[Applause] [Music] hello this is Eric strong and this is the ninth lecture in this series on understanding abgs the topic today is normal an Gap metabolic acidoses the learning objectives are to know the differential diagnosis of a normal an Gap met B acidosis and to be able to identify the specific ideology of a normal an Gap in an individual patient overall I find the differential diagnosis of a normal anap metabolic acidosis is the most frustrating of the five major categories of acid-based disorders it feels just a little more random and less clinically relevant than the other categories which is really just a manifestation of the fact that these problems on average are less acutely important than the pathologies that cause the other disorders it's also because the renal tubular acidosis in particular are complicated incompletely understood and hard to remember but I will try to keep things as simple as possible as we will see again with the metabolic alkalosis there are two major ways to categorize the ideologies of a normal Gap acidosis for the first way we consider whether the primary problem is located in the GI tract or the kidneys and whether that primary problem is a gain of hydrogen ions or a loss of bicarbonate although calling it a GI problem is a bit of a stretch hyperalimentation is frequently listed on this differential diagnosis this basically means that a person is being artificially fed either through two beeds or tpn at a rate far in excess of what his or her metabolism is able to process as a consequence of excessive protein loading there can be buildup of ammonium ion and other acids that exceed the capacity of the kidneys to handle specifically in the kidneys there are two types of renot tubular acidosis or RTA which along with renal failure result in a gain of hydrogen primarily through the kidney's inability to excrete it normally I'll will discuss the rtas quite a bit in a few minutes hyperemia can also lead to a relative gain of hydrogen through two different mechanisms also discussed later on loss of bicarbonate in the GI tract is most commonly the result of diarrhea but can also be due to surgical procedures such as external pancreatic drainage and Ural diversion oral calcium chloride can be converted to calcium carbonate in the gut Lumen providing a pathway for intestinal loss of bicarb chos tyramine is an anine exchange resin meant to exchange chloride with bios salts and thus Aid in their elimination however bicarbonate can also bind to colos tyramine leading to a metabolic acidosis though this rare side effect is seen predominantly in patients with Baseline renal insufficiency loss of bicarbonate in the kidneys is really only caused by type 2 renal tubular acidosis two additional ideologies of a normal anig Gap acidosis that don't clearly fall into the above scheme are infusions of either normal saline or ammonium chloride the former effect is quite common and I'll talk about it a bit later on the other hand ammonium chloride is a rarely used medication indicated only for the treatment of metabolic alkalosis because a number of these conditions are uncommon or esoteric I actually prefer conceptualizing these ideologies according to this chart placing them into either common or uncommon causes of a clinically relevant acidosis in the common list are renal failure diarrhea type four RTA and infusion of saline in The Uncommon list is everything else at this point as I did with the ceding lecture and as I will do with the next several lectures I will discuss the more important of these ideologies in more detail one at a time I will also review a little of the pathophysiology of them along the way this will provide you the background needed to understand why these specific ideologies cause normal Gap metabolic acidosis and why they present the way in which they do the first group of ideologies to discuss is the renal tubular acidosis these are a collection of disorders with the shared features of a normal anap metabolic acidosis a defect in the kidney's ability to maintain acidbase balance and the absence of overt renal failure here's a schematic of a nephron from the kidney that we saw in lecture two and we'll revisit again in lecture 10 the three major mechanisms of acidbase regulation in the nefron are shown and each is linked to one type of RTA type 1 RTA also known as distal RTA is caused by a defect in the collecting duct where hydrogen ions are normally excreted with simultaneous reabsorption of potassium type 2 RTA also known as proximal RTA is caused by a defect in the proximal convoluted tubal where by carbonate is normally reabsorbed finally there is Type 4 RTA which is not a kidney problem per se but rather a deficiency of the hormone aldosterone the ideologies of typee 1 and 2 RTA can be broken down into those that present as children and those that present as adults when type 1 RTA presents in childhood the cause is usually one of a number of rare genetic disorders occasionally the RTA is idiopathic though many of these cases are likely genetic but we just haven't identified the gene or Associated protein defect yet in adults ideologies include a variety of autoimmune disorders best described in shog syndrome rheumatoid arthritis and lupus as well as a number of drugs hypercalcuria obstructive uropathy curosis and chronic taline toxicity type 2 RTA in children is also usually due to various rare genetic disorders or is idiopathic in adults it may be due to multiple Myoma ameloid dois a variety of drugs or heavy metal toxicity this is a good place to point out that type 2 RTA can be further classified as either isolated in which there is only a defect in the reabsorption of bicarbonate or it can be part of fanone syndrome in which a defect in the reabsorption of bicarb occurs concurrently with other defects of reabsorption in the proximal tubule specific molecules can include glucose phosphate and or amino acids as a general rule any cause of isolated type 2 RTA can cause fanone syndrome with the exception of acetazolamide to understand the possible causes of type four RTA I'd like to review a little more of the physiology that controls the actions of aldosterone I'll review this actually in slightly more detail in lecture 10 but on a basic level aldosterone regulation predominantly involves a Cascade of hormones and preh hormones in the adrenal glands and the kidneys but also to to some extent the liver and lungs the Cascade begins in the liver where a prehormone called angiotensinogen is produced angiotensinogen is converted into another preh hormone called Angiotensin 1 with the help of the enzyme renin renin is produced in the ju to glomular cells in the kidney in response to low blood pressure or renal profusion and requires locally produced prostag glanding Angiotensin 1 travels in the systemic circulation to the lungs where is transformed into Angiotensin 2 by the Angiotensin converting enzyme meanwhile in the adrenal glands various steroid precursors are converted into either the hormones cortisol or aldosterone and Angiotensin 2 stimulates the synthesis of aldosterone specifically as you might recall both Angiotensin 2 and aldosterone affect acidbase regulation in the kidney both hormones increase sodium reabsorption and tenson 2 increases bicarb reabsorption and aldosterone increases both potassium and hydrogen secretion the net result as far as acid base balance is concerned is a tendency towards metabolic alkalosis so anything that causes either low renin and or low aldosterone levels can potentially lead to the opposite a metabolic acidosis specifically there are many medications which interfere with reenan Angiotensin aldosterone axis first first and most obviously are the anti-hypertensive ACE inhibitors which as their name implies blocks the action of angiotensin converting enzyme Angiotensin receptor blockers or arbs have the same end effect nids uh interfere with two steps they block synthesis of the prostaglandins which mediate the production Andor release of renin they also block the effect of angot tensin 2 on aldosterone production Hein even as little as the doses used for DBT prophylaxis can interfere with the production of aldosterone by its direct toxic effects on the cells of the Zona glomerulosa cyclosporine and brrum both interfere with aldosterone's effect on the distal tubule as does of course aldosterone receptor antagonist such as spironolactone here is a list of the ideologies of type four RTA pathologies that specifically lead to low renin levels include mild to moderate renal insufficiency especially diabetic nephropathy Neds acute glomular nephropathy and HIV nephropathy pathologies that lead to low Angiotensin 2 levels only include ACE inhibitors and arbs finally a more direct problem just with low aldosterone can be due to adrenal insufficiency known as Addison's disease it can also be caused by medications as just discussed such as aldosterone antagonists Hein and cyclosporine and critical illness High circulating levels of act May shunt steroid precursors towards the synthesis of cortisol and away from aldosterone patients with a 21 hydroxy deficiency form of congenital adrenal hyperplasia also have low adstone levels as do a variety of other rare genetic disorders I'm going to briefly go over a comparison of the three rtas so that you are able to distinguish them based on some common lab tests these cut offs are are going to be just general guidelines and not something to be particularly dogmatic about remember that the primary defect with type one is distal acidification with type two is reabsorption of bicarb in the proximal tubule and with type four it is hypo aism the serum bicarb levels vary such that the lowest levels are seen with type one and the highest with type four the serum potassium is normal or low with both types one and two but almost always elevated with Type 4 Ur pH is usually inappropriately high with type 1 is variable with type two and typically appropriately low with Type 4 finally fractional excretion of bicarb which is an uncommonly ordered test unless one is attempting to specifically confirm a diagnosis of type 2 RTA is elevated in that circumstance but otherwise low I'm sure most of you have already wondered what what about type 3 RTA I haven't actually mentioned that term yet the term type 3 RTA is inconsistently applied to a rare congenital deficiency of Carbonic and hydrates 2 which results in features of both type 1 and type 2 RTA the vast majority of clinicians and certainly no one outside of Pediatrics and genetics ever needs to worry about it another major cause of a normal anap acidosis is diarrhea intestinal secretions distal to the pyloris including those from the pancreatic duct are relatively alkaline as a consequence a normal Gap acidosis frequently accompanies any condition resulting in excessive loss of these secretions this most commonly occurs with diarrhea but can also be seen with laxative abuse external pancreatic drainage an anocutaneous fistula and vomiting secondary to a distal small bow struction in which the vomited bicarbonate from int secretions can outweigh the vomited hydrogen ions in stomach acid in renal failure once creatinine clearance drops below approximately 40 mlit per minute ammonium excretion in the distal tubule begins to diminish as a consequence of retained hydrogen ions a normal anig Gap acidosis develops this is usually but not always accompanied by an elevated Gap acidosis as a consequence of retained phosphate sulfate urate and hippurate all of which are unmeasured annion the normal an Gap component of the acidosis can be treated with either oral sodium bicarbonate or with a low protein diet as protein metabolism is the major source of ammonia infusions of normal saline particularly in patient to or volume replete can lead to a normal anig Gap metabolic acidosis although there is very strong anecdotal evidence of this effect there's a relatively poor understanding as to the exact mechanism or its clinical significance which is thought to be relatively low the acidosis reverses very quickly once saline is stopped provided the patient has normal renal function Dorito diversions are a collection of surgical procedures predominantly used to redirect flow of urine after surgical removal of the bladder here is a picture of an ilal conduit in which a small segment of ilium is removed from the normal course of the GI tract the uers are implanted into one end and the other end is sewn to the outer abdominal wall to form a stoma only urine and minimal intestinal secretions will flow out of the stoma which is known as a urostomy the mechanisms by which Ural diversions can cause in acidosis are complex and Vary slightly depending upon the specific procedure in question however this problem is most prominent when the uers are implant Ed into the sigmoid colon this is known as a uros sigmoid ostomy here is a simple schematic outlining the two major mechanisms by which metabolic acidosis occurs here first chloride in the urine enters the sigmoid colon where an anine exchange pump allows chloride to be removed from the sigmoid Lumin in exchange for bicarbonate being pumped inside where it eventually is eliminated in The stole the second mechanism involves Ura which encounters Ura splitting bacteria normally present in the sigmoid these bacteria break Ura down into ammonium ion which is then directly reabsorbed back through the gut wall using a process not yet entirely understood the net result is excretion of bicarb and reabsorption of hydrogen which results in the acidosis the final ideology I will talk about today is hyperemia there are two major mechanisms by which hyperemia can lead to a metabolic acidosis for the first let me show you a schematic of a cell where these yellow discs will represent potassium ions and the green ones will represent hydrogen in the presence of hyperemia there is a shift of potassium from the extracellular space to the intracellular space in exchange for a shift of hydrogen from the intracellular space to the extracellular space for the second mechanism here again is a diagram of the nefron you may remember from lecture two that hypokalemia is a stimulus in the collecting duct for potassium reabsorption simultaneous with hydrogen excretion in order to maintain electrical neutrality well the opposite also holds true in that hyperemia interferes with this process thus preventing hydrogen excretion from occurring normally this in essence can physiologically mimic a mild type 1 RTA for the final segment in this lecture I will talk a little bit about the urine andon Gap which will then lead into a discussion of an approach to diagnosing the ideology of a normal an Gap metabolic acidosis the urine anion gap which I will subsequently abbreviated UAG is somewhat analogous to the serum anion gap discussed in detail in lecture 5 the calculation is slightly different however in this case it is the urine sodium plus the urine potassium minus the urine chloride so what exactly is this calculation telling us well here is a diagram of the normal breakdown of various positively charged cations ions and negatively charged anons in the urine as you can see the cat ions are composed predominantly of sodium and potassium with a small contribution from some unmeasured cat ions which are predominantly ammonium while the annion are chloride with a slightly larger contribution from the unmeasured annion which are predominantly phosphates and sulfates the UR urine anine Gap is essentially this difference here in most causes of metabolic acidosis here is what changes now in the kidney's effort to get rid of as much extra acid as possible there is a much greater amount of ammonium which significantly increases the amount of unmeasured cations in this situation the urine annion Gap will be very low or in the specific case Illustrated here the urine anine Gap may even be negative so in essence the urine anion gap is an indirect measure of the urine ammonium which cannot be easily measured directly once again in the normal case ammonium is low so the urine anine Gap will be positive anywhere from positive 20 to positive 90 M equivalent per liter in most forms of acidosis the ammonium will be high so the urine anion gap will be low or negative anywhere from -50 to POS 20 mil equivalence per liter metabolic acidoses that are not associated with a negative or near zero urine anine Gap must be associated with impairment in the excretion of ammonium in the distal tubule this includes only chronic kidney disease and types 1 and four RTA so at this point let me present you one possible approach to determining the ideology of a normal anap metabolic acidosis this is not the only approach it's just the one that I personally find the most useful the first step is to either stop any infusion of normal saline or switch it to lactated Ringers if this caused the acidosis to resolve then excessive Salan infusion was the sole explanation if the acidosis persists then check if the creatinine clearance is less than 40 milliliters per minute if so then renal failure is the most likely explanation if creatin clearance is greater than 40 then assess the serum potassium urine pH and urine an Gap if the potassium is normal or low urine pH is low and urine anion gap is either low or negative then that GI cause is the explanation the specific ideology will almost always be evident from history at this point if the pottassium is normal or low the urine pH relatively High and the urine an Gap High then type 1 RTA is the cause if potassium is normal or low and the urine anine Gap is low or normal then type 2 RTA is the most likely cause this can be confirmed by measuring a fractional excretion of bicarbonate if the potassium is high urine pH low and urine anine Gap High then type 4 RTA is the explanation finally if the potassium is extremely high such as above seven and urine pH low then hyperemia is the explanation in and of itself of course hyperemia has its completely separate differential diagnosis that I won't get into at this point in time so that concludes this lecture on the ideologies of a normal anap metabolic acidosis please continue on to lecture 10 which will discuss the ideologies of a metabolic alkalosis [Music]