Crack The Case: Periorbital Edema and Abdominal Distention in a Previously Healthy Toddler

Dr. Kade Goepferd: This is Talking Pediatrics, a clinical podcast by Children’s Minnesota, home to the Kid Experts, where the complex is our every day. Each episode, we bring you intriguing stories and relevant pediatric health care information as we partner with you in the care of your patients. Our guests, data, ideas and practical tips will surprise, challenge, and perhaps change, how you care for kids.

Welcome to Talking Pediatrics. I’m your host, Dr. Kade Goepferd. On our Crack the Case segment, we take real-life patient cases that present to a primary care setting and dissect medical decision making, evidence-based guidance and associated clinical pearls. It’s a case-based journey of a diagnostic dilemma with Dr. Bryan Fate.

Dr. Bryan Fate: So welcome to Crack the Case, where we dive into real cases seen in our Minneapolis continuity clinic, to highlight medical decision making, approaches to general pediatrics topics and life in primary care. I’m Dr. Bryan Fate, a primary care pediatrician at Children’s Minneapolis, and with me today is Dr. Steven Smedshammer. Dr. Steve attended the University of North Dakota for medical school, completed his pediatric residency at the University of Minnesota and has specialty training on the topics of neurodiversity and developmental disorders. He now works as an attending physician at our general pediatrics clinic, and as a talented musician, represents perhaps the missing piece in forming a clinic band. Pierce, our interpreter, plays synth, actually, I just found that out.

Dr. Steven Smedshammer: Perfect.

Dr. Bryan Fate: Yep.

Dr. Steven Smedshammer: All right.

Dr. Bryan Fate: So Dr. Steve, icebreaker question for you today, how has music helped you handle the stressors of medical training and are there ways you infuse music into your practice today?

Dr. Steven Smedshammer: Excellent question. And thank you, Dr. Fate, for having me here today. And as a fellow musician, I hope you appreciate some of my answers there. I’d say for me, music has been kind of ever present. It was a coping mechanism of sorts during the medical education process. When you’re knee deep in reading about all this anatomy, physiology, biochemistry, it’s sometimes nice just to step away and be able to just play guitar and clear your mind for a little bit. Listening to music was always that escape for de-stressing during testing periods and blocks of that nature. So it’s been ever present. It’s my way to do a palate cleanser mentally, I would say, from the stressors that occur from working in medicine.

Also, I think the biggest benefit is it is a commonality in us as humans, whether you like reading, watching movies, for something artistic, something in the arts entertainment field that we can all appreciate. So even if you’re not an avid music listener or getting into avant-garde jazz or drone music or whatnot, you can probably connect with someone to some extent on music. And I’ve found my background as a musician has come in monumentally helpful in terms of being able to get through to the obstinate teenager, to make a connection to the dad in the clinic appointment that’s maybe not quite engaged. It’s a way to wrap everyone together and show that we’re all people, all humans in this together, trying to help each other out, and I think music is that bonding factor.

Dr. Bryan Fate: So I’m going to introduce the case today. So evaluation of a child with edema can be stress inducing given the differential invoked, including nephrotic syndrome, liver disease and heart failure. Determining the cause involves dusting off some principles of physics, which is not my strong suit.

Dr. Steven Smedshammer: Nor mine.

Dr. Bryan Fate: Protein, namely albumin, hangs onto water to maintain intravascular osmotic pressure. So not having enough protein causes leakage into surrounding tissues to create the characteristic puffiness that we see as physicians, begging the question, are we losing protein or not making enough? So if protein and osmosis are not the primary drivers, we must also consider capillary hydrostatic pressure, as we see with the engorged vessels of heart disease or the retention of fluids with chronic kidney disease. So today’s case, we’ll investigate a toddler with an initial complaint of puffy eyes and abdomen. Let’s start the case.

Dr. Steven Smedshammer: So we are working in a pediatric emergency department when we are introduced to our patient today. She is a 14-month-old female named Anna, who’s presenting with a one week history of bilateral swelling around her eyes, per her parents. Her parents report that there’s been no recent illness, there’s no redness or fever to her face or skin, no rash, no falls and no injury, no complaints of any sick symptoms. There’s no cough, runny nose or congestion, but they’ve noticed the swelling growing around her eyes for about the last week now.

Other things that they’ve been paying attention to, her appetite seems to be slightly down over the last few days, and they’re concerned that she’s not making as much urine as she usually would, stating that her urine output is maybe down over the last three days specifically. They have not seen any blood or any changes in her urine, just the frequency. No falls or injuries have been noted, no recent travel, no new medications. The only other thing they can notice is that her abdomen appears to be a little bit more swollen today, and they’re wondering if her skin looks a little pale, and that is how we meet Anna today.

Dr. Bryan Fate: I think in terms of history, first of all, teasing out when we’re thinking about edema, aka interstitial tissue swelling, we want to think about if it is just in one place, so localized or generalized. Localized process can point more towards things like infection, so preceptor cellulitis, orbital cellulitis, lymphatic blockage. So it kind of has a different differential than if swelling is everywhere. So we’d want to know if we are having swelling of our feet, have we outgrown our shoes and our socks, has our weight changed, are we still fitting in our clothes? We can see swelling in the scrotum and labia, so kind of in the GU region. And then thinking about other places fluid accumulates like your lungs, which is a scary thing, so are we having any concerning symptoms for pleural effusions, like shortness of breath, increased work of breathing, so teasing out local or generalized.

And then I think you tapped into a few different things we think about for how we lose protein, like we alluded to. So one way is through our kidneys, classically nephrotic syndrome. So are we having changes in our urine output, are we not making enough protein with our liver? So are we having signs of liver dysfunction like jaundice, acholic stools, vomiting, or are we losing protein through our GI tract? So things like protein-losing enteropathy, we can have diarrhea, bloody stool, signs of malabsorption. So really thinking about general versus localized, as well as are there sources of protein loss or not enough protein being made. Other history that you would want to know too, Dr. Steve?

Dr. Steven Smedshammer: Yeah. I think that approach of localized to general, very helpful to kind of think about what’s coming in and what’s coming out. Thinking the body as being somewhat of a closed system, if we’re adding protein in, is it staying? Things that I would want to expand upon then, too, would be early life development. Is there anything from her early life, say pregnancy? Was there any screening or anatomical abnormalities that were noted during any sort of prenatal scans that would make us be concerned that maybe we only have a solitary kidney? Maybe there’s some sort of cardiac abnormality that’s present. Other things I’d also want to know too is what is the development of this child? Are they ambulatory? Are they bound to, say, a wheelchair, where more gravity dependent areas like scrotal swelling will be more important, where if they’re up and moving around and doing typical 14-month-old mobility, seeing a swollen scrotum would be a little bit of a different kind of approach then. So I think knowing developmentally where they’re at and where they’ve come from would also be helpful.

And then lastly, the social determinants of health I think would be another key point, just to check on the history of the family. Is there any concern for inability to access resources? Is the amount of protein that we’re getting in our diet really low because of certain challenges or barriers to the family, as financially? I think kind of thinking well rounded like that is a good way to avoid falling prey to some of those other differentials that are maybe not quite so medical that you would think about.

Dr. Bryan Fate: So thinking about malnutrition, food deserts, nutritional status. You’ve mentioned this, but no new exposures or known allergens because certainly anaphylaxis can present in a similar way, in terms of generalized swelling, as well as any family history of kidney disease, heart disease, and then hereditary angioedema, people’s faces that get really puffy when exposed to things like ACE inhibitors and NSAIDs. Anything else that came up history-wise, based on that review of systems too, Dr. Steve?

Dr. Steven Smedshammer: Yeah. So some additional history that we got from the family, I’m kind of following up on things like diet and activity, Anna does not take any medications, no herbal supplements, vitamins. Family does note that she drinks about three to four eight ounce bottles of milk each day, but maybe doesn’t finish each bottle. Other than that, she normally would urinate maybe about eight times a day into her diaper, and that’s what’s decreased and kind of caught parents’ attention, but no other history that they bring to the table in terms of international travel, family history of any conditions, whether it be renal, liver, cardiac in nature. And no other big concerns, but mom did say that she thinks maybe Anna’s breathing a little bit faster today.

Dr. Bryan Fate: Great. Well let’s move on to our vitals and physical exam then.

Dr. Steven Smedshammer: Perfect. Well, checking her vital signs today, we had afebrile temperature, so she’s 37 degrees celsius. Her heart rate was a bit elevated today. We’re at 177 BPM. Respiratory rate was at 22 breaths per minute, and we were satting about 96%, showing good O2. Blood pressure is a little high, too, for her age. We’re at 120 over 90 and weight’s stable from previous evaluations. On physical exam, she’s not in any acute distress. She’s reacting appropriately to exam, interacting with her parents, she’s alert. Running through our systems, we have moist mucous membranes present and two-second capillary refill. Atraumatic head on exam, sclera and conjunctiva are clear bilaterally. Checking her ears, no concerns there. Tympanic membranes appear normal, but when looking in her mouth, we do notice some pale mucosal membranes. No issues with the neck in terms of range of motion or strength. Listening to her breathing today, we are clear to auscultation bilaterally, no signs of crackles, fluid. Her work of breathing is normal. We’re not hearing any rails or wheezes.

And her cardiovascular exam is also normal, in terms of slightly higher rate, but a good, steady sinus rhythm, no murmurs appreciated either. On her abdominal exam, we’re noticing that we’re mildly distended, but soft and non tender with no hepatosplenomegaly. And on the rest of our exam, too, we noticed the periorbital edema but no extremity swelling appreciated. On her skin check, no rashes, ecchymosis or abrasions. And neurologically, we have symmetrical phasies, age-appropriate strength. Ambulation appears to be appropriate for age as well, and no other concerning signs found on exam.

Dr. Bryan Fate: Perfect. So it seems like she looks well overall and then is interacting appropriately, is a little tachycardic with the heart rate of 177. Did have an elevated blood pressure of 120 over 90, which would make us a little more concerned about kidney causes, if that is in fact accurate. But it sounds like in terms of scary diagnoses like cardiac failure, we’re not hearing any signs of pleural effusion, which is good.

Dr. Steven Smedshammer: Exactly.

Dr. Bryan Fate: We have had no enlarged spleen or liver, in terms of synthetic liver function. And then I think in terms of whether the edema is generalized or not, we have it in our eyes. And then we also have this question of our abdomen, whether that there could be fluid there. So thinking about is this concerning for something like ascites, is there a fluid wave, are we just constipated? That can be more challenging on exam, but it sounds like if, in fact, we had some fluid in our abdomen, that would be a more generalized picture. Any other exam tidbits you’d want to point out too, Dr. Steve?

Dr. Steven Smedshammer: A couple other good things to keep in mind is that we’re alert and we’re active, so concerns for, say, like a profound anemia or something of that nature, I would expect a little bit more fatigue, more like a generalized pallor. So some pale mucosal membranes definitely keying into that, but hearing that we’re alert, we’re interactive, we’re ambulating, we’re interacting with her parents, it tells me that cognitively we’re in a good spot and that we’re not showing those kinds of systemic symptoms currently.

Dr. Bryan Fate: Thinking about further work up, Dr. Steve, what were your thoughts there?

Dr. Steven Smedshammer: Yeah, I think definitely would be a great candidate for some lab evaluation at this point, as well as a couple of things we can do in the clinic like rechecking that blood pressure, knowing that our little friends when they come in aren’t always exactly calm and appropriate when it comes to checking that.

Dr. Bryan Fate: Correct.

Dr. Steven Smedshammer: And looking at the labs, I think it’s really helpful to break down mentally what are the things that we would need based on what our concerns are? So given that we’re concerned that we’re maybe losing our protein, we want to be able to do labs that would be able to check our kidney status and also something in terms of our GI, so like a stool test would be beneficial in this case. So stool and urine would be two types of samples I think it would be helpful to start off with, and then blood, so then digging deeper into terms of what would be the labs in those specific kind of categories? I would want to look at the stool to see are we seeing blood, is there occult blood present? Is there any sort of protein, like an Alpha-1 antitrypsin that is detectable in the stool as well?

When looking at the urine, I’d like to know kind of general UA-related lab values, looking to see what is our specific gravity, looking to see what the sodium and protein content is there. Is there frank blood present? I think that would be really helpful if we’re looking at our things like nephrotic syndrome, which could be contributing to some of our swelling. And then also, just general kind of function, looking at liver enzymes, getting a CMP to look and see what our electrolytes balances are currently at. And then I think another key component to this would be looking at the CBC to kind of examine and understand where are our red blood cells at in terms of size, the hemoglobin content? Are we seeing signs of know marked iron deficiency or any cell line abnormalities?

Dr. Bryan Fate: Again, returning to this question of are we losing protein, and if so, where is it going or is it not being made? So first of all, what is our albumin, what is our total protein? Our eyes will kind of gravitate to that first. We’ll be able to see from the UA if we’re losing protein in the urine from kidneys, we’ll also be able to see if there’s blood, like different cases of glomerulonephritis, which has a few different causes. We’ll look at our liver panel to make sure that we’re making enough protein and that there’s no liver dysfunction. We can think about stool studies for Alpha-1 antitrypsin if there’s concerns for malabsorption. If we’re losing protein from gut inflammation too, that’s a consideration. And then checking a CBC to follow up on the pallor, the tachycardia, the pale mucosal membranes, so kind of concerned about if we’re anemic, especially given our milk consumption.

And there are some kind of second-line labs and imaging we can consider, of course. If we had concerns for cardiac dysfunction, we think about a chest X-ray, an echo, an EKG, a BNP. If we had that UA initially showed abnormal things like blood and protein, we can think about things like complement studies, further autoimmune vasculitis workup, though we’d probably talk to our friends with nephrology for that. We are in a good spot to hear what Anna’s labs looked like.

Dr. Steven Smedshammer: We were able to obtain labs and samples from Anna today. Lab work was notable for a hyponatremia of 135, low albumin of 2.0, low calcium of 7.7, a low total protein of 3.6, with an otherwise normal CMP. Lipid panel came back notable for an elevated triglyceride count at 256, and otherwise normal, and then the UA also came back as normal. Our CBC resulted of a microcytic anemia with a hemoglobin of 5.1 and then an elevated RDW. Our iron was also measured at low, at 13, and the blood smear performed is currently under works, reassuring against any malignancy.

Dr. Bryan Fate: Got it. So it looks like the cholesterol panels added on probably as part of nephrotic syndrome workup.

Dr. Steven Smedshammer: Smart.

Dr. Bryan Fate: But based on we definitely have low total protein, low albumin, so we don’t have enough protein to keep our fluids in our intervascular space. Again, the question is where is it going? And right now, we actually don’t have a great answer. There’s no protein in the urine. The liver panel looks normal, so we should be making enough protein. If we’re looking in terms of malabsorption in the GI tract for protein-losing enteropathy, that’s going to take a while to come back. We don’t have those studies yet. And I think most alarmingly, we are very anemic with a hemoglobin of 5.1.

Dr. Steven Smedshammer: Yes.

Dr. Bryan Fate: We are symptomatic with that anemia, and has the profile of pretty significant iron deficiency, it sounds like. No other cell lines down, as in malignancy, smear was normal. So yeah, maybe you can talk through, Dr. Steve, what the diagnosis was and why we got puffy and why our protein was low.

Dr. Steven Smedshammer: I think this is a really interesting case in that it kind of presents with some of those key things that were taught early in pediatric training regarding cow’s milk and excessive consumption of it, but the interesting thing about this case, I think, is kind of where this ends up taking us. Per her present illness, there’s definitely a concern for iron deficiency anemia, but given the lab values, we’re also demonstrating something called a protein-losing enteropathy. So given the periorbital edema, energy levels being slightly down, the abdominal distension, it seems that the severe iron deficiency anemia is resulting in a protein-losing enteropathy.

So given the lab values, our primary concern right now is that we’re losing our protein. So we are not concerned for getting the protein into the system, it’s what is causing us to lose the protein. And the interesting kind of sequelae in this case is that we’re potentially losing it through the stool. This whole process has potentially been jump started by the severe iron deficiency anemia secondary to the excessive cow’s milk intake. So in this situation, repleting the iron, our goal would be that the repletion of the iron resolves the hypoalbuminemia and the hyponatremia. Given the low hemoglobin, she potentially could be a candidate for an iron infusion. Different recommendations will exist out there, but typically it’s symptomatic with a hemoglobin of like 6.0 or 6.5 or lower, depending on what sources you’re utilizing. So an infusion would be one potential route. Oral supplementation would be another direction that we could potentially go in that situation as well.

Reviewing the stool labs would be helpful too. So a stool Alpha-1 antitrypsin and occult blood would be our way of confirming that enteropathy as the source of our protein loss, and also can be helpful for ruling out things along the lines of a, say, like a celiac disease for that underlying cause.

So looking at the pathophysiological kind of explanation of how this is occurring, there isn’t really a really well-defined process in place yet. Studies by Yasuda and others in 2018 and a few other kind of, I wouldn’t say meta-analysis, more like grouped case studies, are currently present, and the concern is that the iron deficiency is potentially leading to some form of leaky, increased permeability in the gut. So as a result, the protein’s being lost through the gut due to the leakiness kind of triggered by the iron deficiency.

So again, like Dr. Fate was saying, this can kind of get into a little bit of that physics discussion then of things like Starling forces and other phrases that caused me to get a little uncomfortable flashbacks to, say, med school. I think the easiest and simplest way that I kind of broke it down in my brain is looking at blood vessels and kind of fluid movement in the body as fluid that’s moving through a tube, so like a garden hose, for example, but the garden hose is permeable in that things can move into and move out of the hose. So as fluids moving through the hose, it’s going to keep moving forward, and edema is going to occur in situations where there is a net outward force or an outward movement of fluid from the capillaries into that interstitial space.

And in this particular situation, that’s where albumin comes into play. A lower concentration of albumin in the fluid moving through this vessel is going to cause an osmotic imbalance. It’s going to lead to a decreased osmotic pull, so fluid’s going to end up traveling out of the capillaries and into that interstitial space where if albumin was present traveling through this garden hose, it would be pulling that fluid with it. It would keep that movement and keep that fluid moving. So with a lower albumin in the vasculature, we’re going to see some fluid moving out into that interstitial space.

Areas of increased permeability, areas that we’re going to see more of a clinical presentation of this, would be similar to Anna’s case, in areas like the soft tissue underneath the eyes, so that periorbital edema. For children that are maybe not mobile, for individuals that are utilizing wheelchairs and those kinds of things, we’ll see more of a fluid-dependent swelling like we had mentioned earlier, so like scrotal edema in those cases. For kids that are upright and mobile, you’d also want to check and see, from a generalized edema standpoint, swelling of the ankles. So this being more localized kind of cues us into things more along the lines of those protein-losing enteropathies.

Dr. Bryan Fate: Yeah. I actually saw this Anna back in the day, in 2021, but I had to, yeah, really dig through and read a little bit about that connection between excessive milk consumption, severe iron deficiency anemia, as a cause of low albumin, and protein-losing enteropathy was not known to me and was not something that I had been taught. But looking through the literature and case studies, it’s pretty well documented amongst primarily toddlers, all had excessive milk consumption, all presented in a very similar way, typically with periorbital edema, abdominal distension, and pallor. So the good thing is all of them, essentially all of their proteins normalized, and all of their hemoglobins normalized after repleting iron at a higher dose of six mgs per kg per day. So essentially, when you fix the iron, you cut out the milk and you fix the problem, so it’s a pretty easy fix. But I thought that was an interesting connection that literature is still documenting, but it’s definitely out there.

So I think for our listeners, I was going to just do a couple of take-home points, the first being differentiating between localized and generalized edema is useful for narrowing a differential, where your physical exam should search for pulmonary edema, ascites, facial and/or GU swelling, as well as changes in weight and/or fit of clothes and shoes, so looking at is this just in one place or elsewhere, so a very comprehensive exam. Number two, assessing albumin and total protein tells us if oncotic pressures are responsible, and if low, we should consider where losses are coming from, so from proteinuria in nephrotic syndrome, decreased synthesis as in liver dysfunction, or malabsorption as in the protein-losing enteropathy. So we’re really trying to chase the protein, figure out where it’s going or if it’s not being made.

And then the last one is, as we learned in this case, severe iron deficiency anemia has been documented to cause protein-losing enteropathy, particularly in the setting of excessive cow’s milk intake. So consider CBC and ferritin, in addition to your standard workup for more generalized edema, which includes liver and renal panels and a UA, and then eliminating cow’s milk and supplementing with iron is curative.

Dr. Steven Smedshammer: Perfect.

Dr. Bryan Fate: So thanks so much for joining us. Again, Dr. Steve, it’s been wonderful to have you on.

Dr. Steven Smedshammer: Yeah, my pleasure, and honored to be a guest here.

Dr. Bryan Fate: Until it’s time to crack another case, advocate with volume and kindness, enjoy the puzzles that medicine brings, and tend to your non-medical passions with the same energy.

Dr. Kade Goepferd: Thank you for listening to Talking Pediatrics. Come back next time for a new episode with our caregivers and experts in pediatric health. Our showrunner is Cora Nelson. Episodes are produced, engineered and edited by Jake Beaver and Patrick Bixler. Our marketing representatives are Amie Juba and Krithika Devanathan. For information and additional episodes, check us out on your favorite podcast platform or go to childrensmn.org/talkingpediatrics.