Okay, so now for something completely different from my last talk. I'm going to try to review, in a very short period of time, a rather complex area of biology and hopefully give a couple of clues that might be helpful in board exam studying. I think that most of what I'm going to get time to talk about is going to be focused on the inborn errors and a little bit about the rheumatologic stuff, but it's in the slides and I have several questions at the end of my talk in the slides that you'll see in your handout that we may not be able to, but we'll see. So I'd really recommend to you to review Lisa Alcoma's very detailed talk with the recording that is actually very helpful and very explanatory. So okay, in the very basic description, an inborn area of metabolism occurs when there is usually an enzymatic defect that results in an interruption of a process that either decreases a key metabolite or results in an increase of a substrate that can't be metabolized, and either that substrate in an increase or that metabolite in a decrease creates clinical manifestations. There are a lot of inborn errors of metabolism, way too many to know for us intensivists, way too many to study for an exam, but they involve areas of protein metabolism, fatty acid oxidation, carbohydrate disorders, mitochondrial disorders, and others in a rather big topic. And I hope to give a couple of reasonable algorithms that could help us figure some of these out in an exam situation. First of all, of the inborn errors of metabolism, the one that usually comes to us in the ICU involved neurologic deterioration, and these fall into the group of the urea cycle defects, maple syrup urine disease, methylmalonic aciduria, propionic acidemia, isovaleric acidemia. These are the branch chain ketoacidurias and multiple carboxylase deficiency. Those that often come to us with jaundice or liver failure in the first couple of days of life are galactosemia, fructose intolerance, tyrosinemia. So one of the first algorithms to remember is what to do in the face of hyperammonemia. And the key thing to distinguish is whether there's acidosis or lack of acidosis. If there's hyperammonemia in the face of no acidosis, that sort of channels us right away into the urea cycle defects. If there's acidosis in the presence of hyperammonemia, the next thing we look for is whether there's ketones or not. If there are no ketones in the face of acidosis and hyperammonemia, that points us to the fatty oxidation disorders. If there are ketones present in acidosis, just ketoacidosis, then we go towards the organic acidemias. So let's go for the urea cycle defects. That's someone with a lot of pneumonia, no acidosis. Well the urea cycle is pretty cool. All we ever think about is when things go wrong with the urea cycle. But actually it's kind of important because the urea cycle is how we metabolize ammonia and it's also how we make arginine. So if we don't make arginine, what can't we make? We can't make nitric oxide. So the urea cycle is actually pretty important. Although when it goes kablooey, we have some issues. So one thing to look about when you get your serum amino acids, is there a specific amino acid elevation or are there no specific elevations or are there a specific amino acid elevation? If there's a specific amino acid elevation, that means the defect is actually within the cycle. So that could be your argininosycinic acidemia, your citrullinemia, or argininemia. If there's no specific amino acid elevation, the next thing you check is what's called the urine erotic acid. And urine erotic acid is a deterioration compound formed by carbamoyl phosphate. And carbamoyl phosphate is what happens when ammonia reacts with an acetylglutamate at the very entrance to the urea cycle. And if you don't go into the urea cycle, then erotic acid builds up. And the first thing that happens when you go into the urea cycle is that that block is ornithine transcarbamoylase deficiency. So if you have no specific amino acids on your serum amino acids, you have a high urine erotic acid, then that points you right at OTC deficiency, a bad player. If you have a normal or low urine erotic acid, that puts you towards what's called a CPS or a NAGS deficiency. And those are the pathways that occur actually even before you enter the urea cycle. So in an urea cycle defect, ammonia levels are high. Amino acids may be elevated of the urea cycle intermediates. You often have a respiratory alkalosis with hyperventilation. You may have a metabolic acidosis, but it's often a chronic and not an acute acidosis. And your hepatic transaminases are usually elevated, but not incredibly so. Implementation, and here's the important answer, is hemodialysis. And as we all know, there's nothing better than getting a 36-hour newborn into the ICU and the geneticist is saying, hemodialysis, and you're going, where? Importantly, peritoneal dialysis doesn't work. So the answer is hemodialysis, as well as sodium benzoate and sodium phenyl acetate, those chemicals that we're also giving. We need to supplement the essential amino acids that are missing, and those include arginine and citrulline, and we've got to keep the protein intake low. Long-term liver transplant and nutritional optimization. Okay, again, just repeat that again, hyperammonemia, no acidosis, urea cycle, acidosis with ketones is organic acidemia, with no ketones is a fatty oxidation disorder. If you have metabolic acidosis, what you want to look for is whether you have a lactate or no lactate. If you have a normal lactate in the face of metabolic acidosis, then you can look for your ketones. A normal lactate in the face of no ketones, that moves you towards the fatty oxidation disorder, such as your MCAT or your LCAT. If you have ketones in a normal lactate, that moves you into the world of organic acidemias. The big organic acidemia to know is maple syrup urine disease, MSUD. If your lactate is elevated in metabolic acidosis, then it can be pretty much any. There's a lot of stuff that gives you elevated lactate. Then you might look at your mitochondrial disorders, particularly if you have a low pyruvate. If you have a high pyruvate and low glucose, it could be a glycogen storage disease. If you have elevated pyruvate and a normal glucose, as opposed to the low glucose, that brings you into pyruvate dehydrogenase and carboxylase deficiencies. The organic acidemias may also have an elevated lactate. Here's a question. A three-day-old, full-term, home-born female is admitted to the PICU due to neurologic changes. She initially was doing well, but at approximately 12 to 24 hours of age, the mother noted a sweet caramel-like odor. At two days of age, the infant began to feed poorly, became irritable, and then developed drowsiness and then progressed to lethargy, intermittent apnea, pistotonus, and hypertonia. On day of admission, the newborn developed bicycling movements of the legs. On physical exam, the newborn appears mildly dehydrated, lethargic, and hypertonic. Initial laboratory workup shows mild metabolic acidosis, pH 73, and a blood ammonia level of 280. CBC, lactate, calcium, and glucose are normal. Sepsis workup performed. You perform an inborn, you suspect an inborn error metabolism. Of the following, the best next test to confirm your suspected diagnosis is biotinase level, ceruloplasmin level, lysosomal enzyme screen, serum amino acids, or very long-chain fatty acids. Shout something out. Well, I heard a lot of different answers. The answer is serum amino acids. In this case, this particular case is an example of how maple syrup urine disease could present. Certainly that sweet caramel flavor, smell goes with that. Plasma leucine, isoleucine, valine are markedly elevated. Urine branched-chain hydroxy acids and keto acids on organic acid analysis are present. This is one of the organic acidemias that are listed there. It's autosomal recessive. You present with acidosis, elevated LFT, hyperammonemia, ketosis, low blood glucose, and neutropenia. Actually a better answer in here that actually isn't given would be urine organic acids. This brings us into this whole class of branched-chain organic acidemias. They involve metabolism of valine, isoleucine, and leucine, who are the branched-chain amino acids. Important to remember, leucine is a neurotoxic amino acid. Valine and isoleucine are not neurotoxic. This is essentially leucine poisoning of the brain. In any of these, the deficiencies in the branched-chain alpha-keto acid dehydrogenase, BCKD, enzyme complex, which is where the first processing of the branched-chain amino acids when they enter the mitochondria. Depending on where there might be other interruptions in the branched-chain processing chain, you can present with some of the other organic acidemias, such as propionic acidemia or methylmalonic aciduria. Classic maple syrup urine disease, first few days or weeks of life, poor feeding and vomiting, going to lethargy and coma, hypertonicity, apnea, seizures, cerebral edema, hypoglycemia, peculiar odor of maple syrup in the urine, the sweat, and the cerumen. Leucine is the neurotoxic player. Leucine mismanagement, hydration, glucose infusions, plus or minus insulin, restrict protein intake, eventually isoleucine and valine supplementation once the amino acid levels start to drop, sufficient calories and nutrients intravenously, and hemodialysis is the most effective mode of therapy of lowering the ammonia and the leucine levels. And then, of course, treating cerebral edema as it presents in the ways that we know how to do it. There are other branched-chain amino acid organic acidemias. They include methylmalonic acidemia, MMA, in which there is a lesion in another aspect of the metabolism chain, propionic acidemia, and isovaleric acidemia. Question. A four-day-old female infant at term is admitted to the PICU from the ED due to neurologic changes. Poor suck and difficulty feeding had developed at 24 hours after birth. Her condition progressed to vasomotor instability, lethargy, seizures, and then uptendation. Chest X-ray, LP, head ultrasound are normal, CSF cultures are pending, her CRP is normal, CBC shows thrombocytopenia and neutropenia. Later testing reveals a metabolic acidosis with a high NIN gap, hyperammonemia, ketonuria, and hypoglycemia. A day after admission, you are notified that her newborn screen has an elevated C3-acylcarnitine. This is kind of a you-know-what-or-you-don't-know-what type of question. Of the following, the laboratory test most likely to determine the neonate's diagnosis is 17-OHP level, biotinidase level, carnitine profile, lactate level, or urine organic acids. The answer is urine organic acids because this is the presentation of propionic acidemia. It presents in the newborn period or later in periods of catabolic stress. That's found on the newborn screen with elevated C3-propionylcarnitine. So that is the elevated agent that's found on the newborn screen that gives the diagnosis. Urine organic acids are recommended. So just to review, the basic workup for inborn error metabolism includes serum for acylcarnitine panel, amino acids, ammonia, blood glucose, carnitine profile, electrolytes, lactate, and pyruvate. And then urine for organic acid and ketones. Clinical features, vomiting, dehydration. The presentation of the organic acid areas are at different stages. MMA presents in neonates. Propionic acidemia can vary from the first few days to later in life. And isovaleric acidemia can half present as neonates, some present as older. And that's the one with sweaty feet smell that they have, if that shows up. Infants with IVA have tetany, seizures, temperature instability, smell of sweaty feet. Laboratory profile, anion gap, acidosis, ketonuria, hyperammonemia, hypoglycemia, leukopenia, thrombocytopenia, anemia. Urine studies with MMA is elevated methylmalonate. In propionic acidemia, elevated propionic acid. And isovaleric acidemia, elevated isovaleric acid. And then there's the mitochondrial disorders. They affect multiple organs. Infants may present with developmental delay, stroke, stroke-like events, hypotonia, seizures, oculomotor abnormalities, often with lactic acidemia with elevated lactate to pyruvate ratio, CSF, or serum. Typically in these lesions, since the pyruvate can't enter into the Krebs cycle, then you end up with a lot of lactate, because pyruvate gets converted to lactate. Its diagnosis is by muscle biopsy, looking for ragged red fibers, and mitochondrial DNA testing. Treatment is supportive, nutritional, reduce the acidosis, stabilize cardiac function, and the mito cocktail of coenzyme Q, carnitine, creatinine, and folate. And avoiding drugs that might impair the respiratory chain, valproate, carbamazepine, phenytoin, phenobarb to pyruvate. So that is a quick review of metabolism. Rheumatologic, it's always lupus. We all know that. So the lupus-specific autoantibodies are anti-double-strand DNA and anti-nuclear antibodies. And some of the other antibodies that we frequently send sort of are more specific for some of the other presentations of rheumatologic disease. As we know, tons of clinical manifestations of lupus. What I do want to mention really quickly are things that quite aren't as obvious as lupus, and that's systemic juvenile idiopathic arthritis. Ten to 20% of all cases of juvenile idiopathic arthritis affects males and females similarly, usually diagnosis before 16, and the peak is one to five years. Clinical presentation is daily fever, a macular salmon pink rash, arthritis with arthralgias greater than arthritis, early in disease, wrists, ankles, knees most typical. There's also lymphadenopathy, and there can be cirricitis. And of course, the important ICU complication of JIA is macrophage activation syndrome. Severe with first few days, weeks of disease onset, fever, rash, coagulopathy, pancytotemia, hepatitis, and hyperferritinemia, the big clue. If it's not COVID, it's MAS, and it's a rheumatologic emergency. The white count is elevated, there can be thrombocytosis, CED rates, CRP are high, ferritin's high, dimer's high, AST and ALT is high, albumin's low, urinalysis is okay, and the ANA and the rheumatoid factor are negative. Mild, and this refers more specifically to the JIA, mild is NSAIDs, moderate IL-1 and IL-6 inhibitors, steroids, methotrexate, and for MAS, glucocorticoids plus IL-1 and IL-6 inhibitors. Systemic versus secondary vasculitis might be something that can come up. IGA vasculitis is HSP, Kawasaki's is a medium chain vasculitis, medium vessel size vasculitis. Diagnosis is by general assessment, exam, symptoms, CBC, urinalysis, B1 creatinine, CED rate, CRP, other labs, von Willebrand factor, your ANCA's, your ANA's, complement, your anti-glomerular basal membrane antibodies, and infectious workup. Tissue biopsy is the gold standard. There are CNS vasculitides, which we have to consider with newly acquired neurologic deficits, stroke-like events, new onset of seizures, psychiatric symptoms, often no underlying systemic disorder. Large vessel disease is defined as angiography positive, small vessel disease, angiography negative. Any age, male predominance and angiography positive, childhood large vessel CNS vasculitis. Female and angiography negative, biopsy positive, small vessel vasculitis. Wide range of symptoms, and there can be anything from acute stroke symptoms to progressive cognitive decline. Treatment is immunosuppression, anticoagulation, and a platelet TNF blockade for refractory disease. Okay, what I have next is just some questions, which I'm going to leave undone right now, but they're there for you to look at, and they have answers and explanations for them. Okay, thank you very much.

inborn errors of metabolism

rheumatology

diagnostic algorithms

clinical presentations

board exam preparation