[Applause] [Music] hello this is Eric Strong again and for this 10th lecture I will be talking about metabolic alkyossis the learning objectives of this lecture are to know the differential diagnosis of a metabolic alkyossis and to be able to identify the specific ideology of a metabolic alkyossis in an individual patient one way to classify the ideologies of a metabolic alkyossis is to consider what the primary issues are both which organ between the GI tract and the kidneys the problem is primarily in and what the basic mechanism is between loss of hydrogen and gain of bicarbonate for example loss of hydrogen ions in the GI tract can be due to either vomiting nasogastric suctioning or congenital chloride diarrhea i'm going to be talking much more about the other conditions listed on this chart in a few minutes but congenital chloride diarrhea is a rare genetic defect in an epithelial annion exchanger which results in a syndrome of hyponetriia hypocchlormia and metabolic alkyossis usually presenting immediately after birth conditions in the kidneys which can result in loss of hydrogen include loop and thazide diuretics mineralocorticoid excess contraction alkalossis and barter and gdlman syndromes in the gut gain of bicarb due to the milk alkali syndrome or due to ingestion of sodium bicarbonate and in the kidneys contraction alkalossis can also lead to gain of by carb i personally prefer a different scheme for classifying these ideologies based on whether the conditions are common or uncommon causes of metabolic alkyossis common ideologies include contraction alkalossis diuretics vomiting and NG suction uncommon or rare ideologies include mineralocorticoid excess hypocalemia milk alkali syndrome ingestion of sodium bicarb barter and gtdlman syndromes and congenal chloride diarrhea i'm not suggesting here that hypocalemia is itself uncommon but rather it is an uncommon cause of a clinically relevant alkyossis in the absence of an additional process i'm going to discuss each of these ideologies one at a time including a review of the pathophysiology the reason to go into such detail is to provide you the background necessary to be able to predict which conditions can cause the metabolic alkalossis it will also help you to understand how we diagnose these ideologies and what specific therapies might exist for them one of the most common causes of a metabolic alkalossis and certainly the most common among my own patients is known as a contraction alkyossis this term refers to the metabolic alkyossis that can accompany volume depletion either actual volume depletion or the decreased effective circulating volume that can accompany diseases such as congestive heart failure to understand the physiologic processes that drive a contraction alkyossis I'm going to go through two key diagrams to which I will will be referring again later in this lecture the first is a schematic of a nephron which might look familiar from lecture 2 in the proximal convoluted tubule we can see that bicarb and sodium reabsorption are stimulated by among other things a hormone called angotensin 2 in the distal tubule through a complicated multi-step process another hormone called aldoststerone stimulates reabsorption of sodium in exchange for secretion of both potassium and hydrogen so high levels of angotensin 2 and eldoststerone lead to bicarbonate reabsorption and hydrogen secretion respectively and thus a metabolic alkyossis however what triggers high levels of angotensin 2 and eldoststerone to begin with and how is it related to a patient's intravascular volume the hormonal regulation of intravascular volume as it relates to acid base balance is a very complicated topic but I will try to simplify it as much as possible with a single slide there are several organs involved in this process most prominently of course is the kidney however there are also the adrenal glands the pituitary and hypothalamus adjacent to the base of the brain the liver and the lungs for this diagram I've colored physiologic effects in green enzymes in blue and hormones and preormones in tan regulation of intravascular volume starts with low blood pressure more accurately low renal profusion low renal profusion stimulates secretion of an enzyme called rein from the juxto glomemeular cells in the kidney jux glomeular cells are actually specialized smooth muscle cells within the apherrant arterial whose sole purpose is to secrete rein acts on a pre hormone called angotensinogen which is initially formed in the liver to create yet another preorm called angotensin 1 an angotensin 1 travels in the systemic circulation to the lungs where the uncreatively named angotensin converting enzyme transforms it into angotensin 2 an active hormone some of angotensin 2's actions include vasoc constriction and increased thirst these actions make perfect sense if you remember that low renal profusion was the trigger for this brief cascade of events initially separate from the renan angotensin system is the hypothalamic pitilitary adrenal system this begins in the hypothalamus with the release of a hormone called corticotropen releasing hormone or CR which travels locally to the anterior lobe of the pituitary gland where it triggers release of act act travels systemically to the adrenals where it stimulates conversion of cholesterol into a variety of steroid precursors through a sequence of biochemical steps beyond the scope of this lecture some of these precursors are converted into cortisol in the zona viculata of the adrenal cortex and into eldoststerone in the zona glomeulosa cortisol negatively inhibits the release of CR the direct link between the arian angotensin system and the hypothalamic pituitary adrenal system is the fact that angotensin 2 in addition to its other actions stimulates production of eldoststerone together angotensin 2 and aldoststerone act on the kidney as we just saw on the prior slide of the nephron with angotensin 2 acting in the proximal tubule and aldoststerone acting in the distuble and collecting duct the combined actions in the nephron include sodium reabsorption bicarbonate reabsorption potassium secretion and hydrogen secretion in addition cortisol actually has some activity in the nephron similar to that of eldoststerone which is only clinically relevant when cortisol levels are in great excess this is a good place to mention that eldoststerone cortisol and any other steroid hormone which acts on the kidney in some way to promote sodium reabsorption is known as a mineralocorticoid i will talk more about the mineral corticoids in a few minutes one of the net results of all this of course is a metabolic alkyossis in addition the sodium reabsorption promotes water reabsorption which in turn increases blood pressure and thus renal profusion high renal profusion is responsible for negative feedback on the duck juxto glomemeular cells and subsequent decreased renin secretion although a complete discussion of the regulation of intravascular volume would also include things such as ADH uh and other hormones this diagram is sufficient for an understanding of the generation of a contraction alkalossis the next most common ideology of the metabolic alkyossis is the use of diuretics here is a nephron once again with the proximal convoluted tubial loop of henley early distal tubule and the collecting duct i'm going to add in one additional segment the thick ascending limb which I haven't previously mentioned in this course to understand the role of diuretics in the kidney I first must mention two important transporters which are transmembrane proteins on the luminal side of the cells lining the nephron these transporters are responsible for movement of solutes from the tubular lumin back into the intracellular space from which they will eventually make their way back into the systemic circulation the first of these transporters is in the thick ascending limb where it leads to the simultaneous reabsorption of one sodium ion one potassium ion and two chloride ions the second transporter is in the early distal tubule where it leads to simultaneous reabsorption of one sodium and one chloride ion there are two classes of diuretics that lead to metabolic alkyossis the first are called loop diuretics these include fioamide or lasix bumedtanide or bumx torsomide and ethylrrenic acid loop diuretics inhibit the co-ansporter in the thick ascending limb which prevents sodium reabsorption and thus leads to an increased excretion of water the second relevant class of diuretics is the thioide diuretics these include hydrochloroioide chloroioide also known as diuril chloralone and metalazone thioides act by inhibiting this co-ansporter loop and thazide diuretics can lead to a metabolic alkalossis through two mechanisms first dehydration from excessive diuresis can trigger a contraction alkyossis alternatively blockage of sodium reabsorption proximally will lead to increased delivery of sodium to the collecting duct this will shift the electrochemical balance where sodium is reabsorbed in exchange for secretion of potassium and hydrogen thus diuretics can lead to this effect even if they don't trigger increased levels of eldoststerone next is vomiting and nasogastric suction these two have identical effects on a person's physiology and can lead to a metabolic alkalossis as a consequence of volume depletion and a secondary contraction alkyossis as well as direct loss of hydrogen in gastric fluids rich in hydrochloric acid the effect of vomiting and entuction really is that straightforward the next ideology is mineralocorticoid excess and this is a bit more complicated a state of mineralorticoid excess is suggested by the constellation of hypertension hypocalemia and a metabolic alkyossis so here is this chart again showing how hormones regulate intravascular volume most forms of mineralocorticoid excess are due to defects here in the hypothalamic pituitary adrenal axis however a very similar state can develop on account of excess levels of rein as well when I think about the specific ideologies of mineralorticoid excess I think primarily of two major categories first is hyperaldostroneism in which as the name implies an elevated aldoststerone level is the predominant problem the other category is Cushing syndrome where either an elevated cortisol level or the presence of an exogenous steroid is the predominant problem for those of you curious about medical history Cushing syndrome is named not after an endocrinologist as most assume but rather an American named Harvey Cushing who is actually a neurosurgeon and who had described the syndrome in the context of a malfunctioning pituitary gland uh Kushing led quite an interesting life among which was attending to the mortally wounded son of one of his heroes William Oler in a Flemish battlefield during World War I uh getting back to metabolic alkalossis a hyperalddoststeroneism can in turn be broken down into two subcategories the first is when elevated aldoststerone levels occur on their own in the absence of another triggering hormone abnormality this is termed primary hyperldostroneism primary hyperalddroneism is usually caused either by bilateral adrenal hyperplasia or an adrenal adenoma secretreting aldoststerone this latter condition is called Khan syndrome after Jerome Khan an American endocrinologist from the University of Michigan other more rare causes of primary hyperalddroneism include an eldoststerone secretreting adrenal carcinoma a rare genetic disorder called glucaorticoid remedial aldostroneism in which exogenous corticoids such as prennazone will paradoxically correct hypertension and finally a number of rare forms of congenital adrenal hyperplasia the details of which are fascinating to pediatric endocrinologists but which are well beyond the scope of this talk in addition to primary hyperldostroneism a nearly identical syndrome can be caused by an inappropriately elevated level of renin a condition known as secondary hyperdostism high readin results in high angotensin 2 which in turn stimulates excess production of aldoststerone high renin levels are usually due to stenosis of one or both of the adrenal arteries by either atherosclerosis or fibrouscular dysplasia fibrocular dysplasia is an uncommon but probably underrecognized cause of refractory hypertension presenting under the age of 40 with a slight female predominance venian secretreting tumors of the Jaxto glomemeular apparatus have also been described but are quite rare moving on to Cushing syndrome this can be caused at any step along the hypothalamic pituitary adrenal axis so the first cause is an elevated level of CR uh caused by a CR producing tumor which for some reason is best described in bronchioarcinoid tumors which are quite rare the next step along the axis is an elevated ACT when caused by an act secretreting pituitary adinoma it's called Cushings disease elevated ACT can also be caused by ectopic production by a tumor usually small cell lung cancer next an elevated cortisol can be the result of an adrenal adenoma a cortisol secretreting adrenal carcinoma or from chronic licorice ingestion licorice contains glyceretinic acid a natural steroid that inhibits an enzyme normally responsible converting cortisol into cortisone which has much less mineral corticoid activity a synthetic form of glycoretinic acid known as carbonoxone is occasionally used in the UK for various esophageal disorders and has hyperldroneism as a side effect the final cause of Cushing syndrome is exogenous steroids usually prennazone one final miscellaneous cause of apparent mineral excess is little syndrome which is a rare autotosomal dominant disorder in which there is excess sodium reabsorption and potassium secretion in the collecting duct hypocalemia is the next general ideology of a metabolic alkyossis hypocalemia leads to a metabolic alkyossis through several mechanisms first in the presence of hypocalemia there is a shift of potassium ions from the intracellular space to the extracellular space in exchange for a shift of hydrogen from the extracellular space to the intracellular space in addition within the nephron hypoalemia is a stimulus for the reabsorption of bicarbonate in the proximal tubule and for secretion of hydrogen in the collecting duct milk alkali syndrome this syndrome consists of the constellation of hypercalcemia metabolic alkyossis and renal insufficiency it is associated with the ingestion of a large amount of calcium and absorbable alkali it was originally described in patients consuming larger quantities of milk and sodium bicarbonate for treatment of peptic ulcer disease but currently it is more common in older women taking calcium supplements for prevention of osteoporosis milk alkali syndrome can also be seen in Oceanana and the Far East where consumption of balen nut is sometimes accompanied with either calcium carbonate or calcium hydroxide although the mechanism of pathogenesis superficially seems obvious various attempts to explain the complete pathophysiology of milk alkali syndrome have not been fully convincing and in definitive description of the disease remains elusive martyr and Gdelman syndromes are autotosomal recessive disorders of the membrane transporters in the nefron their shared features include a metabolic alkyossis hypocalemia high rein and aldoststerone levels and a lack of hypertension distinguishing features between the two include the following patients with barter syndrome frequently have mental and growth retardation and hypercalceoria it usually presents in young childhood and is exceptionally rare patients with Gdlman syndrome have a predominant complaint of muscle cramps and are hypocalceoric gdlman syndrome presents in adolescence and is very rare but not as much so as barter to understand exactly how these syndromes work here is a picture of the nephron again with our tubular transport proteins drawn in you will recall that the target of loop diuretics is a sodium potassium chloride transporter in the thick ascending limb in barter syndrome this is the effective protein therefore barter syndrome biochemically mimics treatment with loop diuretics the thioide diuretics block the sodium chloride transporter in the early distal tubule and this is where the problem is with gdlman syndrome which therefore mimics treatment with a thioide the last topic I would like to address in this lecture is how to approach a metabolic alkalossis and establish a diagnosis the first step is to assess volume status if it is low the history will almost always be sufficient to explain the situation as the patient will have either an obvious contraction alkalossis from primary dehydration diuretics vomiting or NG suction if none of those are apparent and the patient is in the appropriate age demographic you may be dealing with one of those rare cases of barter or gdelman syndromes on the other hand if the volume status is either normal or high the next step is to assess the blood pressure and serum potassium level if blood pressure is normal and potassium is low then hypocalemia is in itself the likely cause of the alkyossis of course hypocalemia has its own differential diagnosis which I won't get into here if the blood pressure and potassium are both normal then I would consider either the administration of exogenous alkali such as sodium bicarbonate tablets or milk alkali syndrome finally if the patient has significant hypertension then the condition to worry about is mineralocorticoid excess at that point rein and eldoststerone levels should be checked the appropriate means of measurement and interpretation of rein and eldoststerone is a complicated topic that I won't have time to get into in any detail in this lecture but the basic interpretation can be deduced from the aformentioned discussion of the body's hormonal regulation of intravascular volume therefore a high eldoststerone and low renan level suggest primary hyperldronism a high eldoststerone and a high rein suggest secondary hyperdostism a relatively normal eldoststerone and normal readin suggest Cushing syndrome and finally low eldoststerone and low renin suggest an extra hormonal cause of the apparent mineralquoquid excess such as exogenous steroids licorice ingestion and the rare little syndrome that does it for the differential diagnosis of a metabolic alkalossis the next two lectures will cover primary respiratory disorders [Music]