Robert Frykberg, DPM, MPH discusses the significance of diabetes in our population, the pathophysiology and the importance of diabetic foot complications. Dr Frykberg also discusses current literature revolving diabetic foot ulcers and their recurrence.
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TAPE STARTS – [00:00]
Male Speaker 1: I like to start with an overview of diabetic foot since, you know, our programs have evolved quite a bit over the years, and traditionally this day was about diabetic foot and limb salvage. Although we morphed it into many, many other things, but this is a big part of podiatry practices. And so I'll try to make a difficult subject more simplified and instill down a lot of complex information as easily as possible, because we do know this is a very complicated subject and an increasingly important subject in all of our practice.
These are my disclosures. These are my published learning objectives, just to give you an overview of the frequency, determinants, risk factors for various complications of the diabetic foot. We know that almost 30 million people in the United States alone have diagnosed or undiagnosed diabetes, total cost, or exceeding now $250 billion for diabetes itself. And a large percentage of these cause are due to diabetic foot and lower extremity complication.
It still remains as the seventh leading cause of death in the United States and this figure really hasn't changed much in the last decade or so. But now, we know these are just data from the USA but around the world, the diabetes epidemic just continuous to grow. And as we have more people coming into our country from other parts of the world, our numbers are growing as well. So this will continue to be a big problem for all of us for years to come. Now, if we look at the major lower extremity complications of diabetes, they are familiar to us all.
But first and foremost is always peripheral neuropathy, because that's the underlying predisposing risk factor for many of the other complication. Whereas, ulceration infection, even peripheral arterial disease, all of these are leading to lower extremity amputation. We're not going to talk too much about Charcot foot now but obviously that's the most classic diabetic foot deformity. There is also subject of course to ulceration infection and amputation. So these are all interrelated. I think that's the big key here, learning about the interrelationship between all these severe significant complications of diabetes.
And most of them all relate back to chronic peripheral sensory neuropathy and autonomic neuropathy as well, so very, very important parts of our practices. But you need to be aware that diabetic foot ulcer itself is a predictor of early mortality. This is even independent of all vascular disease, as well as amputation. We used to say, "Well, it's because they're diabetic. They have a lot of amputations and ulcerations, and vascular disease."
But this study by Walsh out of the UK in 2016 show that independent of predisposing vascular disease and amputation diabetes foot ulcers are a risk factor for premature mortality. And this has been shown by several other studies by [Moloch] [00:03:52] in I think 2003 and by [Ed Wyco] [00:03:56] around the same time where diabetic patients have almost a twofold risk of death compared to non-diabetic patients if they have a foot ulcer. Very, very important.
This is old data published by the CDC, the National Diabetes Surveillance System, and they haven't really updated it, but this was published as late as 2014. You can see that the most common diabetes-related reasons for hospitalization are ulcer, PAD, and neuropathy, but of course most of you should be thinking that many of these are all related. Many people with ulcers are going to have underlying neuropathy for sure, and many of them will also had EAD. So it just goes to show these are really significant and growing problems as we go back from the late '80s up into the 2000s, and they continue to increase.
And we know that as we'll see also, diabetic-related hospitalizations have a large component of lower extremity complications as the reason for the initial hospitalization and surgery. So these are big, big problem. Luckily, over the last couple of decades, the incidents of lower extremity major amputations has been going down. I think it was a high point in 1996 where we had somewhere in the neighborhood of almost 90,000 diabetes-related lower amputations just on hospital discharge data, but did not include the VA or military, or DOD hospitals, or any health service hospitals.
As a result, we've seen the non-traumatic amputations decrease over the last certainly decade or so. Minor amputation is pretty much or saying the same but we're doing a better job on preventing the major amputations through our efforts, or our multidisciplinary teams in the vascular intervention and better awareness of course. How many do you have seen this graph before it's one of the most published graphs that actually comes from a 2003 article by Belch in the archives of Internal Medicine, where she was comparing peripheral arterial disease to, and five year mortality rates with five year mortality rates of persons with peripheral arterial disease?
Dave Armstrong, and I think it was in several years ago, expanded this into other complications of diabetes as we can see not just the PAD but a Charcot foot, foot ulcer and amputation. We see how this fit in very nicely and how once a person is amputated even by this study, which is out of Sweden and it's two decades old, 68% five year mortality rate on patients in a good control health system, 68% five year mortality rate and after five years. And then, if we look at several studies that will go over Charcot foot and foot ulcer even portent, an enhanced five year mortality rate, which is greater than colorectal cancer, breast cancer, Hodgkin's disease, prostate cancer.
So we're seeing that some of these severe complications of diabetes have a certain malignancy to them, if you will, because the mortality rates are elevated. These are serious problems that were taken care of. Now, the people don't die of Charcot foot or foot ulcer of course, but it's a marker for underlying significant systemic disease that we need to be aware of. And this data really hasn't changed all that much. I mean, you might see some numbers changed but generally their relationships remain the same today.
This study came from 2010 [Vanbaugh] [00:07:58] and William Jeffcoat out of Nottingham in the UK. And they also looked at one, three, and five year mortality rates, comparing their Charcot patients with diabetic foot ulcer patient. And we can see here five year mortality of Charcot foot patient is very similar to the five year mortality of diabetic foot ulcer patient. And that really hadn't previously been recognized although we know that the Charcot patients are very, very complicated even some – many cases, much more complicated than the diabetic foot ulcer patient. But as we said, DFU is a marker for premature mortality when you hear those patients who've had an ulcer with diabetic patients even who've never had an ulcer. Again, a marker for underlying systemic disease and of course the same which Charcot.
This one came from here in Chicago out of the VA, this was a year before looking at five year mortality. A little bit different data, this was a VA data, and we can see the diabetic foot ulcer 37% of five year mortality, Charcot foot, 28% mortality, all greater than patients with diabetes without this complication. So we see that the patients who have these significant lower extremity complications, you have an enhanced premature mortality because of the significance of their underlying metabolic problem.
This paper came from [Jimrel Bell's] [00:09:33] group at University of Michigan. It was a prospective observational study of almost 7,000 diabetic patients, not just ulcerated patients, but just their cohort of almost 7,000 diabetic patients with 10 years of follow up. And what they specifically were looking at were the prevalence of the cumulative incidents of Charcot foot, foot ulcers and lower extremity amputation. And of course, looking at all-cause mortality.
So they were looking not just the incidents of these problems but also the mortality associated with that. When we look at unadjusted or accrued rates here, these are hazard ratios. They're not controlling for the other important underlying risk factor like neuropathy, cardiovascular disease, peripheral arterial disease, et cetera. So we always have to look at adjusted rates where we're putting all these risk factors into the same model and looking for significant independent variables here. And when we fully adjust these models we see that lower extremity amputation as predicted has almost a two-fold risk for mortality in 10 years compared to patients who don't have lower extremity patient.
Now this was just this cohort which probably is a well-controlled cohort but we are seeing that these lower extremity complications do predict early mortality on our diabetic patient which is why we work so hard to prevent some of these complications and make sure that when they are in existence even like Charcot foot that they do not become infected, ulcerated, and then subsequently amputated. Because we know once these are amputated that the course is set for them or form of premature death in many cases due to the significance of that.
So this was a pretty significant study led by podiatrist at University of Michigan. And here we can see graph similar to many other graphs that you'll see in the literature, it's just a survival curve of patients with varying degrees with based on the status of their amputation. Patients with no lower extremity amputation have a much higher survival at 10 years than do patients with minor amputations but you see the major amputations here drop off faster.
Although, you can see a pretty significant drop off even in patients with minor amputations in this regard because they still do have these underlying risk factors that portent a much poorer survival compared to those who do not have those underlying comorbidities. So we put this together and I come back to a graph that I've used for many years because it really identifies the various underlying metabolic attributions and complications that can be existing in our patients with diabetes and certainly those with the diabetic foot ulcer even.
And you might have seen this before, you might not have, but it's just really a summary of what's going on here. We have always know that neuropathy is a many splendid thing and it underlies many of these complications that we've been talking about. But it's not just sensory glove and stocking neuropathy as we're all familiar with, also motor neuropathy and the all-important autonomic neuropathy as well. Motor neuropathy leads to weakness muscle atrophy the deformities that we see leading to abnormal stresses, high plantar pressures, callus formation and underlying ulceration.
Then we also have of course sensory neuropathy or loss of protective sensation, which is absolutely critical in this regard. We have autonomic neuropathy where many people have not paid attention to until recent years. And we know we have anhidrosis, dry skin, fissures, and decrease sympathetic tone, which means a loss of that protective [indecipherable] [00:13:57] response to injury. And also the dry skin leads to cracking and a portal eventually for bacteria, but very importantly with that sympathetic failure, you also have the altered blood flow regulation.
The microneurovascular normal regulation of your blood vessels is disturbed leading here to microvascular disease and microvascular disturbances, which we must pay attention to under our categories of vascular disease. In the microvascular disturbances, we know we have structural disturbances with thickened capillary basement membrane, but remember the functional AV shunting is out leading to actual capillary hypertension and hyperoxygenation of venous capillary to capillary venules. There's increased blood flow and neuropathic edema. These more or less have an effect on healing and healing disturbances.
Then we also consider the important role of macrovascular disease, which is growing atherosclerotic occlusive disease, which has become a huge problem not just in our country but around the world, which leads to many of these longstanding complication, certainly ulceration in a patient. All these leading to reduced nutrient capillary blood flow, loss of protective sensation. We got a break in the skin, then with the underlying immunopathy that's inherent in the diabetic patient, we have the impaired response to infection.
So we put all these together, have a break in the skin envelope, patient can feel the impending ulceration. They get infected because they keep on walking on. Then, they get gangrene and this can lead to an amputation. So we need to be familiar with all of these underlying metabolic ulcerations so we can be more effective in our approach to healing this patient. But we also need to pay attention to the data that's out there that supports these theoretical premises.
This is an old paper from Gayle Reiber, actually 1999, but it uses Ken Rothman's very simplistic component cross model that just looks at the critical components that might underlie a given disease outcome. And in this case the outcome is a foot ulcer. And what they found after looking at these seven potential predisposing risk factors which they found that in 63% of the causal pathways leading to foot ulceration, neuropathy, deformity, and trauma on that deformity were present. So these were the essential components that lead to that outcome of foot ulcers.
This gives us insight into important risk factors for ulceration and what we might do to prevent them. In this regard, we're not going to do much to reverse neuropathy but we can certainly intervene by preventing trauma. And in many cases, and those patient with deformities we can correct those deformities or be more aggressive with our offloading and our proper foot ware. So these are insightful data that help support why we do what we do in terms of our prevention. It also gives us important clues as to the importance of these various component causes leading to that sufficient cause which is that foot ulcer. Very important paper.
So he mentioned there all of deformity, what are the common deformities in diabetes that can predispose to ulcer. You see this every day, hammertoes. Hammertoes can be due to neuropathy where they can just be idiopathic hammertoes but we know there are important deformity, they can often become callus and ulcerative. Bunions or your hallux valgus form a metatarsal heads of Charcot arthropathy, which is classically due to neuropathy, but it's a classic diabetic foot deformity, even equinus, Achilles contracture.
We did a study years ago and found that equinus was indeed more prevalent in patient with diabetes when compared to non-diabetic person. So it is an important component. You know, it's not always the primary component. Sometimes it comes after the fact like for the Charcot arthropathy, I think more often than that the equinus comes after the foot has collapsed, because no one's measured the equinus or Charcot foot. So you can't really relate it to directly in terms of the incidents of the Charcot.
And then of course partial foot amputations are indeed a very important deformity. Because remember, you're applying the same weight, same force to a smaller surface area leading to a higher pressure as with a partial foot amputations which is why one of the highest risk factors for a foot amputation or ulceration is a previous amputation. Because it leads the higher pressures as you all know, so it's very important.
And Dave Armstrong, and Andrew Boulton, Sicco Bus published an important paper in New England Journal Medicine over a year ago now looking at diabetic foot ulcers and more importantly ulcer recurrence. As we know the presence of one diabetic foot ulcer, heel diabetic foot ulcer is one of the strongest risk factors for our subsequent recurrent ulceration. Patients have the same risk factors even when they heal the ulcer but then they have some scar tissue.
And we know now that we have to be thinking about ulcer free days because we know that most of these patients are going to re-ulcerate either in the same site or a new site down the road. And if you look at this graph which is really a reflection of a number of prior studies, we can see that at five years there's about a 70% incidents of recurrence of these foot ulcers. And if you go on 10 years, almost a 100% of these people will re-ulcerate.
Hence, they need for life long surveillance on this patient because we know they will re-ulcerate and if they re-ulcerate, they can get infected, if they get infected, they can come to some type of an amputation especially as they get older, more peripheral arterial disease, major amputation becomes a more problem. And here if we look at the risk factors, again this is based on a number of studies. Being highest on the list of course is reduced vibration perception threshold, sensitivity, loss or protective sensation.
Very important risk factor and we can see preulcerative lesions prior ulcerative lesions, peripheral arterial disease, and many, many possible factors and I'll refer to this June 2017 article. But importantly I just looked to this again yesterday, there's no studies particularly identified the important role of preexisting deformity. We know that foot deformity isn't itself very, very important risk factor pay attention to. And there's a nice graph of possible sequences or sequences leading to foot ulceration and infection here in that paper, thought I just refer you into that paper.
But again, the causal sequence we're all well aware of underlying peripheral neuropathy, some type of trauma deformity continued walking with or without treatment they get infected, then the constellation of problem develop. So let's talk about infection now as the other important complication here. I'm just giving you a very cursory overview because each one of these problems obviously we can discuss at length for almost a day.
This paper came from Larry Lavery. This is over a decade old now but it just gives a good summary, a good overview on I think it was 150 patients who developed infection from a large cohort of his patient. And they found a bone penetration, almost a seven fold increase risk for infection, wound duration greater than 30 days. Recurrent foot wound, traumatic wound, and peripheral arterial disease. These are all your risk ratios here. So you have bone exposure, you can consider that person has some type of lingering or occult infection and so you do it otherwise.
This is why I believe so strong and I probed the bone test, you know, from operation in 1995. You see bone, feel bone, probe bone, you can plan on that bone being infected, or that joint being infected unless you can prove that it's otherwise. So I think it's a very important clinical clue that should lead you to further investigation because we see from this data that it's important risk factor for ongoing infection.
Now, this year also in diabetes care, there was a new paper published on looking at infection in a large cohort. This was a match case control study out of the UK looking at – well, I think it was primary care patient looking at 102,000 patients with diabetes and comparing them to 203,000 non-diabetic patients. These are age, sex, and practice-matched patients. So they're getting good comparisons of people with diabetes compared to persons without diabetes, and then looking at infection rates during this period of 2008 to 2015. So this is a very large study and one that you can consider fairly reliable.
And they compare the controlled subjects without diabetes. They found that the patients with diabetes had higher rates for all infection. And this has been previously postulated and shown from a large Toronto study by [Sean Hawks] [00:24:12] also in 2003. And they found that the highest interest incidents risk ratios were seen for bone and joint infections, which we see all the time, sepsis and cellulitis. And they found that the incident rate ratios were higher in type 1 or type 2 patient, when they subcategorized the diabetic patients. So we see that the diabetic patients do indeed have an increased risk of infection of all types compared to non-diabetic patients and in those diabetic patients, type 1 had the higher risk than do type 2.
And the death from infection was twofold higher in the diabetic patients compared to the non-diabetic patients. So here we have some good data that really supports the fact, diabetic patients really do have a problem and we need to pay attention very carefully to them. And as I mentioned earlier, as estimated, the 6% of all infection-related hospitalizations and 12% of infection-related deaths were attributable to diabetes.
So this is really good data that supports the significance of diabetes leading to infection, certainly bone and joint infection, and sepsis. These are things that we've always known about and suspected, but now we have real data to support that and to support the fact that diabetic patients are going to die more frequently from their infection than will our non-diabetic counterparts, very, very important. So then, we look at the amputations as – I'm going to try to finish up here quickly. We look at risk factors for amputation. Look, they're pretty much the same as the risk factors for ulceration. Why?
Because ulceration is so closely linked to amputation. Prior amputation is linked not only to prior ulceration but it's also linked to future ulceration and future amputation. So we need to recognize that very carefully. This is an older study from my friend Stephan Morbach in Germany, and really what he was looking at was 200 and almost 250 diabetic referrals to patient, then he followed them for 10 years, and he found the major amputation occurred in those patients really who had severe underlying PAD.
And here in this graph, we can see no PAD, mild, moderate PAD, and then severe PAD with those limbs, and the death rate is really – the limbs fall off quickly and the patients die off much more quickly with severe PAD. So 35-fold increase risk for first major amputation, those patients with underlying PAD. That brings us to our stairway to amputation graph which I really liked. This is published by Lee Rogers in 2010, the Journal of Vascular Surgery.
We have that high risk foot on the bottom here. The bottoms there sustains some type of an injury, blunt injury or an old callus, or a burn like we see in Phoenix from walking barefoot. That patient gets a chronic wound. That wound becomes infected. That infection turns to gangrene if it's not treated properly. And of course once we have gangrene, amputation at some level is always required. And those two individuals in the room here as you all are seeing, there's many ways that we can intervene on this pathway or the stairway to amputation, and prevent the amputation by intervening early at the most opportune times. That's very important.
And so we can prevent these problems through patient and provider education, protective footwear, preventive foot care, prophylactic foot surgery, and appropriate circumstances, and of course multidisciplinary management, which has been shown by multiple studies for the last two decades or three decades over the years. And here we can see one study that came from Scotland, in the UK, where they started in 2004 instituting a multidisciplinary team and followed them over the course of the next five years or so.
And they found a 41% reduction in major amputations and a 30% reduction in total amputation by instituting a multidisciplinary foot care team with a focus on early intervention on amputation. So here we have an old model that I've used for many years. We're podiatrists, a gatekeeper. We got multiple referrals but we work closely with vascular surgeons or diabetologists, endocrinologists, internists, and all of our consultants and ancillary services. The foot in the middle is the patient because we can never be successful without involving now the patient in our team approach.
And by using some kind of a team, whether it's organized, closely knit team, or one of a referral network, it's still a team of people that are used to work for that patient's benefit to get them healed as quickly as possible and prevent further ulceration. So in summary, we know that diabetic foot complications are leading causes for diabetes-related hospitalizations, neuropathy, PAD, ulceration and infection, major risk factors for amputation, both ulceration on amputations as we've seen adversely affect survival. And knowledge of these underlying risk factors for these complications provides an opportunity for early intervention and prevention as we all want to practice on.
Okay, thank you. Good, good. Done. I'm done in time. Thank you very much. Hopefully that was a helpful overview.
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