The field of family medicine is constantly evolving, making it challenging for the interdisciplinary healthcare team to stay up to date with recent developments. This article covers key advancements in the field that may have important implications for clinical practice.

SUCRALOSE DAMAGES DNA, LINKED TO LEAKY GUT: STUDY

Artificial sweeteners, or sugar substitutes, are increasingly used in food, drinks and medicinal products.^[1] These substances were considered to be effective for managing health conditions such as diabetes and obesity; however, recent evidence suggests that sugar substitutes have no impact on glycemic control or body weight.^[2]

In a new study published in the Journal of Toxicology and Environmental Health, Part B, researchers conducted a series of laboratory experiments exposing human blood cells and gut tissue to sucralose-6-acetate.^[3]

The study results were so alarming that researchers suggest people should stop consuming sucralose and that the government should regulate it more. The findings also build on previous research that linked sucralose to gut health problems. The researchers found that sucralose causes DNA to break apart, putting people at risk for disease. They also linked sucralose to leaky gut syndrome,^[4] which means the lining of the intestines are worn down and become permeable. Symptoms are a burning sensation, painful digestion, diarrhea, gas, and bloating.

When a substance damages DNA, it is called genotoxic. Researchers have found that eating sucralose results in the body producing a substance called sucralose-6-acetate, which the new study now shows is genotoxic. The researchers also found sucralose-6-acetate in trace amounts in off-the-shelf products that are so high, they would exceed the safety levels currently allowed in Europe.

The FDA says sucralose is safe, describing it as 600 times sweeter than table sugar and used in "baked goods, beverages, chewing gum, gelatins, and frozen dairy desserts. To determine the safety of sucralose, the FDA reviewed more than 110 studies designed to identify possible toxic effects, including studies on the reproductive and nervous systems, carcinogenicity, and metabolism," the agency explained on its website.^[5] "The FDA also reviewed human clinical trials to address metabolism and effects on patients with diabetes."

DIABETES, FATTY LIVER DISEASE, ULTRAPROCESSED FOODS LINKED

Metabolic-associated fatty liver disease is a leading cause of liver cirrhosis and hepatocellular carcinoma across the globe.^[6] It is commonly associated with type 2 diabetes and when both conditions are present together, there is an increased risk of adverse clinical outcomes.^[7] Diet is, to a certain extent, the common thread tying type 2 diabetes to fatty liver disease. And, as affirmed during the 34th National Conference of the Spanish Diabetes Society, there is mounting evidence that the increase in consumption of ultraprocessed foods is related to this link.^[6]

According to experts participating in a roundtable discussion, the data leave no question as to why metabolic-associated fatty liver disease is a significant cause for concern among endocrinologists in Spain. It is highly prevalent, and rates are trending upward. The roundtable discussion was organized by the Spanish Society of Obesity, the Spanish Society of Endocrinology and Nutrition, and the Spanish Diabetes Society.^[6]

"Metabolic-associated fatty liver disease has become the most common cause of chronic liver disease, and it is estimated that 25% of the world's population suffers from it. However, the worst is yet to come, since it's estimated that cases will increase by 56% over the next 10 years, which could potentially make it the leading cause of cirrhosis," said Rubén Nogueiras, MD, of the Research Center for Molecular Medicine and Chronic Diseases of the University of Santiago de Compostela, who is a researcher with the Spanish Biomedical Research Center for Physiopathology of Obesity and Nutrition.

"Metabolic-associated fatty liver disease is caused by multiple factors," Nogueiras told Medscape Spanish Edition. "The most common causes responsible for the growing number of cases include excess weight, obesity, insulin resistance or type 2 diabetes, abnormal levels of triglycerides and cholesterol, and metabolic syndrome, or having one or more characteristics of this syndrome. Genetic causes also come into play. Having any one of these conditions increases the likelihood of developing metabolic-associated fatty liver disease."

The concern regarding the incidence of this disease appears to be somewhat mitigated by advances in 2 main areas: diagnosis, and basic and clinical research. "Until recently, reliable diagnosis required a biopsy. However, ultrasound technology is now available that can measure liver stiffness, hardness, and fatty changes within the liver. This technique, along with a blood test, allows for a relatively reliable diagnosis of the stage of the disease," said Nogueiras.

Nogueiras pointed out that most studies focus on hepatocytes, which are the most abundant cells in the liver. "We believe that other cells may also be significant and may provide solutions for keeping the disease from progressing to more serious stages, and even for improving the condition."

Nogueiras and his team focus their efforts on studying stellate cell reprogramming. Normally inactive, stellate cells are activated when the liver is injured and are responsible for the hepatic fibrosis that develops when metabolic-associated fatty liver disease progresses, causing more serious injury. "Depending on the type of reprogramming, we are able to activate or deactivate these cells and thereby induce or reverse hepatic fibrosis in animal models," he said.

Medicinal Therapy

Commenting on the main areas that are currently under investigation in this disease, Nogueiras said that many groups focus their research on multiple primary goals. "One of these is to find reliable markers that can predict disease progression and classify patients using biomarkers, since not everyone with metabolic-associated fatty liver disease is the same or responds in the same way to treatment. Different clinical trials have also been performed with different drugs, and looking farther to the future, there is an effort to discover new molecules that could be used as therapeutic targets. Another aim is to find the most appropriate drug for each therapeutic target: in other words, using personalized medicine."

The specialists agreed that despite this progress, the great, unresolved issue in the approach to metabolic-associated fatty liver disease is finding an effective medicinal treatment, since "there is currently no drug approved for treating this disease. There have been clinical trials that have tested different drugs against different therapeutic targets, but they haven't advanced to the marketing stage," said Nogueiras.

When asked about the outlook for discovering a medical treatment in the middle to long term, Nogueiras said, "That's the million-dollar question. It's a highly complex disease, and, like we said, it has many factors. That's why finding an effective drug with few side effects is a real challenge. Up until now, the clinical trials for different drugs — of which some have appeared to be quite promising — have, for multiple reasons, not achieved the level of success we hoped. We'll have to wait for results from ongoing studies. But we predict that in the medium term, we will find an option that will work in at least a sizeable percentage of patients."

Ultraprocessed Foods

Nonalcoholic fatty liver disease was the theme at the plenary session that capped off the meetings. The plenary session was led by the nutritionist Shira Zelber-Sagim, PhD, of the School of Public Health at the University of Haifa in Israel.

Zelber-Sagim discussed how the types of foods that are routinely consumed affect the risks for developing nonalcoholic fatty liver disease and type 2 diabetes. She reported the latest evidence of the close relationship between both diseases. "The most beneficial treatment for nonalcoholic fatty liver disease is weight loss achieved through a Mediterranean diet paired with physical activity. So, people with this disease should eat a healthy diet that includes minimally processed or unprocessed products (fruits, vegetables, pulses, whole grains, unprocessed meats and fish, etc), low in sugar and saturated fat and high in polyphenols, vitamins, healthy oils (like olive oil), and some types of fats (like omega-3 fatty acids)."

The nutritionist also emphasized that the Mediterranean diet encompasses all these factors. "It has been shown that even partial adherence to a Mediterranean diet can be beneficial."

Among the global population, however, exposure to ultraprocessed industrialized foods has "caused the Mediterranean diet to be abandoned and encouraged the adoption of a less healthy diet."

Research such as that conducted by the European Prospective Investigation into Cancer and Nutrition,^[8] which was performed in 10 countries and included 36,034 individuals aged 35 to 74 years, has shown a "dramatic" increase in the consumption of ultraprocessed foods worldwide. According to the study, these foods represent between 61% (Spain) and 78% to 79% (the Netherlands and Germany) of average calorie intake.

Moreover, ultraprocessed foods made up 57.5% of the calories in the daily energy intake of the 9317 participants in the NHANES 2009–2010 study in the United States.

"Soft drinks, packaged snacks, breakfast cereals, instant sauces, and many oven-ready products are your typical ultraprocessed foods," said Zelber-Sagim.

Dose-Dependent Effect

Zelber-Sagim explained that several studies carried out in diverse populations have shown an association between the proportion of ultraprocessed foods in the diet and the risk of developing diet-related chronic diseases, such as obesity and cancer, as well as gastrointestinal disorders, cardiovascular risk factors, fragility, and mortality.

"Therefore, cutting back on how much of these foods we're eating may be an effective strategy for preventing and treating obesity and other associated diseases, like diabetes and nonalcoholic fatty liver disease," she said.

She emphasized that a growing number of researchers have shown a direct and dose-dependent association between eating ultraprocessed foods and developing nonalcoholic fatty liver disease. "A link between red meat and processed meat and this disease has also been observed. Also, eating too many processed foods with high fat, sugar, and fructose content and foods prepared at high temperatures leads to a higher intake of advanced glycation end products, which accelerate liver injury."

The specialist also mentioned other factors tied to the association between nonalcoholic fatty liver disease and the consumption of ultraprocessed foods that could be leading to an increase in prevalence. "Low income and dietary deficiencies may be related to a higher prevalence of nonalcoholic fatty liver disease and advanced fibrosis, very likely due to the affordability of high-calorie processed foods that are very rich in fats and sugars, as well as a general decline in high-quality diets.

"In light of these data, the authorities need to make a pointed effort to take educational and political steps to increase the access of the general population to healthier options and to help reduce the consumption of ultraprocessed foods, not only to prevent nonalcoholic fatty liver disease and diabetes but to improve health in general," she said.

"We need to stand up to ultraprocessed products. They are made from industrial ingredients and contain little or no whole food. So, from their very nature, they're not healthy and should be avoided. They are also often characterized by a lower nutritional quality and a high-calorie density and contain additives, substances from the packaging that comes in contact with the foods, and compounds formed during production, processing, and storage," she concluded.

MENOPAUSE AND LONG COVID: WHAT WOMEN SHOULD KNOW

The COVID-19 pandemic presented a number of clinical challenges. In addition to the acute symptoms experienced post-infection, many patients were burdened by long-term health complications associated with this condition, a state termed ‘long COVID’.^[9]

As clinicians and researchers learn more about long COVID, an interesting fact has emerged: Women experiencing menopause and perimenopause appear to be more likely to experience serious complications from the virus.

British researchers have newly noted that women at midlife who have long COVID seem to get specific, and severe, symptoms, including brain fog, fatigue, new-onset dizziness, and difficulty sleeping through the night.^[10] Doctors also think it's possible that long COVID worsens the symptoms of perimenopause^[11] and menopause. Lower levels of estrogen^[12] and testosterone^[13] appear to be the reason.

"A long COVID theory is that there is a temporary disruption to physiological ovarian steroid hormone production, which could [worsen] symptoms of perimenopause and menopause," said JoAnn V. Pinkerton, MD, professor of obstetrics at the University of Virginia in Charlottesville and executive director of the North American Menopause Society. Long COVID symptoms and menopause symptoms can also be very hard to tell apart. 

Another U.K. study cautions that because of this kind of symptom overlap, women at midlife may be misdiagnosed.^[14] Research from the North American Menopause Society shows that many women may have trouble recovering from long COVID unless their hormone deficiency is treated.^[15] 

What Are the Symptoms of Long COVID?

There are over 200 symptoms that have been associated with long COVID, according to the American Medical Association.^[16] Some common symptoms are currently defined as:

• Fatigue
• Cognitive issues such as brain fog
• Increased heart rate
• Loss of sense of smell and taste

Long COVID symptoms begin a few weeks to a few months after a COVID infection. They can last an indefinite amount of time, but "the hope is that long COVID will not be lifelong," said Clare Flannery, MD, an endocrinologist and associate professor in the departments of obstetrics, gynecology, and reproductive sciences and internal medicine at Yale School of Medicine in New Haven, CT. 

What Are the Symptoms of Menopause?

Some symptoms of menopause include:^[17] 

• Vaginal infections
• Irregular bleeding
• Urinary problems
• Sexual problems

Women in their middle years have other symptoms that can be the same as perimenopause/menopause symptoms. 

"Common symptoms of perimenopause and menopause which may also be symptoms ascribed to long COVID include hot flashes, night sweats, disrupted sleep, low mood, depression or anxiety, decreased concentration, memory problems, joint and muscle pains, and headaches," Pinkerton said. 

Can Long COVID Actually Bring on Menopause?

In short: Possibly.

A new study from the Massachusetts Institute of Technology/Patient-Led Research Collaborative/University of California, San Francisco finds that long COVID can cause disruptions to a woman's menstrual cycle, ovaries, fertility, and menopause itself.^[18] This could be due to chronic inflammation caused by long COVID on hormones as well. This kind of inflammatory response could explain irregularities in a woman's menstrual cycle, according to the Newson Health Research and Education study. For instance, "When the body has inflammation, ovulation can happen," Flannery said. 

The mechanism for how long COVID could spur menopause can also involve a woman's ovaries. "Since the theory is that COVID affects the ovary with declines in ovarian reserve and ovarian function, it makes sense that long COVID could bring on symptoms of perimenopause or menopause more acutely or more severely and lengthen the symptoms of the perimenopause and menopausal transition," Pinkerton said. 

How Can Hormone Replacement Therapy Benefit Women Dealing With Long COVID During Menopause?

Estradiol,^[19] the strongest estrogen hormone in a woman's body, has already been shown to have a positive effect against COVID. "Estradiol therapy treats symptoms more aggressively in the setting of long COVID," said Flannery.

Estradiol is also a form of hormone replacement therapy, or HRT,^[20] for menopause symptoms. "Estradiol has been shown to help hot flashes, night sweats, and sleep and improve mood during perimenopause," said Pinkerton. "So, it's likely that perimenopausal or menopausal women with long COVID would see improvements both due to the action of estradiol on the ovary seen during COVID and the improvements in symptoms."

Estrogen-based HRT has been linked to an increased risk for endometrial, breast, and ovarian cancer, according to the American Cancer Society.^[21]

"Which of your symptoms are the most difficult to manage? You may see if you can navigate 1 to 3 of them. What are you willing to do for your symptoms? If a woman is willing to favor her sleep for the next 6 months to a year, she may be willing to change how she perceives her risk for cancer," Flannery said. "What risk is a woman willing to take? I think if someone has a very low concern about a risk of cancer, and she's suffering a disrupted life, then taking estradiol in a 1- to 2-year trial period could be critical to help." 

What Else Can Help If I Have Long COVID During Menopause?

Getting the COVID vaccine, as well as a booster, could help. Not only will this help prevent risk of reinfection with COVID, which can worsen symptoms, but a new Swedish study says there is no evidence that it will cause postmenopausal problems like irregular bleeding.^[22]

"Weak and inconsistent associations were observed between SARS-CoV-2 vaccination and healthcare contacts for bleeding in women who are postmenopausal, and even less evidence was recorded of an association for menstrual disturbance or bleeding in women who were premenopausal," said study co-author Rickard Ljung, MD, PhD, MPH, professor and acting head of the pharmacoepidemiology and analysis department in the Division of Use and Information of the Swedish Medical Products Agency in Uppsala, Sweden.

In terms of self-care, patients should try to relieve any hormonal symptoms they might have had prior to long COVID. Treating perimenopause symptoms can be helpful, Flannery said. Doing so may reduce your discomfort from long COVID as well, if your health problems are indeed intertwined. "Good nutrition — avoiding carbs and sweets particularly before periods — plus getting at least 7 hours of sleep and regular exercise, reducing your stress, and avoiding excess alcohol can help women ovarian function during ovarian fluctuations," Pinkerton said. Taking these sensible steps can help you feel better.

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