Liver Archives - ENCORE Research Group

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Medical terminology can be hard to understand. Much of it is in Latin, some is in Greek, several words are named after people, and terminology can change. Sometimes that change is a good thing, though. In June 2023 a collaboration of hundreds of experts in liver disease released new names for the liver diseases previously known as Nonalcoholic Fatty Liver Disease (NAFLD) and Nonalcoholic Steatohepatitis (NASH).

Adapted from Rinella, M. E., et al., 2023

Under the broad category of Steatotic Liver Disease (SLD) we now have Metabolic dysfunction Associated Steatotic Liver Disease (MASLD), which can progress to Metabolic Dysfunction-Associated Steatohepatitis (MASH) and Metabolic Alcohol-associated Liver Disease (MetALD, which is MASLD and increased alcohol intake). This change was made for many reasons. The terms “non-alcoholic” and “fatty” may have been confusing, stigmatizing, or inaccurate. People who are not overweight may still have the disease, and those with the disease may still be consuming alcohol. Finally, naming a disease after what it isn’t (“nonalcoholic…”) is less than ideal.

The new system describes the same symptoms but with more specific language. Steatosis is the accumulation of fat inside of cells and the disease is caused by changes in the metabolic system; how our cells change food into energy. A critical change has also been made with the adoption of the new term MetALD. MetALD describes people who have MASLD, but who still consume some alcohol. Alcohol affects the disease progression, but metabolic disruptions do as well. Hence, a term was developed to describe this overlap.

These terms were planned and adopted by an international group of clinical researchers, scientists, educators, industry experts, and patient advocates. The American Association for the Study of Liver Disease (AASLD), European Association for the Study of the Liver (EASL), Asian Pacific Association for the Study of the Liver (APASL), and Asociación Latinoamericana para el Estudio del Hígado (ALEH) made up most of the participants and have ensured widespread adoption of the new terminology

Staff Writer / Editor Benton Lowey-Ball, BS, BFA

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References:

Rinella, M. E., Lazarus, J. V., Ratziu, V., Francque, S. M., Sanyal, A. J., Kanwal, F., … & NAFLD Nomenclature consensus group. (2023). A multi-society Delphi consensus statement on new fatty liver disease nomenclature. Annals of Hepatology, 101133. https://doi.org/10.1097/HEP.0000000000000520

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Nonalcoholic Steatohepatitis, or NASH, has no approved medications available for treatment. This isn’t because the disease is safe, however. NASH can lead to cell death, cells going rogue, collagen accumulation, fibrosis, cirrhosis, and liver cancer. One problem with treating NASH is that it is a multifactorial disease, meaning there are many possible causes that all lead to the same outcome. The current best methods for treating NASH are exercise, weight loss, and treating other conditions that may contribute. We will discuss scientifically backed information regarding these treatment options, but it is critical that any medical advice be discussed with your doctor. NASH has many many causes and affects a lot of body systems. Medical professionals that may be involved in NASH treatment include your primary care physician, a hepatologist, dietitian, endocrinologist, cardiologist, and others. Every person is an experiment of one, and your specific circumstances may contraindicate one or all of the methods discussed below. Talk to your doctor.

Weight loss is the go-to method of treating NASH. A combination of diet and exercise is the best method to achieve weight loss. This ensures fewer calories enter the body than exit it, and that the body is burning weight from fat instead of from muscle. Losing weight very rapidly can be dangerous, so be conscientious of your body’s overall health (and speak with a professional!) Research has shown that reducing weight by as little as 5% (12.5 lbs for a 250 lb person) can help improve steatosis, the fat buildup in the liver. Losing 7% or more (17.5 lbs for a 250 lb person) also shows a reduction in inflammation and improved health of liver cells. When patients, particularly obese patients, lose 10% of their body weight (25 lbs for a 250 lb person) the structural liver changes known as fibrosis start to regress or stabilize. For NASH patients of a normal weight, they may see results when losing as little as 3-5% of body weight.

Exercise is a great way to lose weight, but studies have shown that exercise can help your liver even when you aren’t losing weight. The exact mechanisms for how this works are complex and not fully known. Scientists have found that exercise helps make the body more sensitive to insulin – which helps it regulate blood sugar better. It can also help cellular metabolism. Exercise is associated with a reduction in the markers of liver inflammation and may help liver cells stay healthy. Aerobic exercise, also called “cardio,” is highly recommended. Resistance training, called strength training, is also helpful, especially if aerobics are not possible. NASH patients start seeing benefits when doing exercise for 150-300 minutes (2 ½ – 5 hours) per week of moderate intensity exercise or 75-150 minutes (1 ¼ – 2 ½ hours) per week of high intensity exercise. Always ease into a new exercise routine to avoid injury. Talking to a medical professional is also a good idea before starting new exercises (there is a theme to this article).

Exercise burns calories, but to lose weight we also want to manage what calories we take in. Consult with your doctor or dietitian, but reducing caloric intake to around 500 fewer than the daily recommended value may help. Further, the number of calories is not directly correlated to the quality of the calories. NASH patients find improvements when reducing items that can damage the liver, including fructose and saturated fats. Fructose is a form of sugar that is often added to sugary beverages (usually in the form of high fructose corn syrup) and contributes to insulin resistance. Saturated fats are found in meats, including red meats and processed meats. As for specific diets, research is ongoing. The Mediterranean diet has the most research backing its success in NASH patients. It is rich in fruits, vegetables, whole grains, seafood, nuts, legumes, and olive oil. Other diets may be suitable as well, including intermittent fasting, ketogenic diet, and others. One recommendation is to take the Mediterranean diet and adjust it to fit you. Regardless of the diet choice, alcohol should be limited. For smokers and former smokers, alcohol should be eliminated entirely. It should go without saying that making major adjustments to your diet should be consulted with your doctor.

Other than diet and exercise, treatments for NASH are all achieved by treating other conditions that contribute, and will vary depending on the individual. Conditions that contribute are obesity, diabetes, high blood pressure, high cholesterol, cardiovascular disease, and obstructive sleep apnea. Cardiovascular disease and obstructive sleep apnea are major contributors of mortality for NASH patients and should be taken seriously. Obviously these conditions are best treated by going to your doctor.

NASH is a progressive disease that gets worse over time and leads to serious, occasionally deadly complications. Clinical trials may give us a medical NASH treatment in the future. Until then, give yourself a leg up (or liver) by consulting your doctor about treatments through diet, exercise, and underlying condition management.

Staff Writer / Editor Benton Lowey-Ball, BS, BFA

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References:

American Liver Foundation. (March 16, 2023). What are the treatments for NAFLD and NASH? NASH Treatment, https://liverfoundation.org/liver-diseases/fatty-liver-disease/nonalcoholic-steatohepatitis-nash/nash-treatment/

Van der Windt, D. J., Sud, V., Zhang, H., Tsung, A., & Huang, H. (2018). The effects of physical exercise on fatty liver disease. Gene Expression The Journal of Liver Research, 18(2), 89-101. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5954622/

Younossi, Z. M., Corey, K. E., & Lim, J. K. (2021). AGA clinical practice update on lifestyle modification using diet and exercise to achieve weight loss in the management of nonalcoholic fatty liver disease: expert review. Gastroenterology, 160(3), 912-918. https://doi.org/10.1053/j.gastro.2020.11.051

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Is the liver the most amazing organ? Yes. It turns food into usable molecules. It makes proteins, bile, and hormones. It filters dangerous drugs and toxins. Without it, you would die within minutes. Also, the liver can regenerate (like a lizard’s tail!), which is basically magic. The liver is estimated to have over 500 individual functions and interacts with most body systems. In this article we’ll look at the liver, zooming in from basic facts to its cellular units. Then we’ll explore the functions of the liver.

If you were to guess the largest organ in the body, would you guess the liver? I hope not, because it’s the skin. But the liver is in second place! It makes up around 2% of your body weight and usually contains about 10% of your blood. It’s located under the ribs, right below the diaphragm that inflates the lungs. It’s smooth and reddish brown when healthy (note: if you can see your liver’s color you are probably having a bad day). The liver can be divided into four parts called lobes and thousands of sub-parts called lobules. These are hexagonal columns of cells arranged so that blood can travel through carrying nutrients in and toxins and waste out.

Four types of cells make up the liver: hepatocytes, epithelial cells, Kupffer cells, and stellate cells. Most of the liver is composed of hepatocytes. These are the workhorses of the liver. Hepatocytes convert fats (called lipids), sugars (called carbohydrates), and proteins (called proteins) into usable forms. They detoxify dangerous things and excrete bile and cholesterol. The barrier epithelial cells line the walls (including blood vessel walls) inside the liver and do some filtering of small particles. It is thought that these may also do some clearance of viruses. Kupffer cells are the resident immune cells. These large cells eat bacteria and debris that enter lobules. They are always touching these dangerous particles and exhibit a constant, low-level inflammation. Disruption of these cells can result in widespread, damaging liver inflammation. Finally, stellate cells store vitamin A, a critical vitamin. They are critical for promoting the liver’s amazing ability to regenerate. They form temporary scars that allow for healing. When they are damaged, however, they lose vitamin A. Damaged stellate cells can “activate” and run amok, secreting a lot of collagen that causes fibrosis and permanent scarring called cirrhosis.

To understand the liver’s major functions, let’s first look at our body cells. Cells need to have a balance of chemicals to function properly. Normally cells control what goes in and out of them using special proteins. To keep unwanted things out, cells are separated from the environment around them. This separation is done by a membrane made of phospholipids. The –lipid at the end is another word for fat. Since the borders of our cells are made of fats, things that can pass through fats (called fat-soluble) can easily pass through the cell membranes. Cells can’t control this very well, so we use the liver instead.

Let’s run through the liver’s major functions of storage, conversion, and creation. Storage is fairly simple. The liver stores fat-soluble vitamins and converts some of them into usable forms. It stores a quick supply of energy in the form of glycogen. Blood is stored in large quantities in the liver. This makes sense, because the liver is filtering the blood. Usually it holds a little more than 10% of the body’s blood, but the liver can expand to hold much more if needed. It can also squeeze blood out if the body is bleeding profusely. This probably isn’t great for the liver, but then again neither is bleeding out and dying.

The liver converts a huge amount of material from one form into another. It acts as a gatekeeper for nearly all the blood in the body, including blood directly from the digestive tract. This includes tasty nutrients like fat and sugar, and dangerous toxins, like alcohol and methamphetamine. Blood is carried across the lobules and filtered through the hepatocytes and Kupffer cells. The liver doesn’t just remove dangerous particles, however, it metabolizes them! Metabolism is the conversion of chemicals from one form to another. One of the most important metabolic functions is detoxification. To make drugs and toxins less dangerous, the liver converts them from being fat-soluble (able to pass through cell membranes) to being water-soluble (able to be released through urine but much harder to enter cells). Carbohydrates are converted to glycogen for storage. The liver changes fats into energy for use. Proteins are broken into building blocks and waste products are removed. Remnants of dead blood cells called bilirubin are turned into bile and used for digestion.

The conversion of materials into component parts helps the liver’s third broad function, creation. The liver creates, or synthesizes, many molecules that are used all around the body. It creates important hormones like angiotensin and thyroxine. It makes chemicals for the blood like prothrombin, fibrinogen, and clotting factors. It also makes the aforementioned bile, which is critical for digesting fats.

The liver is the ultimate hero. Through all of these functions, the liver acts in the best interest of the body. It takes the hit from dangerous chemicals and sacrifices its own blood when we need it most. The liver is a team player of the highest degree. When it goes wrong we suffer throughout our whole body. Take care of that liver!

Staff Writer / Editor Benton Lowey-Ball, BS, BFA

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References:

Eng, F. J., & Friedman, S. L. (2000). Fibrogenesis I. New insights into hepatic stellate cell activation: the simple becomes complex. American Journal of Physiology-Gastrointestinal and Liver Physiology, 279(1), G7-G11. https://doi.org/10.1152/ajpgi.2000.279.1.G7

Geerts, A. (2001). History, heterogeneity, developmental biology, and functions of quiescent hepatic stellate cells. In Seminars in liver disease (Vol. 21, No. 03, pp. 311-336). https://doi.org/10.1055%2Fs-2001-17550

Kalra, A., Yetiskul, E., Wehrle, C. J., & Tuma, F. (2018). Physiology, liver. https://europepmc.org/article/nbk/nbk535438

Lautt, W. W. Hepatic Circulation: Physiology and Pathophysiology. San Rafael (CA): Morgan & Claypool Life Sciences; 2009. Chapter 2, Overview. https://www.ncbi.nlm.nih.gov/books/NBK53069/

Ozougwu, J. C. (2017). Physiology of the liver. International Journal of Research in Pharmacy and Biosciences, 4(8), 13-24.

Vaja, R., & Rana, M. (2020). Drugs and the liver. Anaesthesia & Intensive Care Medicine, 21(10), 517-523. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7508170/

Yin, C., Evason, K. J., Asahina, K., & Stainier, D. Y. (2013). Hepatic stellate cells in liver development, regeneration, and cancer. The Journal of clinical investigation, 123(5), 1902-1910. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3635734/

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ENCORE · Cirrhosis: When the Liver Fails, the Brain Suffers

The liver is critical to maintain body function. Unfortunately, millions of Americans suffer from liver disease. When the liver suffers prolonged damage, scarring can form. This scarring, called cirrhosis, is debilitating and reduces liver function. Cirrhosis is sometimes called end stage liver disease, and is irreversible. On its own, cirrhosis can be painful and cause suffering, but is frequently made worse through complications. One of these is encephalopathy.

Encephalopathy is a broad term used to describe several diseases and disorders. The unifying concept is that these diseases change the brain’s structure or function. When the cause of this change is through cirrhosis, the condition is called hepatic encephalopathy. This is the condition caused by cirrhosis of the liver, and can be horrible. It comes with a high mortality rate, over 25%, and affects over 30% of people with cirrhosis.

The full mechanism of how hepatic encephalopathy works isn’t fully known. The most likely candidate for hepatic encephalopathy is a buildup of ammonia in the bloodstream. Ammonia is a common waste product for many cells. A damaged liver has trouble filtering ammonia from the blood. The ammonia accumulates in the blood where it can travel to the brain and cause confusion and disorientation at first. Additionally, liver damage can result in reduced muscle mass and immunosuppression. Muscles can remove excess ammonia from the blood, but may become damaged without a functional liver and be unable to help. A reduced immune system can lead to a buildup of harmful bacteria that produce excess ammonia. These combine to create excess toxic levels of ammonia in the bloodstream that make their way to the brain.

The brain is normally protected from toxins in the blood through the blood brain barrier. Astrocytes are special cells in the brain that surround blood vessels and help filter the blood, letting only specific nutrients and particles through. Excess ammonia in the blood appears to damage astrocytes, with wide ranging effects on the brain. When the blood-brain barrier is reduced, toxins can enter the brain. This can lead to damage in neurotransmission, meaning the brain cannot function effectively. There is also an increased chance of infection in the brain and alterations to brain metabolism.

This is a devastating compilation which can drastically reduce quality of life. In the early stages of hepatic encephalopathy, people may experience a general slowing of the brain. This is noticeable in attention, some motor response, and other vague areas. As the encephalopathy progresses, people experience more severe symptoms. Changes in personality have been reported, such as irritability and impulsivity. They may angrily buy m&ms in the checkout line. It also slows the brain and reduces its ability to function. People may become disoriented, experience distortions of time and space, become excessively sleepy, and descend into a coma. Clearly this condition needs medical attention!

Luckily, hepatic encephalopathy can be reversible in many patients! The most important short-term treatment is to get rid of excess blood ammonia. The current standard of care is lactulose, a chemical that binds to ammonia and expels it rectally. This helps in the short term, and can also be recommended to help reduce recurrence. Though effective, lactulose is a laxative and can cause bloating, cramping, and other undesirable side effects. Because of this, many patients don’t like using this drug long term. Since the immune system is suppressed with cirrhosis, antibiotics may help as well. In fact, antibiotics may be helpful in preventing hepatic encephalopathy in the first place by eliminating harmful, ammonia producing bacteria before they can produce too much ammonia. Used with or without probiotics and drugs that help restore normal brain chemistry, we may be able to lower the burden of hepatic encephalopathy for those who suffer.

Written by Benton Lowey-Ball, BS Behavioral Neuroscience

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Sources:

Bustamante, J., Rimola, A., Ventura, P. J., Navasa, M., Cirera, I., Reggiardo, V., & Rodés, J. (1999). Prognostic significance of hepatic encephalopathy in patients with cirrhosis. Journal of hepatology, 30(5), 890-895. https://doi.org/10.1016/s0168-8278(99)80144-5

Ferenci, P. (2017). Hepatic encephalopathy. Gastroenterology report, 5(2), 138-147. https://doi.org/10.1093/gastro/gox013

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ENCORE · Why You Should Consider Getting A Fibroscan

Fatty liver disease is incredibly prevalent in the United States. Some estimates place the number of Americans with non-alcoholic fatty liver at over 30%, that’s around 100 million people in this country! Liver diseases are deadly serious; the liver is a critical organ and without it we cannot survive. The biggest problem with all liver diseases is that they frequently progress without symptoms. Because of this, the disease may progress to a dangerous or irreversible stage before it is even detected. Clearly, early, and routine testing for people at risk is critical.

We can’t see the liver from the outside, so the only way to learn about how it is doing is by looking at it. We can look through the skin using technology or under a microscope using a biopsy.

A biopsy – looking at a section of the liver under the microscope – is the “gold standard” of liver diagnostic techniques. This has drawbacks, however. Patients typically need to dedicate half a day to the procedure, and there can be rare complications. A biopsy is an invasive procedure requiring a piece of the liver be taken and examined. It is a critical piece of the liver diagnosis pie but is not a routine procedure to be done without cause.

Imagining techniques can be very effective in diagnosing a fatty liver. Some techniques, such as a CAT scan and ultrasound, can’t diagnose the amount of scarring on the liver but can give an indication that there is fat present. CAT scans use x-rays, but imaging is otherwise safe. An ultrasound is fast and non-invasive. It is an excellent first step that many doctors use when they suspect a fatty liver. Magnetic Resonance Imaging (MRI) is the next best diagnostic procedure to a liver biopsy. With an MRI, doctors can clearly see the state of the liver. They are expensive, however. This again means they are an excellent tool for those who are known to have fatty liver but may not be an option for all patients to use regularly.

Ultrasonic elastography is a different technique. It is commonly called Fibroscan, after the manufacturer of the diagnostic tool. Fibroscan uses sound waves to gently shake the liver and measure how it responds. The liver will stretch slightly. In a healthy liver, the tissue stretches more, but hard scar tissue is less elastic. The fibroscan can interpret the difference and determine how much fat and scar tissue is present. The test is very similar to an ultrasound; it is painless, fast, and safe. The fibroscan does not replace other imaging techniques but is cheap and effective at determining the stage of fatty liver present. Unlike other techniques, a Fibroscan can be done routinely for anyone who is at risk of having fatty liver.

Fibroscans are very popular around the world, including in Europe, Asia, South America, and Canada. It is a cheap procedure with little reimbursement for practitioners, which unfortunately prevents widespread use in the USA. Risk factors for non-alcoholic fatty liver include being overweight or obese, being prediabetic or having diabetes, and eating a high-fat diet. If you are concerned about fatty liver, talk to your primary care physician and/or contact ENCORE Research Group for a complimentary Fibroscan.

Written by Benton Lowey-Ball, BS Behavioral Neuroscience

Enrolling Studies

Afdhal, N. H. (2012). Fibroscan (transient elastography) for the measurement of liver fibrosis. Gastroenterology & hepatology, 8(9), 605.

Koren, M. (Host). (2022, July 20). Common fibroscan technology questions [Audio podcast episode]. In Medevidence! Truth behind the data. ENCORE Research Group. https://encoredocs.com/medevidence/

Koren, M. (Host). (2022, July 13). You cannot live without your liver [Audio podcast episode]. In Medevidence! Truth behind the data. ENCORE Research Group. https://encoredocs.com/medevidence

GRID VIEW

MASHing the Nash

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What Can You Do About NASH Today?

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The Liver: Our Unsung Hero and Guardian of Life

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Cirrhosis: When the Liver Fails, the Brain Suffers

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Why You Should Consider Getting a Fibroscan

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