told I have a fatty liver. I'm titrating off of Depakote and my endocrinologist says the blood work anomalies reflect that. But it seemed like he just read my chart literally right before he walked in the room. I just wanted to get some of your opinions. I've been having some liver problems. After a sonogram I was told I have a fatty liver. I'm titrating off of Depakote and my endocrinologist says the blood work anomalies reflect that. I just wanted to get some of your opinions. Lymphocyte % 40.7 % (Normal) Date Mar 19, 2015 06:57 p.m. CDT Reference Range 20.0 % - 51.0 % Platelet 176 x 10(3)/mcL (Normal) Date Mar 19, 2015 06:57 p.m. CDT Reference Range 150 x 10(3)/mcL - 400 x10(3)/mcL Imm Grans Ct 0.0500 x 10(3)/mcL (High) Date Mar 19, 2015 06:57 p.m. CDT Reference Range 0.0034 x 10(3)/mcL - 0.0310 x 10(3)/mcL Lymphocyte Ct 2.43 x 10(3)/mcL (Normal) Date Mar 19, 2015 06:57 p.m. CDT Reference Range1.20 x10(3)/mcL - 5.60 x 10(3)/mcL Imm Grans % 0.80 % (High)Date Mar 19, 2015 06:57 p.m. CDT Reference Range% - 0.50 % Basophil %0.2 % (Normal) Date Mar 19, 2015 06:57 p.m. CDT Reference Range% - 1.0 % Basophil Ct 0.01 x 10(3)/mcL (Normal) Date Mar 19, 2015 06:57 p.m. CDT Reference Rangex 10(3)/mcL - 0.20 x 10(3)/mcL Eosinophil % 6.5 % (High) Date Mar 19, 2015 06:57 p.m. CDT Reference Range% - 5.0 % Eosinophil Ct 0.39 x10(3)/mcL (Normal) Date Mar 19, 2015 06:57 p.m. CDT Reference Rangex 10(3)/mcL - 0.40 x10(3)/mcL Monocyte % 15.7 % (High) Date Mar 19, 2015 06:57 p.m. CDT Reference Range 2.0 % - 10.0 % Monocyte Ct 0.94 x10(3)/mcL (High) Date Mar 19, 2015 06:57 p.m. CDT Reference Range 0.10 x10(3)/mcL - 0.80 x10(3)/mcL Neutrophil % 36.1 % (Low) Date Mar 19, 2015 06:57 p.m. CDT Reference Range 40.0 % - 75.0 % Neutrophil Ct 2.15 x10(3)/mcL (Normal) Date Mar 19, 2015 06:57 p.m. CDT Reference Range 1.80 x10(3)/mcL - 8.30 x10(3)/mcL RDW-SD 51.0 fL (High) Date Mar 19, 2015 06:57 p.m. CDT Reference Range 39.3 fL - 46.1 fL RDW-CV 14.4 % (Normal) Date Mar 19, 2015 06:57 p.m. CDT Reference Range 12.0 % - 14.6 % MPV 13.2 fL (High) Date Mar 19, 2015 06:57 p.m. CDT Reference Range 9.4 fL - 12.4 fL MCV 95.8 fL (Normal) Date Mar 19, 2015 06:57 p.m. CDT Reference Rang e80.0 fL - 100.0 fL MCHC 32.5 gm/dL (Normal) Date Mar 19, 2015 06:57 p.m. CDT Reference Range 32.0 gm/dL - 36.0 gm/dL MCH 31.1 pg (Normal) Date Mar 19, 2015 06:57 p.m. CDT Reference Range 28.0 pg - 34.0 pg Hgb 14.1 gm/dL (Normal) Date Mar 19, 2015 06:57 p.m. CDT Reference Range 14.0 gm/dL - 17.4 gm/dL Hct 43.4 % (Normal) Date Mar 19, 2015 06:57 p.m. CDT Reference Range 42.0 % - 52.0 % Bili Total 0.3 mg/dL (Normal) Date Mar 19, 2015 06:57 p.m. CDT Reference Range 0.2 mg/dL - 1.2 mg/dL AST 92 unit/L (High) Date Mar 19, 2015 06:57 p.m. CDT Reference Range 5 unit/L - 35 unit/L Alk Phos 46 unit/L (Normal) Date Mar 19, 2015 06:57 p.m. CDT Reference Range 38 unit/L - 126 unit/L ALT 110 unit/L (High) Date Mar 19, 2015 06:57 p.m. CDT Reference Range7 unit/L - 56 unit/L A/G Ratio 1.6 ratio (Normal) Date Mar 19, 2015 06:57 p.m. CDT Reference Range 1.0 ratio - 3.0 ratio Albumin 4.7 gm/dL (Normal) Date Mar 19, 2015 06:57 p.m. CDT Reference Range 3.5 gm/dL - 5.0 gm/dL Total Protein 7.6 gm/dL (Normal) Date Mar 19, 2015 06:57 p.m. CDT Reference Range 6.0 gm/dL - 7.8 gm/dL AGAP 15.0 mmol/L (Normal) Date Mar 19, 2015 06:57 p.m. CDT Reference Range 8.0 mmol/L - 16.0 mmol/L Chloride 102 mmol/L (Normal) Date Mar 19, 2015 06:57 p.m. CDT Reference Range 101 mmol/L - 111 mmol/L CO2 27 mmol/L (Normal) Date Mar 19, 2015 06:57 p.m. CDT Reference Range22 mmol/L - 31 mmol/L Sodium 144 mmol/L (Normal) Date Mar 19, 2015 06:57 p.m. CDT Reference Range 136 mmol/L - 145 mmol/L BUN/Crea 14.1 ratio (Normal) Date Mar 19, 2015 06:57 p.m. CDT Reference Range 6.0 ratio - 20.0 ratio Glucose 103 mg/dL (Normal) Date Mar 19, 2015 06:57 p.m. CDT Reference Range 65 mg/dL - 110 mg/dL Potassium 4.4 mmol/L (Normal) Date Mar 19, 2015 06:57 p.m. CDT Reference Range 3.5 mmol/L - 5.1 mmol/L BUN 18 mg/dL (Normal) Date Mar 19, 2015 06:57 p.m. CDT Reference Range7 mg/dL - 21 mg/dL RBC 4.53 x10(6)/mcL (Normal) Date Mar 19, 2015 06:57 p.m. CDT Reference Range 4.50 x10(6)/mcL - 5.80 x10(6)/mcL WBC 5.97 x 10(3)/mcL (Normal) Date Mar 19, 2015 06:57 p.m. CDT Reference Range 4.50 x 10(3)/mcL - 11.00 x 10(3)/mcL Creatinine 1.3 mg/dL (Normal) Date Mar 19, 2015 06:57 p.m. CDT Reference Range0.5 mg/dL - 1.4 mg/dL
Hello everyone, this will by my last big post for a little while. I wanted to address hepatotoxicity since it seems to be this big grey area for a lot of people. Drug metabolism is a very complicated processes, so I have tried to condense it into a readable format. I wanted to address how drugs are metabolized, how drug metabolism can affect the liver, how to determine liver damage, and how to prevent it. Please feel free to ask questions! Drug Metabolism When it comes to drug metabolism, the liver’s primary function is to metabolize the drug into a form that is suitable for elimination by the kidneys. The main goals of this metabolism is to reduce fat solubility, make the drug water soluble, and to decrease its biological activity so that it stops working. This occurs for not only foreign substances (known as xenobiotics, which drugs are considered), but also endogenous chemicals. Drug metabolism in the liver exists in two main phases, phase I and phase II.
Phase I: Phase I metabolism happens primarily in the smooth endoplasmic reticulum of hepatocytes. The main purpose of this phase is to make lipid soluble compounds water soluble. This typically renders the metabolites of the drug to be inactive, but not always.
Phase II: Phase II metabolism takes place in the cytosol of hepatocytes. In this phase, the products from phase I will undergo conjugation to increase their water solubility.
The efficacy of the enzymes used in drug metabolism are age-dependent. In newborns and the geriatric, the ability to metabolize drugs is greatly decreased. Smoking can increase the efficacy of drug metabolism through the inhalation of polycyclic aromatic hydrocarbons. This is most noticeably manifested in the increased metabolic activity of caffeine. Drug Induced Hepatotoxicity Drug induced hepatotoxicity can have many causes. Some medications cause direct damage to hepatocytes while others block certain metabolic processes. As an example, acetaminophen itself is not the source of hepatotoxicity, but rather one of its metabolites. When taken in extreme quantities, this metabolite accumulates because the enzymes required are unable to keep up in phase II metabolism and cell damage occurs. Likewise, mitochondrial damage can increase oxidative stress which can damage hepatocytes. These causes are categorized in seven general categories based on the mechanism of hepatotoxicity. The main categories where AAS and ancillaries are implicated are:
Steatosis: Steatosis is the accumulation of triglycerides in the liver. Liver function tests (LFTs) are unreliable when it comes to the diagnosis of hepatic steatosis. Often will have an AST/ALT ratio < 1. Imaging and possible biopsy is required to make an accurate diagnosis. AST and ALT both upwards of 4 times ULN. Tamoxifen and raloxifene have been shown to induce hepatic steatosis.
Zonal Necrosis: Zonal necrosis is essentially the death of cells in a specific zone of the liver. This is the most common manifestation of hepatotoxicity. This will cause an increase in ALT with normal ALP levels. This can be caused by C-17-alpha-alkylated (C17aa) steroids.
Cholestasis: Cholestasis is the impediment of biliary flow from the liver through the biliary tract. This is the cause of jaundice. The increase in bilirubin causes a yellowing of the skin and that is occurs with itching. C17aa steroids may cause hepatotoxic cholestasis. This can be seen on labs as normal levels of ALT and > 2 times ULN ALP. The mechanism of this is not well known. Testosterone and 19-nortestosterone compounds have been implicated in cases of hyperbilirubinemia, but rarely to the point of jaundice.
Hyperplasia and Neoplasia: C17aa compounds have been implicated in cases of hepatic hyperplasia and neoplasia, essentially cancer. However, non-C17aa steroids have also been noted as a cause of liver cancer in medical case reports.
Vascular Lesions: These vascular lesions are known as Peliosis Hepatis. These lesions are present on endothelial cells of hepatic vasculature and is typically asymptomatic. This can eventually lead to hepatomegaly (enlarged liver) and frequently death if untreated.
Effects of liver damage include jaundice, ankle edema, gynecomastia, increased bleeding due to decrease in clotting factor synthesis. Most of these effects come from deficiencies in synthesis of their respective plasma proteins. For example, damage to hepatocytes that are responsible for synthesis of SHBG will result in a decrease in SHBG. This will alter the free estrogen/free androgen ratio, potentially inducing gynecomasta. Likewise, a decrease in plasma proteins will change the blood colloid osmotic pressure, causing a change in capillary net filtration pressure leading to edema in the lower extremities. Liver Function Tests LFTs can be done to assess hepatic function. These are not exactly conclusive and require some sort of follow up to assess the degree of severity. Often this will be some sort of imaging or biopsy. Most of these biomarkers are assessed in a multiplication of the upper limit of normal (ULN), which is the top end of the normal range. Aminotransferases: Aminotransferases are enzymes that are used in the synthesis of amino acids. There are two aminotransferases that are checked as part of an LFT.
Aspartate Transaminase (AST): Reference range: 8 - 40 IU/L. While AST is found in the liver, this enzyme is also found in great quantities in cardiac and skeletal muscle. Because of these other sources, AST alone is not a good indicator of liver damage. Essentially, AST does not require the entire cell to be damaged for it to enter the plasma, where ALT does. This is due to its location within the cell. If AST is elevated then there is a good possibility that the source of the AST is from muscle damage. This can be caused by myocardial infarction (heart attack), rhadomyolysis, and even resistance training. This is why slightly elevated AST levels should not be of concern if you lift frequently.
Alanine Transaminase (ALT): Reference range: ≤ 52 IU/L. Much like AST, ALT is an enzyme used to catalyze the synthesis of amino acids. Unlike AST, ALT is found predominantly in the liver and requires significant damage to hepatocytes for it to be released in to the plasma.
AST to Platelet Ratio Index (APRI): This typically won’t be included in lab tests, but it is easy to figure out. An online calculator can be found here. APRI has been shown to be a predictor of liver cirrhosis. Alkaline Phosphatase (ALP): Reference rage: 30 - 120 IU/L. ALP is an enzyme that is located within hepatic biliary ducts. Elevations in plasma concentrations of this enzyme are indicative of either cholestasis or biliary obstruction. In these pathologies, ALT and AST may remain unaffected. Total Bilirubin: Reference range: 0.1-1.0 mg/dL. Bilirubin is a byproduct of hemoglobin catabolism. The heme group of hemoglobin is broken down into biliverdin, then bilirubin, which is transported to the liver for the production of bile salts along with urobilin (the pigment that makes urine yellow) and stercobilin (the pigment that makes feces brown). High hepatic sources of bilirubin are indicative of cirrhosis or hepatitis. 5'-nucleotidase (5'NTD): Another biomarker used int he diagnosis of cholestasis. Liver Protection
Cessation: Hepatotoxic drug withdrawal is the widely accepted treatment for drug induced liver damage.
Tauroursodeoxycholate (TUDCA): TUDCA is a bile acid that was found in bears. It is currently being researched in the treatment of ophthalmologic and neurologic conditions. TUDCA has been shown to reduce cholestasis, hepatic steatosis, cirrhosis, and transient liver enzyme levels. The extent of this efficacy still needs more research and clinical trials. No research exists to support its use in zonal necrosis, peliosis hepatis, or hyperplasia.
Milk Thistle: This is bullshit, don't waste your money
Lecture 1 (06/04) -- The hemoglobin-oxygen complex
As mentioned in the syllabus one aspect of Biochemistry deals with two direct yet deceptively simple questions. These are: (1) where did it come from, and (2) where does it end up? In this lecture, we will ask these two questions to the hemoglobin-oxygen complex. As we answer these questions, we will touch upon oxygen transport to the cells, the expression and degradation of proteins, and the biosynthesis and breakdown of heme. In the introductory lecture, we attempted to perform some run-of-the-mill, double-entry accounting. Each time we inhaled, we learned that a certain percentage of oxygen molecules were getting ‘fixed’ inside our body. Let’s pick up from there. The oxygen we inhale not only dissolves in our blood, but it also binds tightly to a special protein found in our erythrocytes called Hemoglobin. The protein data bank (PDB) contains more than 80,000 structures of proteins, and the following GIF was downloaded from that site. The PDB also has a section called the molecule of the month. In this section, they describe in crisp, atomic detail how some select proteins do what they do. Their section of hemoglobin is linked HERE. Specifically, one molecule of oxygen binds to a central Iron atom in another molecule called heme. The heme molecule contains 4-pyrrole rings linked by methylenes. Hemoglobin, contains a heme portion, and a protein portion called globin. Oxygen is transported to the tissues by means of this oxygen-hemoglobin complex. Let us pay close attention to the structure of this complex and ask: (1) where did it come from, and (2) where does it end up? In the case of this particular complex, let us divide the first part into 3 subsections, and ask: (a) where did the oxygen molecule come from, (b) where did the globin protein come from, and (c) where did the heme ring come from? Similarly, we can divide the second question into 3 subsections: (a) where will the oxygen end up, (b) where will the globulin protein end up, and (c) where will the heme ring end up? Let’s address each of these questions one by one: Oxygen 1 (a): Where did the oxygen come from?
Oxygen is present in the air we inhale, and most of the oxygen molecules in air come from plants. Specifically, the oxygen molecules come from deep inside a plant’s chloroplast. There, each oxygen molecule is created from two molecules of water by a protein-complex known as the oxygen-generating complex. Inside this complex, the oxygen atoms of two water molecules get hitched together into one oxygen molecule. Prior to this moment, these two water molecules were independent. They may have originated from two very different places. However, after a trip to the chloroplasts, the oxygen atoms of these two water molecules get hitched, and now they must spend their lives together as one oxygen molecule. (Imagine the first water molecule evaporating from the surface of the Pacific Ocean, near Hawaii, 10 months ago; and the second water molecule evaporating from the surface of the Indian Ocean, near the South African coast, two years ago. The two water molecules, then, floated as clouds, until last week when they drizzled-down as rain on our neighborhood park. After working their way through the wet mud, and then up some plant root, they finally reached the oxygen-generating complex of a blade of grass, together. On this blade of grass, the oxygen atoms of these two, formerly independent, water molecules, that originated from two random places on the planet, were hitched together to produce one oxygen molecule. This oxygen molecule was floating in the air until just a few seconds ago. Then, it entered our lungs and was promptly picked up by our hemoglobin).
2 (a): Where will the oxygen end up?
This answer also requires a story. In the lungs, oxygen molecules do two things: (1) they dissolve into the blood solution, and (2) they bind to hemoglobin. Hemoglobin behaves as an oxygen reserve. If we only relied on the ability of oxygen to dissolve in blood, we would have nowhere near all the oxygen our body needs. The ability of hemoglobin to bind an oxygen molecule, and subsequently release it, allows us to achieve ~70 fold higher concentrations of oxygen. Nitrogen molecules don’t bind hemoglobin very well, but they do dissolve in blood. Carbon monoxide, on the other hand, binds hemoglobin ~200 fold more tightly than oxygen. If carbon monoxide was present in the inhaled air mixture, it would out-compete oxygen for binding to hemoglobin. Carbon monoxide thus leads to some pretty serious problems. Coming back to the complex of oxygen and hemoglobin, we notice that the complex is itself enclosed inside erythrocytes. As the heart beats, blood is pumped through the body, and the erythrocytes that were near the lungs now start flowing away. As these cells flow away, the oxygen molecules start leaving the oxygen-hemoglobin complex, and enter into the blood solution, from where they enter into other cells in the body. In the muscle, oxygen molecules can also bind to myoglobin, a protein like hemoglobin. Eventually, most oxygen molecules find themselves at the edge of the mitochondrial inner membrane, deep inside cells. Up to this stage, the entire transport process, or the journey, of oxygen from our lungs to the edge of the mitochondria can be understood more or less as a physical process. In other words, it can be understood as a series of binding and unbinding events between oxygen molecules, proteins, and the blood. What happens next to the oxygen molecules at the edge of the mitochondrial inner membrane is not a physical transformation but a chemical one. The transformation of oxygen to water will be a topic for discussion in Lecture 2.
Globin 1(b): Where did the globin come from?
The globin protein was synthesized from DNA by using several different RNA: including ribosomal RNA, transfer RNA, and messenger RNA. Considerable amount of energy was spent to do this. In fact, protein synthesis is one of the most expensive things a cell can do. The information in the globin gene (which is structurally represented by a strand of DNA) was transcribed on to messenger RNA, and then this protein was synthesized, one expensive peptide bond at a time.
2(b): What will happen to the globin?
Most erythrocytes have a life-span of ~3 months. As the RBC die, the globin protein is broken down to its individual amino acids. Amino acids are considered too valuable to be squandered as fuel by the body, so they are typically re-used. However, under some circumstances, amino acids can also be burned as fuel by involving transamination, the Urea cycle and the TCA cycle.
Heme 1(c): Where did the heme ring come from?
The heme ring was synthesized in our body by a series of enzymatic transformations from the amino acid glycine and succinyl CoA, a molecule of the TCA cycle. (The TCA cycle is also a topic for later discussion). First, glycine combined with succinyl CoA to generate a product that upon decarboxylation gave δ-Aminolevulinic acid (ALA). Two ALA molecules were then condensed to give porphobilinogen. Subsequently, four porphobilinogens were deaminated give hydroxymethylbilane that cyclized to uroporphyrinogen. The uroporphyrinogen was decarboxylated to coproporphyrinogen, which was subsequently oxidized to protoporphyrin. Heme is obtained once iron adds to protoporphyrin. The biosynthesis of heme is important because we all need heme to bind oxygen. However, another reason why these transformations are important is because their malfunction results in disease. Specifically, improper execution of some of the steps of heme biosynthesis leads to porphyrias (diseases in which the urine exhibits unnatural colors).
2(c): Where will the heme end up?
When erythrocytes die, the iron atom is stripped-off from heme and recycled. The protoporhyrin is converted into biliverdin, which is then transformed to bilirubin. Bilirubin is not very soluble, and must be conjugated with glucuronic acid to make it more soluble. This conjugate exits the body via the bile. In addition, intestinal bacteria can convert a small portion of conjugated bilirubin to urobilinogen – a molecule excreted in the urine, and a larger portion of conjugated bilirubin into stercobilinogen - a molecule excreted in the stool.
Let’s step back, and take a moment and think about the origin and fate of biomolecules. For the past three months a heme molecule, bound to globin, dutifully brought oxygen from all over the planet, to every cell in our body. It brought oxygen to the muscles of our heart, allowing it to beat. It brought oxygen to the neurons in our brain, contributing to our thoughts. However, very soon this heme molecule will leave our body. Right now, there might also be some spanking new heme molecules binding to oxygen for the first time in their life. And then, in around three months, they too will be out of our body. This is also a good place to introduce the winner of the 1930 Nobel Prize in Chemistry: Hans Fischer and the Award Speech Assignment 1: Draw the following structures showing interatomic bonds as lines: You can use a white board and marker, pen/pencil and paper, or use any freely downloadable drawing software.
(1) Oxygen
(2) Water
(3) Carbon Monoxide
(4) Pyrrole
(5) Glycine
(6) Succinic Acid and Succinate
(7) Glucuronic Acid
(8) Heme
Assignment 2: Write a short research memo (one or two paragraphs) about any Porphyria using available internet resources.
[University Clinical Chemistry] Jaundice, Bilirubin, and Urobilinogen
I'm having a bit of trouble trying to figure out this question. A patient is admitted to the hospital. Urinalysis and chemistry results are given. Urinalysis results: Nothing noteworthy except for 3+ positive for bilirubin, amber appearance, and normal urobilinogen (3umol/L). Chemistry results: Total bilirubin, direct bilirubin, AST, ALT, ALP, and GGT are all elevated (high). T.Bil: 47 umol/L D.Bil: 40 umol/L ALP: 535 U/L AST: 90 U/L ALT: 97 U/L GGT: 415 U/L Total Protein (65 g/L) and Albumin (48 g/L) results are normal. The question asks what type of jaundice this patient has, list several conditions that can cause it, and also asks why the urine urobilinogen result is normal. Based on the AST, ALP, ALT, and GGT results I believe this is post-hepatic jaundice and I've listed several conditions relating to it. The problem is I have no idea why the urine urobilinogen would be normal. From my understanding if the biliary system is obstructed, then there will be decreased amounts of conjugated bilirubin traveling from the liver to the intestine where it will be converted to urobilinogen, which some of it will be excreted from the kidneys. Would there not be decreased urobilinogen instead?
[Science] Gilbert’s Syndrome Successfully Treated with the Paleolithic Ketogenic Diet
Abstract Gilbert’s syndrome (GS) is a common hyperbilirubinaemia syndrome caused by reduced conjugation of serum bilirubin by the liver. Although it is considered as a common and harmless condition not requiring treatment symptoms associated with GS may be unfavorable. Here we present a case of GS where high level of total and direct bilirubin, yellowish discoloration of the sclera as well as associated symptoms including migraine, fatigue and granulomatosus dermatitis were reversed following a shift toward the popular paleolithic and then toward the paleolithic ketogenic diet.
In the liver, bilirubin is changed into a form that your body can get rid of. This is called conjugated bilirubin or direct bilirubin. This bilirubin travels from the liver into the small intestine. A very small amount passes into your kidneys and is excreted in your urine. This bilirubin also gives urine its distinctive yellow color. This is unconjugated (indirect) bilirubin which is conjugated with a glucuronie molecule in the liver, resulting in conjugated (direct) bilirubin. Jaundice is the discoloration of body tissues caused by abnormally high blood levels of bilirubin. Jaundice results from a defect in the normal metabolism or excretion of bilirubin. Das direkte Bilirubin ist die wasserlösliche Form des Bilirubins. Durch das Enzym UDP-Glucuronosyltransferase wird in der Leber Glucuronsäure an Bilirubin konjugiert, es entsteht konjugiertes Bilirubin. Zum direkten Bilirubin wird auch das wasserlösliche Delta-Bilirubin gezählt, bei dem konjugiertes Bilirubin durch eine kovalente Bindung fest an Conjugated bilirubin (direct bilirubin) —formed in the liver when sugars are attached (conjugated) to bilirubin. It enters the bile and passes from the liver to the small intestines and is eventually eliminated in the stool. Normally, no conjugated bilirubin is present in the blood. Figure 1. Unconjugated bilirubin and conjugated bilirubin metabolism Conjugated or direct hyperbilirubinaemia occurs when the the liver is able to conjugate bilirubin, but the excretion is impaired. Causes include: failure of bilirubin excretion by hepatocytes: Dubin-Johnson syndrome; Rotor's syndrome; obstruction to biliary flow i.e. cholestasis, both intra-hepatic and extra-hepatic The bilirubin is bound to glucuronide to form conjugated bilirubin (direct bilirubin). Direct Bilirubin measurement is accomplished by a colorimetric method. Direct Bilirubin in biological fluids reacts with sulfanilic acid at acidic pH to produce a red colored complex. The conjugated (direct) bilirubin level is often elevated by alcohol, infectious hepatitis, drug reactions, and autoimmune disorders. Posthepatic disorders also can cause conjugated hyperbilirubinemia. Bilirubin is formed by a breakdown product of heme rings, usually from metabolized red blood cells. Click to see complete answer. Objectives: Although screening for biliary atresia (BA) is associated with improved outcomes, no screening program currently exists in the United States. In this study, we explore the possibility of a screening strategy based on newborn direct or conjugated bilirubin (DB or CB) measurements. A prototype KODAK EKTACHEM Clinical Chemistry Slide (BuBc) provided a measurement of serum conjugated bilirubin which was at least as sensitive to developing conjugated hyperbilirubinemia as values provided by a direct (diazo) bilirubin assay. Under conditions where the impairment of hepatobiliary e … Conjugated bilirubin reacts quickly as compared to unconjugated bilirubin. In order to produce Azobilirubin, which is a red-violet compound; dyes are added to blood sample. Conjugated bilirubin is known as direct bilirubin whereas unconjugated bilirubin is known as indirect bilirubin.
Difference Between Conjugated and Unconjugated Bilirubin ...
https://www.facebook.com/ArmandoHasudunganSupport me: http://www.patreon.com/armandoInstagram:http://instagram.com/armandohasudunganTwitter:https://twitter.c... SpACE and XpertCare Case Discussions January 16 2019. http://www.handwrittentutorials.com - This tutorial is the first of the Bilirubin series. It explains the Bilirubin Pathway from the destruction of Red Blood... Bilirubin test procedure in hindi - This lecture explains about the bilirubin test in hindi for the general audience. Bilirubin test is a major indicative t... Unconjugated bilirubin is not water-soluble and so is not excreted in the urine.The difference between unconjugated and conjugated bilirubin is that unconjug... About Press Copyright Contact us Creators Advertise Developers Terms Privacy Policy & Safety How YouTube works Test new features Press Copyright Contact us Creators ... bilirubin- conjugated and unconjugated bilirubin in hindi laboratory tuition bilirubin pathway in hindi tusion medical conjugated bilirubin in hindi unconjug... يتناول الفيديو شرح المسار الطبيعي للصفراء المباشرة وغير المباشرة في الدم Click on this link to subscribe https://www.youtube.com ... a medical student teaching video on heme catabolism, bilirubin metabolism in the liver. Particularly useful in understanding the difference between direct an... Enjoy the videos and music you love, upload original content, and share it all with friends, family, and the world on YouTube.
