Abnormal Laboratory Results
This podcast series aims to highlight the prevention, diagnosis, and treatment of patients with diseases commonly seen in internal medicine. Host, Anil Harrison, MD, discusses patient cases with residents and with prominent experts to help educate clinicians in treating patients using a multidisciplinary approach.
In this podcast episode, Dr Harrison discusses several case presentations of patients with abnormal laboratory values, including the evaluation of liver function test results, urinalysis results, and comprehensive metabolic panel results.
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Anil Harrison, MD, is the Program Director and Chair of the Internal Medicine Residency Program at the University of Central Florida and HCA Florida West Hospital (Pensacola, FL). Dr Harrison is board certified in India and the United States.
TRANSCRIPTION:
Jessica Bard: Hello everyone, and welcome to Multidisciplinary Dialogue: Clinical Rounds and Case Reviews with your host Dr Anil Harrison, who is the program director and chair of the Internal Medicine Residency Program at the University of Central Florida and HCA Florida West Hospital in Pensacola, Florida. Today, we'll discuss abnormal laboratory values. The views of the speakers are their own and do not reflect the views of their respective institutions or the views of Consultant360.
Jessica Bard: Good morning, Dr. Harrison, how are you?
Anil Harrison, MD: Good morning, Jessica. I'm absolutely fine.
Jessica Bard: It's nice to see you. We have a few cases of folks with abnormal liver function tests, otherwise known as LFTs. But first, would you guide us through the evaluation of LFTs?
Dr Harrison: Yeah, absolutely, Jessica. So, a reasonable way of remembering is, and ALTs start about 30 to 40, and the alkaline phosphatase is three times that, which is about 120. A normal albumin is 3.5 and above, and a protein which is greater than 15 draws concern. If the alkaline phosphatase and direct bilirubin are elevated, this represents cholestasis. If it is only the alkaline phosphatase which is elevated, one can either fractionate the alkaline phosphatase to see if it is coming from bone, or one can get a GGT or a 5 nucleotidase, since isolated alkaline phosphatase elevation, especially in the elderly, is usually suggestive of Paget's disease. If the AST and ALT are significantly elevated and the alkaline phosphatase is either normal or mildly elevated, it represents hepatocellular injury. On the contrary, if your alkaline phosphatase is more than three times elevated and the AST and ALT are normal or mildly elevated, this probably represents cholestasis. If one confirms an obstructive pattern, getting an ultrasound of the hepatobiliary system is the next step.
Jessica, there is another way of doing this, which is to calculate the R factor, which is the patient's ALT divided by the upper limit of normal ALT, in the numerator position, of course, with the patient's alkaline phosphatase divided by the upper limit of normal of alkaline phosphatase in the denominator position. The great thing about this is, if the R factor is greater than five, this points towards hepatocellular injury; whereas, if the R factor is less than two, it points towards cholestasis. And then, of course, the next step is to either get a GGT or a 5NT. If for some reason the R factor is between two and five, this usually represents a mixed picture, which is what one finds in most instances.
Jessica Bard: Could we discuss the causes of AST and ALT evaluations, and what should one do with isolated evaluations of AST and ALT?
Dr Harrison: Sure. So, if the AST and ALT are elevated twice normal, it is considered mild, but, if it is more than 15 times normal, it is considered severe, while moderate elevations are from two to 15 times normal. Some causes, Jessica, for significant AST and ALT of moderate to severe elevations of more than 1,000, I would say, would be things like acute viral hepatitis, medications, and toxins, and, of course, one can't forget ischemia or congestion of the liver. Whereas mild to moderate elevations of AST and ALT occur with alcohol or non-alcoholic fatty liver disease, certain medications, drugs, toxins, even autoimmune conditions, along with metabolic and genetic abnormalities such as Wilson's disease, hemochromatosis, and alpha-1 antitrypsin deficiencies can do that.
With abnormalities in liver function tests, the thoughts ought to be, does the patient have symptoms or is it an incidental finding? What has the pattern been in the past? Which means, what have the ASTs and ALTs done before? Is this something new? Is it stable? Is it improving or is it actually getting worse? Is the abnormality mild, is it moderate, or is it severe? Of note, if both elevated AST and ALT, and the patient has a altered mental status, and is jaundiced, has right upper quadrant pain, and is nauseated, and is vomiting, has malaise, and especially if the INR is more than 1.5, then the patient has acute liver failure.
It is unlikely with ASTs and ALTs being twice normal that the patient can be symptomatic, but it can happen. What one looks for is a history of alcohol, drugs, herbs, supplements, metabolic signs and symptoms, any signs or symptoms of congestive heart failure, and, of course, what are the risks for hepatitis B and C? In this scenario, you might consider repeating the liver function test in about, let's say, two to four weeks. If one discovers an etiology during this period, one intervenes; otherwise, recheck these labs in three to six months while waiting for any alarming symptoms.
If after six months, if the AST/ALT are still elevated and there is no history of alcohol, you can consider getting an ultrasound of the liver, hepatitis B and C profiles, iron studies, and some other labs. Depending on the severity of AST and ALT elevations, and also depending on how the patient is doing, one can request LFTs, coagulation screens, hepatitis serologies, also testing for Epstein-Barr virus and the cytomegalovirus, checking for anti-mitochondrial antibodies, anti-smooth muscle antibodies, anti-liver-kidney microsomal antibodies, ANA, P-ANCA, TTG, serum acetaminophen levels, urine copper and serum ceruloplasmin to rule out Wilson's disease, and ferritin to rule out hemochromatosis. I must say, I usually get a transferrin percent because ferritin can be elevated with inflammatory conditions.
Jessica Bard: Can we get some clues historically when addressing abnormal liver function tests?
Dr Harrison: You're right on that, Jessica, one can get certain clinical clues with chronic AST and ALT elevations, such as the viral hepatitises. Discovering viral hepatitis is important because hepatitis C now is a treatable disease, and the WHO is working towards complete eradication. Without treatment, hepatitis C might lead on to chronic hepatitis, cirrhosis, and liver cancer, and, of course, death; hence, offering treatment after screening folks for hepatitis C is imperative.
Most adults, about 95%, who get hepatitis B recover completely as opposed to if it's a neonate who gets hepatitis B infection. The idea, therefore, is to prevent chronic liver disease and its implications. Therefore, in pregnant women, checking for hepatitis B is important so that the baby can be inoculated. Similarly, as I said, the baby can be inoculated immediately in birth and have a 95% chance of the baby not developing chronic hepatitis B.
With hepatitis C, the country of origin is important because of quite a few numbers of immigrants who do not know that they have hepatitis C, and this could have been because of faulty inoculation or blood transfusions. The incidence of hepatitis C is about 20% in Egypt, which means one in five people walking have hepatitis C. And they probably got it from the vaccinations they received in the 1960s and the 1970s. Thus, the importance of checking for hepatitis B surface antigen is important, and checking for hepatitis C antibodies with reflex to titers, if indicated.
Of course, one can suspect non-alcoholic fatty liver disease in a person who's obese, who has hypertension, who's a diabetic, and who has hyperlipidemia. Similarly, a history of alcohol and drugs is important. A history of exposure and reversal with treatment during withdrawals gives you an idea that it could be alcohol or drug related. Likewise, one might suspect hemochromatosis if the patient presents with pseudogout, diabetes, a family history, and cardiomyopathy, or a possibility of autoimmune hepatitis when there are other autoimmune issues occurring with the patient, especially if the patient is a female. Consider Wilson's disease a possibility if there is a history of neuropsych issues, hemolytic anemia, Kayser-Fleischer rings in a young person less than 40. I say this because it is unusual for Wilson's to present after age 40, since most patients present much before that.
Jessica Bard: What if, on LFTs, the serum alkaline phosphatase is elevated?
Dr Harrison: Sure. So with isolated elevations in the alkaline phosphatase, Jessica, the first thing to do is to rule out physiological causes such as, is the person pregnant, was the blood checked immediately after the person having eaten, which can cause alkaline phosphatase levels to go up one to one-and-a-half and sometimes even two times the upper limit of normal. If so, one should, therefore, repeat it on a fasting stomach.
If the alkaline phosphatase is elevated, as I mentioned, you can either fractionate the alkaline phosphatase to see if it's coming from bone or you can do a five NT or a GGT. If the 5NT and/or GGT are normal, then the alkaline phosphatase is likely of bone origin, and, therefore, one should evaluate for bone disorders. If, however, the alkaline phosphatase, the GGT, or the 5NT are elevated, doing an ultrasound on the liver and the hepatobiliary tree is the next step.
You see, an ultrasound of the liver or the hepatobiliary tree is like doing an EKG. It gives you information as to if there might be an obstruction and/or an infiltration outside the liver or within the liver. With extrahepatic obstructions, related to, it might be the gallbladder or the common bile duct, the ampulla of Vater, the pancreas. Other etiologies, such as primary sclerosing cholangitis, with extrahepatic strictures are possibilities, and, of course, tumors and infections and infestations are some other possibilities. If it's within the liver, which means intrahepatic obstruction, it can be caused because of primary biliary cirrhosis or primary sclerosing cholangitis. Certain drugs can do that, infiltrative diseases and disorders can do that, total parenteral nutrition can do that, and, of course, cirrhosis and cancers can do that.
If the alkaline phosphatase along with the GGT or 5NT are elevated, a right upper quadrant ultrasound, as I mentioned before, is required, where one might see dilated bile ducts. And if so, then the next step is to get an MRCP or an ERCP. If on the ultrasound there is no biliary duct dilatation, the next step is to check for anti-mitochondrial antibodies. If the anti-mitochondrial antibodies are positive but the ultrasound is normal, or the anti-mitochondrial antibodies' negative, or the hepatic parenchyma is abnormal, one should proceed with the liver biopsy. If the anti-mitochondrial antibody is negative and the ultrasound is normal, absolutely normal, the next thing to do is to assess the degree of elevation of alkaline phosphatase. If the alkaline phosphatase is more than 50% elevated, proceed with an MRCP or an ERCP or a liver biopsy; but if it's less than 50% elevated, you could observe.
Jessica Bard: What if, on a comprehensive metabolic panel, one notices abnormalities of serum albumin and prothrombin?
Dr Harrison: So if on a comprehensive metabolic panel you discover a low albumin coupled with an elevated prothrombin time, this might suggest an etiology involving the synthetic function of the liver. If, on the other hand, it is an isolated low albumin, then you have to consider possibilities, could it be because of malnutrition? Could it be because of protein-losing enteropathy? Could it be because of nephrotic syndrome? Or, could it be because of acute inflammation?
If it is an isolated prothrombin time which is elevated, the etiologies can be problems with absorption of vitamin K, or it could be the liver itself, or certain drugs which might be causing the same.
Jessica Bard: Excellent. So moving on, we have a different scenario related to the heart. We have a couple of patients for you I want to run by you here, Dr. Harrison. A 35-year-old with shortness of breath has a BNP of 60. What are your thoughts there? And then also, a 60-year-old with diabetes, hypertension, coronary artery disease, and heart failure presents with shortness of breath. His troponins are elevated and his BNP is 800. What are your thoughts?
Dr Harrison: Yeah, those are great questions. Jessica. You see, the utility of a BNP, which refers to brain natriuretic peptide, or an NT-pro-BNP, depends actually on the clinical scenario, because asymptomatic individuals can have elevated levels of these and symptomatic individuals with heart failure can have normal levels. The half-life of BNP is about 20 minutes, whereas the half-life of NT-pro-BNP is about 70 minutes. NT-pro-BNP levels rise much more than BNP levels. Giving an example, an NT-pro-BNP level of about 900 equals a BNP of 100. One has to remember, folks who are on ARNIs, which is a combination of neprilysin inhibitors and angiotensin receptor blockers such as Entresto, one needs to measure NT-pro-BNP instead of BNP.
Jessica Bard: So what are other causes for elevated BNP? When would you do a BNP and why?
Dr Harrison: Well, this could be cardiac related, such as with heart failure. Both left and right heart failure, systolic and diastolic heart failures, coronary artery disease, valvular heart disease, myocardial disease, pericardial disease, and arrhythmias, they can all cause an elevation in BNP. Lung causes, such as infections of the lungs, pulmonary embolism, pulmonary hypertension, COPD, sleep apnea, they can all cause an increase in the BNP levels. There are other etiologies that can have elevated BNP levels, such as with stroke, with sepsis, with cirrhosis, burns, and, of course, with respiratory failure.
Low levels of BNP can be seen in obese people or in very young people. Having said that, a BNP less than 100 has an excellent negative predictive value for heart failure as a cause. BNP greater than 400 most often occurs with heart failure. BNP and troponins also provide prognostic value in acute and chronic heart failure, and should be done upon a admission. However, tracking BNP levels during a patient's stay with heart failure is not recommended.
NT-pro-BNP ranges. So, for example, if a person is less than age 50, you think below 450 is normal; ages 50 to 75, below 900 is normal; and for folks who are over age 75, an NT-pro-BNP of less than 1,800 is normal.
Therefore, coming back to your question, Jessica, the 35-year-old with shortness of breath who has a BNP of 60, this tells me the shortness of breath is not because of heart failure, as a BNP of less than 100, as we mentioned, has an excellent negative predictive value for ruling out heart failure. The other patient is the 60-year-old with diabetes, hypertension, coronary artery disease, and heart failure, who presented with shortness of breath and chest discomfort. His EKG revealed ST depressions in the anterior leads, and his troponins were elevated, and his BNP was 800. So, rightly so, the troponins and BNP were done. This patient with a history of heart failure with new changes on the EKG has myocardial ischemia, which perhaps is contributing to his worsening heart failure.
Jessica Bard: Fantastic. Now, moving on to the renal system, we have a 55-year-old patient. Could you actually tell us about this 55-year-old patient, Dr. Harrison?
Dr Harrison: We have a 55-year-old smoker known to have lupus, hypertension, and hyperlipidemia, who's found to have microscopic hematuria on routine exam. On dipstick, he is found to have a specific gravity of 1.020, a pH of five. He has 1+ protein, 2 WBCs, and more than 100 RBCs. Glucose ketones, leukocyte esterase, and nitrite are negative. He has bilirubin. He has no bilirubin nor urobilinogen, okay.
So, talking about a dipstick, Jessica, a dipstick only detects albumin. So trace protein in the urine means five to 30 milligrams of albumin per deciliter. 1+ is 30 milligrams per deciliter. 3+ is 300 milligrams per deciliter. 2+ is about 100 milligrams per deciliter. And if, on a dipstick, we have 4+, that means that the person has more than 1,000 milligrams per deciliter of albumin.
You see, the other kinds of protein in the urine could be related to things like low molecular weight protein, which is seen in tubulointerstitial disease and Fanconi syndrome. Similarly, my globulin, hemoglobin, and monoclonal light chain proteins are other proteins that can be found in the urine. Also remember, in an alkaline urine, you can get false positive dipstick for protein.
Jessica Bard: So if the dip stick detects only albumin, how does one determine the other kinds of proteins?
Dr Harrison: Yeah, that's a great question, Jessica. So if the dipstick only detects albumin, to detect other proteins, you must do the sulphosalicylic as a test, such as for light chains or Bence Jones proteins. The other interesting thing is, in acute kidney injury, the albumin in the urine might be low, but if you do a sulphosalicylic acid test and it is positive, it is very suggestive of cast nephropathy.
Quantitatively, the protein creatinine ratio should be less than 150 milligrams per grams, which is equivalent to less than 150 milligrams of protein in 24 hours. Normal albumin should be less than 30 milligrams per 24 hours. 30 to 300 milligrams is moderate microalbuminuria, and greater than 300, if present over six months, is chronic renal insufficiency, and it signifies significant microalbuminuria. An albumin creatinine ratio of 30 to 300 is moderate, and greater than 300, as I mentioned, is severely increased albuminuria. So you would be monitoring for microalbuminuria in patients who have diabetes or who have lupus.
The other thing I would like to mention is you could get between 150 to 200 in tubulointerstitial diseases, glomerular diseases. And, of course, as all of us know, nephrotic-range proteinuria is greater than 3.5 grams confirmed with two samples of urine. One can get transient proteinuria if one's unwell, has fever, or if one has exercised excessively. And, of course, there is an entity called orthostatic proteinuria as well, which can be confirmed with split urine albumin testing.
Talking about glucose, you can get glucose in the urine with normal blood sugars, such as with Fanconi's syndrome, with pregnancy, and certain proximal renal tubular abnormalities. Ketones in the urine are found, of course, in diabetic ketoacidosis, alcoholic ketoacidosis, starvation ketoacidosis. But remember, remember, ketones in a dipstick will check only for as acetoacetate. It does not check for beta-hydroxybutyric acid, because in alcoholic ketoacidosis, you have more of beta-hydroxybutyric acid.
The other thing you mentioned was leukocyte esterase. So leukocyte esterase is an enzyme which is present on the WBCs. And for nitrites to be positive alongside, you must think of microorganisms such as Klebsiella, or E. coli, proteus, and pseudomonas. Of note, false negative nitrites in a person who has a urinary tract infection could be secondary to a gram-positive organism such as enterococcus.
Greater than three WBCs per high power field is abnormal. Leukocyte esterase and nitrites positive in a patient signify a UTI. Urine for bilirubin and urobilinogen, they, Jessica, are low yield. Bilirubin that you find in the urine is conjugated bilirubin, which can be seen in obstructive jaundice and severe liver disease. False positive urine for bilirubin can be seen with chlorpromazine, and false negative can be seen with ascorbic acid. Urobilinogen comes from when bilirubin is converted to urobilinogen in the gut, which is then reabsorbed and excreted in the urine, and this is seen with hepatic necrosis and can also be seen with hemolytic anemia.
Jessica Bard: How would you evaluate our patient with hematuria?
Dr Harrison: That's a good question, Jessica. With microscopy, there are three things that you look for, cells, casts, and crystals, the three Cs. Greater than 3 RBCs per high power field is considered hematuria. Of course, false positive hematuria could be because of menstrual periods, rifampin, phenytoin, beets, myoglobin, rhubarb, and, of course, porphyrias. Hematuria can be gross described as seeing blood or blood clots. Microscopic hematuria could be because of hemolysis, infections, exercise, kidney causes. Examples being, rapidly progressive malignancies, thin membrane disease, IgA nephropathy, chronic glomerulonephritis, are all causes for microscopic hematuria.
The main thing is, when evaluating the hematuria, one should look for the type of red cells. This is very important. Are they dysmorphic or are they isomorphic red cells? Because, why is this important? Dysmorphic red cells would represent hematuria secondary to glomerular causes, whereas isomorphic red cells would represent coming from genitourinary etiologies. You would look out for red cell casts with microscopic hematuria, although, although they are not seen every time. Therefore, it is more sensitive to look for acanthocytes, which kind of look like vesicles jutting out of red cells, kind of like Mickey Mouse faces. Therefore, if you have urinary acanthocytes or red cell casts, fever, hypertension, joint pains, and greater than 300 milligrams per gram of proteinuria, this points towards a glomerular cause. And in this scenario, one should get an ultrasound of the kidney followed by, perhaps, a biopsy.
Jessica Bard: You mentioned GU malignancies as the etiology for hematuria when isomorphic red cells are seen on microscopy. What are some of the risk factors and how should one proceed?
Dr Harrison: Sure, absolutely. So the risk factors, Jessica, for GU malignancies, or genitourinary malignancies, would be male greater than age 35 using tobacco, exposure to benzene products, aromatic products, someone who's had chemotherapy or irradiation, or who's had chronic urinary tract infections. The best non-invasive way is doing an ultrasound; however, the most sensitive modality for evaluating genitourinary malignancies is a CTU, which is a CT urography, along with the cystoscopy. If these are negative, you could follow them in six months, then 12 months, 24 months, and 36 months.
Jessica, I would like to point out, if you have a patient with blood clots who is on an anticoagulant, do not take it for granted that it is because of the anticoagulant, other etiologies need to be evaluated.
Jessica Bard: What about white blood cells in the urine?
Dr Harrison: So greater than 4 WBCs per high power field is significant, and if you have a positive leukocyte esterase and nitrites, it signifies a urinary tract infection. Sterile pyuria, which means you have WBCs in the urine but the cultures are negative, could be secondary to tuberculosis or allergic interstitial nephritis caused by antibiotics, nonsteroidal anti-inflammatory medications, or even proton pump inhibitors. And, of course, you can have sterile pyuria because of kidney stones. Or, if there is a transplant rejection, you can get culture negative white cells in the urine.
Urine detected by the right stain, they are non-specific. They can be seen with so many conditions like allergic interstitial nephritis, rapidly progressive glomerulonephritis, it can be seen with embolic disease, prostate infections, parasitic infections, urinary tract infections, small vessel vasculitis, and so on, and so on; therefore, eosinophils in the urine have a poor sensitivity and specificity.
Jessica Bard: What are the other cells seen on urinalysis?
Dr Harrison: The other cells that can be seen, the renal tubular epithelial cells, which are about one and a half to three times the size of the WBCs, whereas the transitional epithelial cells can be seen anywhere from the renal pelvis to the proximal urethra, which are slightly larger than the renal tubular cells. Squamous epithelial cells are huge, they're large, irregular, and with a small nucleus, and they come from the external genitalia, or the distal urethra, and signify contamination with casts.
The matrix is composed of Tamm-Horsfall protein, which now is called uromodulin, which collects a lot of cellular debris or lipoprotein droplets. So the tubular casts take the shape of the tubules and, because there is necrosis, they're described as tubular, muddy brown-pigmented casts with a shape that is cylindrical. The more the muddy brown cylindrical cast that you see depends on how severe the acute tubular necrosis is. Erythrocyte casts are specific, but not sensitive, for glomerulonephritis, and, as I mentioned, it's better to look out for acanthocytes instead. WBC casts signify tubular inflammation.
Jessica Bard: Could you talk about crystals and casts in urine?
Dr Harrison: Absolutely, Jessica. So, crystals in the urine can be seen with the folks who are receiving intravenous acyclovir, folks who are receiving a methotrexate. Calcium oxalate crystals, they're like an ox, are dumbbell-shaped or are envelope-shaped, and are seen with urine calcium, when the urine calcium is elevated, and is also seen with ethylene glycol poisoning with the type two renal tubal acidosis and with urinary tract infections.
Calcium phosphate crystals, phosphates, and PFA prisms are like prisms, and are also seen with your distal type one RTA, tumor lysis syndrome, and with phosphate nephropathies.
MAP, where your life has been mapped out and you lie in a coffin, the magnesium ammonium phosphate crystals, and you see them with chronic UTI secondary to urease-splitting microorganisms, also termed struvite stones.
Uric acid crystals, they resemble a needle, they're needle-shaped, rhomboid, and you can see them with gout or tumor lysis syndrome, can see them with obesity, with diabetes, and when the urine pH is low.
Cystine stones are hexagonal and, as mentioned, muddy brown casts are seen with acute tubular necrosis.
So, therefore, our patient, a 55-year-old smoker with lupus, hypertension, and hyperlipidemia, who was found to have microscopic hematuria needs microscopic examination to determine if the red cells are isomorphic or dysmorphic, while also looking for casts and crystals. If the red cells are dysmorphic, this would point to glomerular etiologies, and I can think of lupus and hypertension in this patient as possibilities. But, if they are isomorphic, the etiologies could be the urogenital system, and, with this patient's history of smoking, a malignancy needs to be ruled out with a CTU and a cystoscopy.
Jessica Bard: Thank you. So moving on to issues with potassium, we have a 50-year-old with weakness discovered to have a serum potassium of 3.2 milliequivalents per liter. What are some causes of hypokalemia, and how does it affect our patient, and how do we go on to evaluate the patient?
Dr Harrison: Sure, Jessica. So the majority of the potassium that is filtered at the glomerulus is reabsorbed in the proximal tubule and the loop of Henle. Whereas, most of the potassium that is excreted is actually derived from the tubular secretion by the principle cells in the connecting tubule and the cortical collecting tubules. Aldosterone plays a central role in this process. An increase in the plasma potassium stimulates the secretion of aldosterone, which then appropriately increases potassium secretion to return the plasma potassium to normal. So some causes for hypokalemia are vomiting, diarrhea, diuretics, redistribution, and, of course, hypomagnesemia.
Hypokalemia, or low potassium, can result in muscle weakness, cardiac arrhythmias, certain renal effects, and glucose intolerance. So when evaluating low potassium, the important thing is, what is the patient doing? How does the patient feel? What is the degree or the severity of hypokalemia? Would this necessitate an electrocardiogram to look for changes related to hypokalemia, such as ST depressions, T-wave inversions, U waves, prolonged QT interval, etc.? Similarly, other questions that should come to one's mind, does the patient have metabolic acidosis or alkalosis? How low is the potassium and what is the heart doing? Is the magnesium normal? Therefore, getting a BMP and a magnesium and perhaps a thyroid panel would be appropriate.
Jessica, a serum potassium of less than 3.5 milliequivalents per liter, the question comes as, is this related to metabolic acidosis or alkalosis? One can get a 24-hour urine for potassium to see if the potassium is less or more than 30, three zero. This can be cumbersome, and, therefore, getting a spot potassium creatinine ratio is a more reasonable idea to see if the potassium creatinine ratio is less than 13, one three, or more than 13. Understandably, if the 24-hour urine potassium is more than 30 or a spot urine potassium creatinine ratio is more than 13, this signifies that there is urinary potassium wasting. Conversely, if the potassium creatinine ratio is less than 13 or a 24-hour urine for potassium is less than 30, three zero, this could relate to GI losses, transcellular shifts, prior diuretic use, or a poor intake of potassium-containing foods.
If the patient has metabolic acidosis with low urinary potassium, this might represent lower GI losses, such as with diarrhea. If the patient has metabolic acidosis with a high urinary potassium, this would be because of diabetic ketoacidosis or type one or type two renal tubular acidosis. On the contrary, if the patient has a metabolic alkalosis, the first thing to do is, what is the blood pressure doing? If the blood pressure is normal or if it's low with a high urine potassium, this would be because of vomiting, Bartter or Gitelman syndrome, or due to prior diuretic use. If, with the metabolic alkalosis and hypokalemia, the patient's blood pressure is elevated and also has elevated urinary potassium, this could be because of mineralocorticoid excess or because of renal vascular disease or current diuretic use.
The treatment. The treatment of low potassium depends on its severity and how the patient feels and what the heart is doing and what the rhythm is doing. Potassium can be replaced as potassium chloride or potassium bicarbonate or its byproducts, such as potassium acetate and potassium citrate, or one can replace potassium as potassium phosphate. Therefore, a patient who has hypokalemia with metabolic acidosis, replacing it with either potassium bicarbonate or potassium citrate or potassium acetate would make sense. On the other hand, if a patient has a proximal renal tubular disorder and is losing a lot of phosphate, replacing it with potassium phosphate would be ideal.
The severity of hypokalemia and what the heart is doing also determines whether potassium ought to be given orally or parenterally. If the patient's potassium is between, let's say, 3 and 3.4 milliequivalents per liter, giving potassium 10 to 20 milliequivalents maybe three to four times a day while monitoring serum potassium levels would be appropriate. For patients with chronic hypokalemia, you could also add amiloride, which would be appropriate. On the other hand, if the potassium is low, really low, between, let's say, 2.5 and 3, most patients are symptomatic or the heart is misbehaving, giving 20 milliequivalents parenterally every two to three hours while checking serum potassium every two to four hours is appropriate. Rates as high as 40 milliequivalents per hour have been used for life-threatening hypokalemia.
Of note, rates above 20 milliequivalents per hour are highly irritating to the peripheral veins. When such high rates are given, they should be infused in a large central vein or into multiple peripheral veins. If a patient has hypokalemia with hyperaldosteronism, adding spironolactone or eplerenone is appropriate.
Jessica Bard: While we're talking about potassium, we have another patient where the lab calls in with a potassium value of 6.2 milliequivalents per liter on a patient that you are covering for. What would you do, and how would you go about evaluating and treating?
Dr Harrison: Yeah, sure, Jessica. So the potassium that is greater than six milliequivalents per liter, one could repeat the potassium again, the patient might have pseudo hyperkalemia, which is not true elevated potassium, or you can get blood gases along with a repeat potassium. One needs to know what the patient's symptoms are to see if he or she is experiencing tingling muscle weakness, paralysis, etc. And, of course, one should get an EKG if confirmed that the potassium is greater than six. Once confirmed that it is true hyperkalemia, on the EKG, one should look for tall T-waves, absent P-waves, a wide QRS, heart block patterns, ventricular fibrillation, or a sine wave, which are some of the things that are seen on the electrocardiograph. And understanding, one should consider reasons for high potassium and categorize them as, are they due to either transcellular shifts, seen with acidosis, hyperthermia, or beta blockers, or is it because of cellular destruction, such as with hemolysis, rhabdomyolysis, excessive burns, tumor lysis syndrome, crash injuries, trauma, etc., etc.?
The other thing, it could be that it's a problem with the kidneys, such as, does the person have renal failure, and with a patient using salt substitutes, which has a lot of potassium in it. And, of course, lastly you have to think of, does the patient have impaired aldosterone, or if the patient has type four renal tubular acidosis.
Now, of course, if the potassium is elevated, one has to quickly think about, how do we treat it? And it would depend on the symptoms or the EKG changes, and it can be categorized as acute for immediate treatment and late treatment. So in the acute or in the immediate setting, that would entail giving 10 ml of 10% intravenous calcium gluconate or calcium chloride. And now, this lasts for about 10 minutes. The other thing one can do is to give 10 units of rapid acting insulin with 50 cc or 50% dextrose. The onset of action is in about half an hour, and it lasts for about six hours. Another thing one can do is to give a beta agonist, such as albuterol, where the onset is quick, it's in about 15 minutes, and its action lasts for about two to four hours. One can also administer 20 grams of sodium or calcium polystyrene sulfonate; the onset of action is in two to four hours, and its effect can last for several hours.
So the treatment of hyperkalemia under specific conditions would be also, for example, if somebody has high potassium with renal failure, that patient might require dialysis. If the hyperkalemia is with hypervolemia, then diuresis would help. And if it's hyperkalemia with acidosis, the patient might benefit from sodium bicarbonate, 8.4%, 100 cc. And, of course, if hyperkalemia is secondary to adrenal insufficiency, that patient would benefit from hydrocortisone, 100 milligrams parenterally.
Jessica Bard: Now, we have two cases in regard to sodium abnormalities. Could you present those for us please?
Dr Harrison: Jessica, so the first question is, we have a 50-year-old who presents with weakness and is found to have a sodium of 128, a potassium of 3.5, a chloride of 100, a BUN of 20, a creatinine of 1.2, and a blood sugar of 600. What will you do next with regards to the sodium?
And the second question is, a 80-year-old with dementia is evaluated for confusion, and investigations reveal a sodium of 149. His urine sodium is five. What will you do next?
Okay. So to do this, let us take or consider two compartments, the intracellular and the extracellular compartments, lying side by side, partitioned by a porous sieve, which allows only water to be shared between them. These two compartments, Jessica, the intracellular and the extracellular, constitute 60% of one's body weight, or approximately 40 liters of fluid. After which, the intracellular compartment has 40% of the body weight, or 25 liters of fluid, while the extracellular compartment has 15 liters of fluid, or about 20% of body weight. So the extracellular compartment can further be divided into the interstitial fluid volume, which equals 12 liters, or 80%, of extracellular fluid, and the plasma volume, which is three liters, or 30%, of extracellular fluid.
Remember, sodium is predominantly in the extracellular compartment, and, as mentioned, it cannot pass through the pores in through the intracellular compartment. All the water can, or water does move between the intracellular and extracellular compartments. So, therefore, if you consider a faucet is opened into the extracellular compartment, water is going to go through the pores into the intracellular compartment as well. And if it's the brain that we are talking about, the brain can swell, called cerebral edema, because of this. On the contrary, if a lot of salt is added to the extracellular compartment, where there is more salt than water, it is going to draw fluid out of the intracellular compartment causing the intracellular compartment to become devoid of water, analogous to a plum turning into a prune. One needs to imagine what would happen to the brain cells.
Dr Harrison: Now, let us say there is excessive salt and water which reaches the kidneys, which, therefore, suppresses the juxtaglomerular apparatus causing a decrease in the secretion of renin and, hence, angiotensin II, aldosterone, and ADH. This, therefore, would result in more sodium being dumped into the urine. And because ADH is also suppressed, there is a lot of water that gets dumped in the urine as well. Hence, the urine sodium would be elevated, which means more than 20. However, the urine osmolality would be low, because ADH is suppressed and there is water that is being excreted into the urine; hence, a urine osmolality which is below 300 occurs.
Conversely, if the kidneys are deprived of salt and water, the juxtaglomerular apparatus is stimulated to produce renin, which stimulates angiotensin II production, which stimulates aldosterone, and, hence, this stimulates ADH as well, resulting in a lot of reabsorption of salt and water, thus causing urine sodium to be below 10 and the urine osmolality to be high, which is greater than 300.
The issue with age or the syndrome of inappropriate ADH secretion, there seems to be excess volume in sodium, which suppresses the juxtaglomerular apparatus, and, therefore, there is reduced production of renin, angiotensin, and aldosterone. However, there is a disconnect with the ADH, and ADH continues to be created inappropriately. This results in sodium being dumped into the urine but water being retained in the body, and hence, the urine sodium is more than 20 and the urine osmolality is greater than 300.
So how does one treat disorders of sodium and water deprivation? Well, if the problem is water, then you give the person water orally or intravenously or as a de-fied water. If the problem is due to sodium, give normal saline either orally or parenterally, and, of course, treat the underlying cause.
While evaluating, Jessica, hyponatremia, the thing that is important to know is how is the patient doing, which comes from a good history and physical exam. Additional labs while evaluating hyponatremia would be to get a serum and a urine osmolality along with a BMP and a urine for sodium. When the lab measures serum osmolality, it measures all the osmoles present in a person's blood. Whereas, when one calculates a serum osmolality, which is two times sodium plus blood glucose divided by 18 plus blood urine nitrogen divided by 2.8, this is dependent predominantly on the amount of sodium in a person's blood, provided, of course, the blood glucose and blood urea nitrogen are stable. The serum tonicity is two times sodium plus glucose divided by 18, and, as you see, it does not take blood urea nitrogen into the calculation; hence, the difference between serum tonicity and osmolality.
Dr Harrison: Causes of, a greater than 10 between the measured and calculated serum osmolality would constitute hypertonic hyponatremia or hyperosmolar hyponatremia. Meaning, thereby, that there are other osmoles present in the extracellular compartment, which is drawing water out from the intracellular compartments and is causing sodium to be apparently low. These would be things such as mannitol, sorbitol, urea, glucose. So giving an example, while conducting urological and gynecological surgical procedures, the irrigation fluid that is used contains sorbitol, which would be an example in a person who can get hyperosmolar or hypertonic hypernatremia. Similarly, when mannitol is given, for example, in a person with an intercerebral bleed in order to reduce the intracranial tension, this can also result in a hypertonic hyponatremia.
If the measured and calculated serum osmolality are the same, but the person has hyponatremia, it would be worthwhile looking at the person's lipids and proteins, because elevated levels of these two can cause hyponatremia, or, rather, this is called pseudohyponatremia. When both the measured and the calculated osmolality are low and a patient has hyponatremia, this is referred to as hypotonic or hypoosmolar hyponatremia.
The next thing to do is to do a careful history and physical in trying to determine the person's volume status, such as, does a person have excessive volume? Is the person hypovolemic, or lack of volume, or is the person euvolemic, where the volume, the fluid status, does not seem to be an issue? When considering hypervolemic hyponatremia, things like cardosis, nephrosis, and cirrhosis need to be considered, where cardosis refers to heart failure, nephrosis to kidney failure, and cirrhosis, of course, to liver failure.
In conditions with hypovolemic hyponatremia, this occurs due to fluid loss or when fluids have been restricted. When considering euvolemic, where the volume status is okay, euvolemic hyponatremia, consider the pneumonic RATS, where R stands for renal tubal acidosis type four, A for Addison's disease, T for thyroid disorders, and only after these have been ruled out, then consider the letter S, which stands for SIADH.
While considering treatment of hyponatremia, one tries to figure out if it is acute or if it is chronic. Understandably, if it's mild, you treat it with salt or with Gatorade. If moderate, you treat it with normal saline. And if the hyponatremia is severe, which means either the serum sodium is less than 120 or the person is having seizures or is in a coma, in that scenario, you treat it with hypertonic saline, or a 3% normal saline.
While treating hyponatremia, one must be cognizant and not overdo it or overtreat it because, if you remember, if there is too much of salt or if the salt increases rapidly in the extracellular compartment, it can draw fluid out from within the cells, causing plums to become prunes, resulting in the central demyelinating syndrome or the central pontine myelinolysis. With treatment of moderate to severe hyponatremia, the milliequivalents of sodium which needs to be replaced depends on your desired sodium minus your current sodium multiplied by 0.6 multiplied by your body weight in kilograms.
Dr Harrison: For severe or symptomatic hyponatremia of a sodium that is less than 120 milliequivalents per liter, the correction of sodium needs to be from 120 milliequivalents to 125 milliequivalents per liter, and, within four hours, using 3% sodium chloride. 3% sodium chloride equals 513 milliequivalents per liter, and the dose of 3% sodium chloride will be equal to... So if you have to get the sodium up to 125, so that would be 125 minus your actual sodium, multiply it by body weight in kilograms, multiply it by 0.6, and this amount has to be given in four hours. Delay in correction may cause death. Now, the rest of the correction can be done over the next 48 hours, but the first four hours are crucial to get the serum sodium up to 125 milliequivalents.
If the hyponatremia is not severe, the correction formula remains the same, however, the correction of sodium should be less than eight milliequivalents in the first 24 hours and less than 18 milliequivalents over 48 hours.
Therefore, if you take the first patient, the 50-year-old who presented with weakness and was found to have a sodium of 128, a potassium of 3.5, a chloride of 100, BUN and creatinine were normal, but the person's blood sugar was 600. In this scenario, the hyponatremia is secondary to elevated blood sugar in the extracellular compartment, and the correction should be 1.6 times every 100 milligram increase in blood sugar over 100 to 400; and after 400, the correction has to be 2.4 milliequivalents.
So with our patient's blood sugar of 600, 400 minus 100 equals 300, and, therefore, three times 1.6 would be 4.8, and from 400 to 600 would be 2.4 times two, which is 4.8. So a total of 9.6 milliequivalents of sodium needs to be added to the patient's serum sodium of 128, which would be 138, which, as we know, is normal serum sodium. Hence, as this patient's blood sugar comes down, his serum sodium will revert to normal.
When the serum sodium is greater than 145, this refers to as hypernatremia. So that is your second case. How do we categorize hypernatremia? Hypernatremia can be secondary to increase in volume, where sodium and water are increased, or this could be secondary to euvolemia, where the volume is normal, or hypovolemia, or low volume states.
Dr Harrison: So, Jessica, some examples of hypernatremia with low volume, this can be divided into renal and extrarenal causes. Renal losses would be secondary to osmotic diuresis, and the urine sodium in this case is more than 20, whereas extrarenal losses occur in the elderly who cannot get to water. The other etiology has been significant sweating or diarrhea, where, again, the amount of water lost is greater than the amount of sodium lost. And in these scenarios, the urine sodium is going to be less than 10.
The treatment of hypernatremia in these scenarios would be to give normal saline, because 0.9% sodium chloride is going to be hypotonic as compared to the patient's serum. Hypernatremia because of an increase in volume might occur when we are very excited and give a lot of intravenous fluid, as sodium chloride, giving soda bi carb, but it could occur in situations such as hyperaldosteronism, and the treatment in these scenarios would be to give diuretics and address the primary etiology.
Hypernatremia with normal volume occurs because of low anti-diuretic hormone, because folks try and maintain normal volume by drinking more water. Now, this could be due to a lack of ADH or due to resistance to the ADH functions in the kidneys, and these folks have a low urine osmolality. And the treatment is with sodium chloride, you can give ADH, you can try hydrochlorothiazide, amiloride, or you can give them indomethacin.
Now, with regards to treatment of elevated sodium, or hypernatremia, this depends if it is acute or if it is chronic. If it is acute hypernatremia, which would be when the sodium has risen within the last 48 hours. Anything after 48 hours is considered chronic hypernatremia. Most often, a hypernatremia that we discover is chronic. The reason for this distinction is acute hypernatremia, which means you've found elevated sodium in the past 48 hours, the correction needs to be done within 24 hours; whereas, if it is chronic hypernatremia, the sodium correction should be at about 12 milliequivalents in 24 hours. To do so, the water deficit needs to be calculated, which is a formula being the patient's sodium divided by 145 minus one multiplied by body weight in kilograms multiplied by 0.4, which gives you the amount of water that needs to be replaced in liters. Once again, if the patient is awake, you give them water to drink. Otherwise, the fluid replacement can be with de-fi water or half-normal saline or quarter-normal saline.
Jessica Bard: Well, Dr. Harrison, I think that concludes our episode for today on abnormal laboratory values. We appreciate you walking us through all of that. We'll see you next time on the next episode of Multidisciplinary Dialogue, Clinical Rounds and Case Reviews. Thank you again.
Dr Harrison: Thank you so much, Jessica. Thank you, everyone