Best Strategy for Early Septic Shock; Hormone Therapy and Blood Clot Risk

TTHealthWatch is a weekly podcast from Texas Tech. In it, Elizabeth Tracey, director of electronic media for Johns Hopkins Medicine in Baltimore, and Rick Lange, MD, president of Texas Tech Health El Paso, look at the top medical stories of the week.

This week’s topics include blood-based cancer screening impact, the best strategy for early septic shock, hormone therapy and thromboembolic risk, and lean metabolic dysfunction-associated steatotic liver disease (MASLD).

Program notes:

0:40 Lean MASLD

1:40 Biopsy-confirmed MASLD

2:40 Elastography for diagnosis

3:41 Liver transplant often needed

4:04 Hormone therapy and thromboembolic disease

5:04 Venous thromboembolism (VTE), ischemic stroke, and myocardial infarction (MI)

6:04 Oral estrogen increased risk

7:07 Liquid cancer biopsy impact

8:07 Not had cancer compared to routine screening

9:07 Not seeing a positive impact

10:05 Inter-interval breast cancers

10:31 How to manage early septic shock

11:31 Main outcome alive and out of the hospital at day 90

12:30 Both are equally effective

13:20 End

Transcript:

Elizabeth: What’s the best management strategy for early septic shock?

Rick: Does blood testing for multiple cancers affect late-stage cancer diagnosis?

Elizabeth: What are the dangers, or not, of menopausal hormone therapy?

Rick: And what is lean metabolic dysfunction-associated liver disease?

Elizabeth: Yikes! That’s what we’re talking about this week on TTHealthWatch, your weekly look at the medical headlines from Texas Tech University Health Sciences Center in El Paso. I’m Elizabeth Tracey, a Baltimore-based medical journalist.

Rick: And I’m Rick Lange, president of Texas Tech Health El Paso.

Elizabeth: Well, we, I think, need to turn right to JAMA for that extremely complex intro that you did looking at non-alcoholic steatohepatitis. Gosh, we call it so many different things. It’s all about you, Rick.

Rick: Absolutely. So, you’re right. We’ve now tried to put all together what has been known as non-alcoholic fatty liver disease. We now call MASLD, metabolic dysfunction-associated steatotic liver disease. Wow! It’s liver disease not related to alcohol. And we usually associate it with obesity and type 2 diabetes, because most individuals that have those have metabolic dysfunction that results in the liver disease. Increasingly, there are a number of individuals that don’t have a high BMI [body mass index], and they don’t have a high waist circumference, yet they nevertheless still develop non-alcoholic liver disease.

So what these investigators did was attempt to characterize these individuals. This is a multinational, retrospective, observational study of adults that have biopsy-confirmed MASLD from 41 different countries. What did the liver disease look like and how did it manifest? And was there a lower mortality from it? And how often does it occur? Among over 18,000 individuals, about 6-7% had lean MASLD. These were individuals that had a lower incidence of type 2 diabetes, less advanced fibrosis, and when they looked at their overall mortality, it was very similar. And it appeared that the mortality was related to the degree of fibrosis. How they could best determine the fibrosis, there are two ways it’s done.

One is a routine survey called the FIB-4, where you look at the person’s age, their different liver enzymes, you determine what’s the likelihood. Or else you do liver elastography. And the latter was more precise in those with lean MASLD than the routine survey. What does this tell us? We see it in about one in 13 individuals. Once they develop fibrosis, their mortality is just the same as those with obesity and type 2 diabetes.

Elizabeth: Sounds also like the elastography is the method of choice with regard to diagnosis and staging, probably.

Rick: Absolutely. So if the FIB-4 does in fact suggest you have fibrosis, that’s great. But if it’s negative, you can’t rely upon that. You have to do the liver elastography.

Elizabeth: I’m wondering about the etiology, and I know this study doesn’t address that. We’ve had a lot of discussion about people who have obesity and type 2 diabetes and a higher level of inflammation, and is that the underpinnings of the development of this condition in those folks. In those who are lean, however, I’m kind of at a loss.

Rick: Yeah. So, Elizabeth, it suggests that these people, when they have fat deposition, it just occurs in the liver, not in their central body. That’s one thing. These patients also have sarcopenia. They can have insulin resistance, despite having a normal BMI. It might be the microbiome in the gut, genetic variants. It could also be dietary things. It’s still metabolic associated.

Elizabeth: And I would just say, Rick, finally, I find it very distressing to see these folks in the hospital because ultimately they require a liver transplant, and that is not an easy path for anybody.

Rick: Right. They require a liver transplant because, obviously, severe fibrosis. The other thing they’re predisposed to is hepatocellular liver cancer. We need to identify both the etiology and also things we can do to reverse it.

Elizabeth: I agree.

Let’s turn to The BMJ, this ongoing issue, what about menopausal hormone therapy and are there risks? And I said, “or not,” with regard to that therapy for women who have transitioned through menopause or are doing so.

I love this study. It’s from Denmark. I always love those studies because their robust databases are so persuasive. It’s their national health registry, of course, and they identified 9,800-plus women with venous thromboembolism, 18,000-plus with ischemic stroke, and just shy of 12,000 with MIs. All those women had been taking hormone therapy and then they were matched with women who never took it. These women did not have a medical history of VTE or arterial thrombosis, cancer, liver disease, or a host of other conditions that might have been confounders in examining the role of hormone therapy in this case.

In looking at these three outcomes — VTE, ischemic stroke, and MI — what they found was that there was really not much of an increased risk. It was a little bit of an increased risk and that was almost all involved with oral forms of estradiol. They also found that transdermal therapy was not associated with increased thrombotic rates compared with no current use, with the exception of an increased risk of MIs with transdermal combined cyclic therapy. So there was an increased risk with that.

My hope is that this study is going to be able to put to rest a lot of the concerns that seem to persist as a result of the flawed data of the Women’s Health Study, and that women who are utilizing this therapy for management of what amount to mostly vasomotor symptoms are going to feel OK about this choice.

Rick: It’s interesting is that there’s concordance. When women took oral estrogen therapy, it increased the risk of all three thrombotic events. And I do agree with you, it seems to be with oral estrogen therapy as opposed to transdermal, but it was pretty consistent. And it increased the risk between 30% and 60% overall. I don’t want to minimize that.

On the flip side, it occurs very rarely. A 30% to 60% increase sounds like an awful lot. But if the incidence is fairly low, that’s a whole different thing. I think we both agree there are women that are at increased risk for thromboembolic events — either cigarette smokers, they have a genetic predisposition, or they’ve already had a thromboembolic event — and those are the women we’re most concerned about.

Elizabeth: According to guidelines, it’s almost all transdermal or other modes of application. I’d have to say that I think the risk is even lower because this is a retrospective study, of course.

Rick: It’s interesting because in Denmark about 85% of the estrogen use was in fact oral therapy. Now, it may have switched. So, no, again, reassuring that there does not appear to be an increased risk with transdermal, probably regardless of which country in which it’s used.

Elizabeth: Let’s move on to the New England Journal of Medicine.

Rick: It’s the use of liquid biopsies, taking a blood sample to detect cancers that otherwise you wouldn’t detect by routine screening. When you look at 60% of the cancers that are diagnosed — we’re talking about things like lung, head and neck, pancreatic cancer, myeloma, liver, bile duct cancer, stomach, esophagus — there’s no routine screening for those.

There are some blood tests that have been developed, and those blood tests detect methylated changes in circulating DNA from the cancer. If we can identify that someone has one or more of these cancers and subject them to screening, using an MRI or a CT scan, then we can detect cancers in their early stage and avoid late-stage cancers.

That’s what this study examined. It’s called the NHS-Galleri trial, and it’s from a company that makes a multi-cancer early detection test from a blood screen. This is a randomized controlled trial to evaluate the clinical utility of this test in individuals between the ages of 50 to 77 who had not had cancer, compared to just routine screening. Over 71,000 participants. Half had the blood test and standard routine screening. The other half just had the standard routine screening. And they looked at the incidence of stage III and IV cancer over the course of not only 3 years of blood testing, but another 17 months afterward. And what they discovered was there was no difference in the incidence of stage III or stage IV cancer.

Elizabeth: It’s a very disappointing result, of course, because all of us would love to see something that could really pull those things out. Because there’s that often-repeated paradigm that we want to catch these things early because that’s when we have the best chance of cure. I’m wondering about how that’s going to really change going forward because these tests are getting better and better at pulling out this kind of DNA that’s circulating in the blood, but we’re just not seeing any real positive impact.

Rick: No, we’re not. Not now. And it could be for a number of reasons, Elizabeth. One is the tests may need to get better. There could be false positives. And in fact, in those that had positive tests, a relatively large number didn’t have detectable cancer. Now, this is an evolving story. I think we’re going to hear more about this over the next several years.

Elizabeth: I think that’s unquestionably true. One thing that it calls to mind for me is this idea that we are all constantly producing a certain number of cancer cells, and they’re dying and releasing their DNA. And maybe that’s what this is detecting, and that our immune systems in general are pretty good at keeping that stuff in check. And then there comes a point where that’s not true. And that’s when we have a frank cancer manifest.

Rick: That and/or the cancer develops so rapidly. Is it in between testing it appears and it’s so aggressive it becomes late-stage before the next blood test reveals it?

Elizabeth: Let me just bring to mind the breast cancer paradigm, where these so-called inter-interval breast cancers, those that are detected in between the times when women would have routine mammography, have a much higher mortality rate than those that are found at routine screening. So I think that also points to the idea that you’ve just identified that, gosh, those things that arise and then just rapidly gain traction, those are the bad actors that we’re missing.

Rick: Absolutely.

Elizabeth: So finally, remaining in the New England Journal of Medicine, something that’s of interest to me, of course, since I spend a lot of time in the chaplain role in critical care, this idea of vasopressors or fluids in early septic shock.

So when people come into the ED [emergency department] and they present with septic shock, the question is, should we either give them more fluids or should we initiate vasopressors to support their blood pressure early? This has been an ongoing question and this notion of the practice, what’s the best thing to do is just not even remotely settled.

So this is an Australian study that assigned adult patients who came to the ED with early septic shock to receive either fluids at restricted volumes and early vasopressors or higher volumes of fluids, again, in a strategy to maintain their blood pressure, and later vasopressor therapy for at least 6 hours and up to 24 hours. They had a thousand patients in this study, and their main outcome was the median number of days alive and out of the hospital at day 90.

The disappointing result was what the study found was that, gosh, it really didn’t matter. It didn’t matter whether you initiated vasopressors early and restricted fluids, or you gave fluids and you initiated the vasopressors later. There essentially was not any difference between these two groups.

Rick: You might say it’s disappointing. The nice thing to say is, depending upon resources you have available, you can have the same outcomes. When you use vasopressors, the person typically has to be in the intensive care unit (ICU), and oftentimes they have intra-arterial monitoring that demands special expertise. But let’s say you’re in a developing country and you don’t have ICU access. Well, knowing that you can give intravenous fluids and get the same outcome could actually be good news.

Elizabeth: This is really pretty dire, as you’re well aware. I was hoping something was really going to emerge as, yeah, this is really effective, and that’s just not the case.

Rick: You could say that both are equally effective. This will be helpful because, up to date, the guidelines have been really kind of wishy-washy. I mean, they really haven’t known what to do. There were some studies that suggested there was no difference, and there were meta-analyses and observational studies that suggested that vasopressors may be beneficial, and nobody really wanted to put a hard stamp on it. And I think this study, very well done in a large number of patients, says, listen, whatever you have access to, whatever you’re more comfortable using, you can get equivalent results.

Elizabeth: On that positive spin, then, that’s a look at this week’s medical headlines from Texas Tech. I’m Elizabeth Tracey.

Rick: And I’m Rick Lange. Y’all listen up and make healthy choices.