Transcript
PLEASE NOTE: While an effort has been made to correct errors in this AI-generated transcript, some mistakes may have been missed by the non-clinician moderator. This transcript should be taken merely as supporting material to the podcast discussion and neither is as an authoritative last word on the subject matter.
MIC CAVAZZINI: Welcome to another Pomegranate Case Reports, developed by Trainees of the Royal Australasian College of Physicians. Today’s case was published as a “Lessons from Practice” article in the Medical Journal of Australia from 2020. There’s a link in the show notes if you want to see the associated imaging for yourself, but if you want to test yourself without spoilers, just sit back and listen to the exposition from the series host, Dr Stephen Bacchi. He is an advanced trainee at Lyell McEwin Hospital in Adelaide. As well as his specialist interest in neurology, he has a commitment to medical education and is currently undertaking a Fulbright Scholarship in the USA.
STEPHEN BACCHI: Hi everyone. Thanks for joining us. My name's Stephen Bacchi, I’m a neurology registrar at the Lyell McEwin Hospital and today with us I have Dr Andrew Vanlint, who's a clinical haematologist and general physician working as a medical education consultant at the Lyell McEwin Hospital. He's also a lecturer at the University of Adelaide and undertaking a master's through Flinders University. And with him I have Sarah Foo, who is a basic physician trainee at the Lyell McEwin Hospital who has an interest in infectious diseases. Thanks for joining us.
ANDREW VANLINT: Great to be here.
SARAH FU: Thanks, Stephe.
STEPHEN BACCHI: As previously, we'll be discussing a published case report in a step by step manner with a focus on content that is relevant to trainees and a generalist audience. Sarah, could you please introduce the case?
SARAH FU: Sure. So, in this case, we have a 48-year-old male who presents with a 3-month history of non-bloody diarrhoea, accompanied by abdominal pain and 8kg of weight loss. Of note, he had a history of recent pulmonary oedema, abdominal lymphadenopathy noted on a computed tomography scan three years ago, and polyarthralgia for the last 5 years. Now that’s a bit to unpack in this scenario. Dr Vanlint, what would be your approach the differential diagnosis in this scenario?
ANDREW VANLINT: Great question and this was a very unusual case. And I'll give a little bit of narrative along the way we this was in my third year of BPT at the Queen Elizabeth Hospital. So, post exams, I was on gastro and this was referred to me from the acute medical unit. I think when you kind of outlined it like this, it's good to think about the individual symptoms and then to think about are there any, kind of, Occam's razor unifying diagnosis?
So, we've got a more of a subacute presentation of diarrhoea and it's helpful to think in terms of causes. It's probably not going to be viral, but something could be a prolonged bacterial infection. It could be something more parasitic or an unusual bacterial infection that is a more subacute-chronic. It could be inflammatory, especially because it's been going on past the acute phase—so inflammatory bowel disease or other inflammatory disorders would come to mind. And then it could be malabsorptive, which obviously crosses over with inflammatory as well. It's a bit unusual to have those kind of malabsorptive inflammatory conditions appear suddenly in somewhat middle-aged men, but it can happen.
So, then the next one is abdominal pain. It's really broad and we don't know the with the pain is that more acute or is that accompanying the diarrhoea? I think the timeline, the character and the severity are really important to get a clearer differential. So very broad, lots of different things that can cause pain, which I won't cover in detail. Weight loss, definitely both as a general physician and haematologist whenever I think about weight loss, I'm thinking about malignancy. But in this case, I'd also strongly consider whether the diarrhoea and associated malabsorptive issues from the diarrhoea, whatever the cause may be, is likely to contribute to weight loss. So that would be my natural bend is to attribute to the diarrhoea until I prove otherwise. But then, of course, this could be a unifying diagnosis of some kind of chronic infection that is both causing abdominal pain, diarrhoea and contributing to weight loss, independent of the diarrhoea or in combination. So that's what I'd be thinking in terms of the weight loss.
The pulmonary oedema is the particularly unusual feature here. And I do want to comment on that. There's a 48 year old—he was very fit and had no other very significant aast medical history beyond the arthritis and lymphadenopathy, as been mentioned. So this was very strange. Approaching this again, I'd be thinking, is this an unusual manifestation of heart failure from maybe more of a genetic or inherited form of heart failure, like a dilated cardiomyopathy or hypertrophic cardiomyopathy and it just hasn't kind of reared its head yet? Could this be a myocardial infarction with an acute heart failure precipitant? Could it be a pneumonia or some kind of acute lung infection precipitating that edoema as part of that, more like an ARDS type presentation? So that's a bit unusual. It seemed very brief and had resolved, and it never happened previously, so I wasn't sure what to make of it. Even now I'm not 100% sure how it fits into the scheme of things.
Then you get what I think is always more interesting; lymphadenopathy. So, this is definitely a chronic lymphadenopathy and that instantly rules out the more acute infections that you would get localised lymphadenopathy from. So, obviously, we needed to check is that still present now? I think it said three years ago, three years ago had been watched a couple of times and seen by one of my senior colleagues in the clinic and they hadn't biopsied it. Definitely an indolent non-Hodgkin's lymphoma should be considered. Follicular mantle cell, achronic lymphocytic leukaemia can also cause chronic lymphadenopathy, and they can be reasonably dormant or very slowly progressive. They don't have to be rapidly growing unless they're acute.
And then you can think of things that are less common but can cause lymphadenopathy, and I think of things like Castleman’s disease and IgG4 disease. Neither of these completely fit with the other symptoms, but the fact that you've got this kind of chronic lymphadenopathy means you need to expand your differential to these less common inflammatory disorders that are there.
And then lastly, you've got this polyarthalgia. You know, is this just pain? Is there arthritis there, that's not really clear. Definitely rheumatoid arthritis, osteoarthritis, then less common things like lupus or rarer things like connective tissue disorders would be amongst the differential there. So that that's how I'd probably unpack the individual ones and go, what are the common themes here? And probably the common things we're seeing here is some kind of chronic infection or maybe some kind of inflammatory or malignant disorder. They're probably my top three that would potentially unite these things, but it's not 100% clear.
STEPHEN BACCHI: Thank you for that thorough dissection of a complex presenting complaint. So now we have additional information. He has previously had BCR-ABL tested which is negative, and a negative serum protein electrophoresis. But today on examination, it's essentially unremarkable. So with further investigations, he has a complete blood examination that demonstrates a microacidic anaemia and an elevated C-reactive protein of 168. Now, there's a few possible causes for this anaemia, but in the context of the patient's presentation, I was wondering about an anaemia associated with malabsorption or an anaemia associated with chronic disease. Could you please explain how you'd approach this anaemia and distinguish between such possibilities?
ANDREW VANLINT: Yeah, absolutely. So, the first two tests just for those that are less familiar with them. So BCR-ABL able testing is for our stock standard chronic myelocitic leukaemia. There are atypical forms of CML that are not BCR-ABL positive, but they're pretty rare. So, I don't know that that was needed, CML is not associated with lymphadenopathy, but anyway someone's done it. It's definitely not CML, wasn't thinking it was CML anyway, but that's fine.
Then, SPEP is serum protein electrophoresis—it has a few other different acronyms that can describe it—and effectively there you're looking for a monoclonal gammopathy, so some antibodies and IgG and IG M and IGA, most commonly, that can be associated with myeloma can be associated with lympho proliferative disorders, particularly things like marginal zone lymphoma. Can be found in CLL. Always found, pretty much, in Waldenström macroglobulinemia. We're not seeing that at all, so thatt's just taking off another thing. It would be very unlikely to be a plasma cell disorder as well, which are known to cause anaemia and all of those other things I mentioned can be associated with anaemia either from direct involvement with the bone marrow or from secondary effects.
So, in terms of the anaemia itself and delineating between what you've put there—microcytic, you're always going think iron deficiency. If it's pretty much been lifelong, think about thalassemia. I don't think that's what we're dealing with here, I think he's had normocytic anaemia and then non-anaemic previously. So, that's probably ruled out reasonably and it wouldn't go with haemoglobin electrophoresis in that setting. Then you can get heavy metal poisoning, which is rare, but does happen in some places, even in Australia. So, lead poisoning would be the classic one for microcytic. If you're not from Port Pirie or particular areas of the NT, that is very rare. So, this person was not so I wouldn't following that one up.
So, the key here in terms of, is this stock standard ion deficiency or is this anaemia of chronic disease is the iron studies mainly for the transferrin saturation. So if the transferrin saturation is down and the ferritin is down, that's just your stock standard ion deficiency. If the ferritin is normal or elevated perhaps from inflammation, but the transferrin saturation is less than 20%, and particularly if it's less than 10%, then that's going to fit really nicely with anaemia of chronic disease. And particularly those that have a ferritin that is normal but below 100 and transferrin saturation's below 20, those are the group that have probably the best evidence that they've benefit from IV iron infusions for managing that. Whilst the ones that have higher ferritin have questionable benefits. Not that you can't do it, but it's probably not as black and white as that particular subset with the ferritin below 100.
SARAH FU: Excellent. Thank you, Dr VanLint. So, we don't have information about the iron studies unfortunately, but we have a repeat computed tomography of the abdomen. It showed a stable mesenteric and retroperitoneal lymphadenopathy and splenomegaly. However, the lymph nodes were found to have abnormally low, fat-density hypoattenuation. Acknowledging this is a podcast, and the scans are available in the article, could you explain to us what “low attenuation lymphadenopathy” is, and the types of conditions in which it may be seen? And how would it affect your workup?
ANDREW VANLINT: Yeah. I think we named the case report in this way because this is one of these hallmarks that led to the suspicion of the diagnosis in the end. And I had a vague idea of what attenuation was but I had no idea of the very specific differential that arises from low attenuation lymphadenopathy. So, just to revise attenuation is the reduction of intensity of an X-ray beam, which is the same for CT, as it traverses matter. And I think in one sense, this is not completely true, but in one sense it's a surrogate of density, of like radiological density. So, it doesn't actually have to be dense tissue, but things like calcification and bones have a very high attenuation, and things like fat and fluid have a very low attenuation, and soft tissue sits part way in between those two extremes.
There's some exceptions in that uf you give IV contrast, that's obviously a fluid, but it will attenuate the X-rays really strongly, so it will look potentially even denser than bone does. So that's why I say, in one sense, think of it like radiological density. And there are radiologically dense without being physically dense.
These nodes are effectively less attenuated, less radiologically dense than other soft tissues. That's the definition of low attenuation, it has to be lower than the soft tissues around it, and that, in a really basic sense—it's either because they have more fluid or necrosis because necrosis will produce swelling and fluid in there, so cystic or necrotic features. Or because they have more fat because fat has more fluid as well. And if you think about things that might cause that fluid necrosis can be found in some lymphomas. So, it's not to say that low attenuation lymphopathy is lymphoma, just saying that some that have more cystic and necrotic features will fit this particular definition.
Metastatic disease does not typically produce low attenuation lymph nodes, but they can, again, if they're a necrotic or cystic components to it. And then there are rarer inflammatory disorders that cause this picture like, the well known, Kikuchi-Fujimoto disease, which of course Sarah and Steven know very well. And I definitely didn't just revise that last night. And then on the latter one, in terms of fat, that's associated with things like Whipple's disease, and it can be other fatty disorders like a myelolipoma that's outside of the typical tissue that you find that in. So, in terms of \ is it low attenuation or not, that wouldn't really as a haematologist make me think it was or wasn't lymphoma. I think if it's warranting a biopsy of its own accord, then this particular report feature won't sway me to do it more, or to do it less.
STEPHEN BACCHI: Great, thank you. And in this instance, the trading team possibly itself considered Whipple's disease a possibility in that context. And this was subsequently supported following endoscopy and colonoscopy which showed PAS, Periodic acid-Schiff staining and Tropheryma whippelii positive polymerase chain reaction or PCR. The patient had a prolonged course of ceftriaxone followed by trimethoprim sulfamethoxazole and had substantial improvement. So, what a diagnosis?
ANDREW VANLINT: Yeah, I'll add a bit of narrative to that. So, this was a Friday afternoon and one of our registrars was off sick, and I don't usually hold the consult phone and we got a call from AMU and they said, “look, there's this gentleman with this description” of what we've talked about at the beginning of this case and the radiology report from the CT that was done just two days before he came in as just part of his monitoring of the lymphoma had been done by a colleague and he was preparing for his radiology exams and was clearly feeling very academic, and had written this low attenuation radiology lymphadenopathy comment, and then said, think about lymphoma and infection, but consider rarer options such as Whipple’s disease.
With that, I was like, “oh, Whipple's disease. I remember studying that for my exam”. Let me brush up and I will recommend the Uptodate article on Whipple's disease is honestly a really succinct and great, easily read summary and I can't say that of every Uptodate article, it's a really nice one. So, if you wanted to read about, I'd recommend that.
And it clearly said there are these four main features that they have, which is diarrhoea, abdominal pain, weight loss and then with a potentially months or years long history of a seronegative arthralgia. And I was like, Whoa. Radiologically we've got a feature, symptomwise it fits. It probably isn't, this is a condition that only happens to about 30 to 40 people in the world per year. It's very rare and there's probably only something like 700 or 1000 recorded in history. This is a very rare disease.
And I then went and saw the patient. He had all the classic features and I managed to convince our afternoon endoscopy consultant to do an endoscopy and it found these plaques basically in the stomach, the small bowel and the large bowel—which typically they say the GI is affected from the lower oesophageal sphincter to the anus. And this is exactly what we saw and no one in the department had ever seen these plaques before. But we Googled “endoscopy Whipple's disease and it looked exactly like that”. And so, we were pretty convinced.
And then subsequently I went and sat with the pathologist and he was excited, without showing a lot of excitement in a probably stereotypical pathology way, in that he said, “Oh, this is a really interesting case. Hey, look at this textbook that I've pulled out”. Physically showed me the textbook picture, and he goes, “Look, it's almost exactly like this slide”. And so that was the PAS-D staining, and then the PCR came back later in the week as positive. And we started the ceftriaxone. So, this is a usually very fit guy, and the next day with only one dose of ceftriaxone his diarrhea stopped, the cramps went away and his appetite returned. It was like a remarkable difference.And he subsequently went on to a year-long course of Bactrim, which worked really well. So that's the narrative there.
STEPHEN BACCHI: Thank you for sharing. Could you please give us more of an overview of Whipple’s disease?
ANDREW VANLINT: So, like I said, these four main symptoms, diarrhoea, abdominal pains, particularly cramps and weight loss and this precursor or heralding arthralgia, which is seronegative arthritis-type presentation. It's typically a migratory polyarthritis, that sounds like rheumatoid, but you won't find any markers that are positive. And it typically happens in middle-aged men from Eastern Europe, and this guy was a middle-aged man from Eastern Europe who returned to Eastern Europe once a year to see his family. It had actually come on after he'd returned earlier that year.
So, what we understand from this is if you do all these samples, there's this infection of Tropheryma whippelii, which is named after Dr Whipple, who described this. Different from Whipple's procedure—that was a surgeon, this guy's a pathologist, both in America—some say they may have met or may not have met because they lived at the same time. But different parts of the country. And trophe is to grow, an eryma is barrier. So, the classic descriptions, these people just waste away without treatment and subsequently die of cachexia. So, that's where it's got its name from.
And we think—because it's a very small number of people that have Whipple's disease—they respond very well to antibiotics. It seems like they're colonised throughout the bowel and many other organ systems and the immune system does not fight it. And it does produce some paraneoplastic-almost like symptoms that we think are an indirect component of the immune system being dissuaded from fighting it. So, we don't know whether there's a genetic disposition in this particular cultural group or ethnic group that prevents the immune system recognising it. Or maybe the bacillus itself downregulates the immune system and therefore evades it. Really interesting—there's not enough cases to do proper research on it, so maybe we'll never know, we won't know for a long time. In terms of the other features other than that classic four that I discussed, fever occurs in 40% up to.
Endocarditis, which can occur separately from Whipple's disease classic or as part of Whipple's disease is another manifestation that's important and actually a study of culture-negative endocarditis, where they've taken out valves, showed that Whipple's disease was the most common unculturable infection of those valves, which is really interesting. That was only 6%. So, there's a whole lot of other infections that they could find on microscopy, but they couldn't culture in the blood. Rarely pericarditis, myocarditis. If it gets into the brain, it can cause dementia, and it can cause skin hyperpigmentation. And then a few rarer pulmonary manifestations like pleural effusions, intestinal lung disease and pulmonary hypertension, hypertension. And we did wonder whether that little flash APO thing that had happened a few weeks prior was some kind of lung manifestation. But regardless, these patients usually respond really well to treatment, although it can be difficult and a decent number, maybe you know 20 to 30% of people will relapse after completion of treatment, need to go back on long-term treatment to properly clear it.
SARAH FU: Perfect. Now, to wrap up the case for the listeners. Could you please outline a couple of key learning points or take-home message that you took from the case?
ANDREW VANLINT: So, I thought of three things. Firstly, this is a great example that multidisciplinary collaboration always value adds to patient care. Sometimes it's a bit messy, but it's well worth it. So, this was a great collaboration between acute medicine, gastroenterology and radiology. And three of those disciplines contribute to writing up the article and obviously a little bit from pathology and haematology in the background as well. Without that collaboration, without it being specified in Marco's radiology, particularly academic radiology report, we may not have got that diagnosis here. We may not have pushed for an endoscopy.
Probably he would have got in obviously at some point, but we got that diagnosis quickly and he got a quick response from treatment because of that. So I'm grateful that he was setting his exams at that time. Secondly, Whipple's disease, it's rare, but it's probably under-recognised and so, has four features as we've recommended and those rarer manifestations. Interestingly, even though it responds to ceftriaxone and bactrim it, there are a range of antibiotics that it will respond to. So, this guy had had some augmentin for about 5 days, about a month prior to coming in and he noticed that when he took the augmentin, the diarrhoea resolved for about five or six days. And then a few days after he stopped the antibiotics, it came back again. And so, in retrospect, we think that was the Whipple's disease responding temporarily to that antimicrobial therapy.
And lastly, lymphadenopathy, it's easy to go, “Oh, maybe it's lymphoma, maybe it's metastases or local infection”, but I think this case and our discussion does highlight that there are some less common but important differentials to consider when you've got lymphadenopathy and whether it's acute or chronic will make a big difference to the way you consider that.
STEPHEN BACCHI: Fantastic. Thanks, doctor Vanlint. And again, what a great diagnosis. So for people who want to read the full details of the case it’s titled Low attenuation lymphadenopathy on computed tomography leading to diagnosis of Whipple disease. It was published in the Medical Journal of Australia in 2020. The first author, Doctor Andrew Vanlint, who's joined us today, and senior author Sam Costello. Thank you again, Doctor Vanlint.
MIC CAVAZZINI: Thanks again to Stephen Bacchi and Sarah Fu, two physician trainees who have volunteered to produce this educational resource for their peers. They do both have day jobs, so please take this podcast as a prompt to read more, rather than the authoritative last word on the subject.
As well as these [Case Reports] there are a few different podcast formats published under the Pomegranate banner. [IMJ On-Air] showcases authors who have recently published in the Internal Medicine Journal, flagship publication of the Royal Australasian College of Physicians. The [Journal Club] episodes feature College members who have presented impactful research in other publications. In both cases I have guest hosts with speciality expertise driving the interviews for me. And you’ll also some episodes labelled [Guest Lecture]. These are presentations from College members that I’ve spotted through other academic institutions and thought were worth sharing more broadly.
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And don’t forget all the other online resources at elearning.racp.edu.au. For trainees there is the College Learning Series containing hundreds of detailed medical lectures, and then in the Medflix channel there are lots of special interest webinars from outside the core curriculum.
This podcast was recorded on the lands of the Kaurna and Gadigal clans. I pay respect to their elders and teachers over many thousands of years. I’m Mic Cavazzini. Thanks for listening.