Category Archives: Liver Disease

DiabetesDaily informed me of a new drug available for treatment of a liver disease that affects “up to 20% of people with diabetes. The disease is MASH: metabolic dysfunction-associated steatohepatitis, something else I’d never heard of. (Shouldn’t the acronym be MDASH?) The drug is resmetirom, sold in the U.S. as Rezdiffra. Click for the FDA announcement. MASH can lead to liver scarring (fibrosis), which then qualifies the patient for resmetirom. The DiabetesDaily article is well-written and includes alternatives to this new drug.

I’ve long been aware of NASH: non-alcoholic steatohepatitis). THIS is the liver disease target according to the FDA announcement, which states “Rezdiffra is a partial activator of a thyroid hormone receptor; activation of this receptor by Rezdiffra in the liver reduces liver fat accumulation.” Furthermore:

The most common side effects of Rezdiffra included diarrhea and nausea. Rezdiffra comes with certain warnings and precautions, such as drug-induced liver toxicity and gallbladder-related side effects. 

There may be potential significant interaction of this new drug with others, particularly statin cholesterol-lowering drugs.

Color me skeptical. If only because the drug was on the “accelerated approval pathway.” But I’ll keep an open mind.

I’m not sure, but it appears that candidates for the drug will need a liver biopsy showing fibrosis (scarring).

Steve Parker, M.D.

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…according to Iranian and Brazilian researchers who studied an Iranian population. The risk reduction was an impressive 50%.

Thanks to Frontiers In Nutrition for publishing the study for free.

A Clinics In Gastroenterology article in 2019 suggested a different diet for treatment of NAFLD (non-alcoholic fatty liver disease).

Steve Parker, M.D.

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Experts are predicting an epidemic of NASH: non-alcoholic steatohepatitis. In other words, fat build-up in the liver with associated inflammation and scarring (fibrosis). Which is related to it’s precursor, NAFLD: non-alcoholic fatty liver disease. These are significant issues particularly for folks with type 2 diabetes. From Diabetes Care:

“The clinical burden of both NAFLD overall and NASH specifically has increased steadily since the 1980s. NAFLD currently affects 25% of the global population and >60% of patients with T2D. Studies evaluating the prevalence of NASH suggest that it may involve an estimated 1.5%–6.5% of the general population and as many as 37% of people with T2D. Prevalence of NASH is expected to increase by 63% between 2015 and 2030. Although these numbers seem substantially lower than those for NAFLD overall, they still translate to 4.9 million to 21 million Americans and more than 100 million individuals worldwide. Modeling data estimate that the number of patients with NASH-related advanced fibrosis will likely double by 2030, resulting in 800,000 liver-related deaths.

NASH is already the number 1 indication for liver transplantation in women, patients older than 54 years, and Medicare recipients. Beyond the significant impairment of quality of life experienced by individuals with NASH and advanced fibrosis, Younossi et al. estimated in 2017 that the overall lifetime direct costs of NASH in the United States would be $222.6 billion, and approximately $95.4 billion over the next 2 decades, suggesting a substantial economic burden.”

Loss of excess weight is one way to combat or avoid non-alcoholic fatty liver disease.

Steve Parker, M.D.

PS: The Paleobetic Diet can help you lose excess weight and keep it off.

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There’s a silent epidemic in folks with type 2 diabetes: 50 to 70% have non-alcoholic fatty liver disease. Non-alcoholic fatty liver disease is an important contributor to cirrhosis, i.e., scarring in the liver that impairs liver function. In the study at hand, a ketogenic diet reduced liver fat by 31% over just six days. I don’t have many details of the diet used, but it reduced carbohydrates to 20 grams/day.

Significance

Ketogenic diet is an effective treatment for nonalcoholic fatty liver disease (NAFLD). Here, we present evidence that hepatic mitochondrial fluxes and redox state are markedly altered during ketogenic diet-induced reversal of NAFLD in humans. Ketogenic diet for 6 [days] markedly decreased liver fat content and hepatic insulin resistance. These changes were associated with increased net hydrolysis of liver triglycerides and decreased endogenous glucose production and serum insulin concentrations. Partitioning of fatty acids toward ketogenesis increased, which was associated with increased hepatic mitochondrial redox state and decreased hepatic citrate synthase flux. These data demonstrate heretofore undescribed adaptations underlying the reversal of NAFLD by ketogenic diet and highlight hepatic mitochondrial fluxes and redox state as potential treatment targets in NAFLD.

Abstract

Weight loss by ketogenic diet (KD) has gained popularity in management of nonalcoholic fatty liver disease (NAFLD). KD rapidly reverses NAFLD and insulin resistance despite increasing circulating nonesterified fatty acids (NEFA), the main substrate for synthesis of intrahepatic triglycerides (IHTG). To explore the underlying mechanism, we quantified hepatic mitochondrial fluxes and their regulators in humans by using positional isotopomer NMR tracer analysis. Ten overweight/obese subjects received stable isotope infusions of: [D7]glucose, [13C4]β-hydroxybutyrate and [3-13C]lactate before and after a 6-d KD. IHTG was determined by proton magnetic resonance spectroscopy (1H-MRS). The KD diet decreased IHTG by 31% in the face of a 3% decrease in body weight and decreased hepatic insulin resistance (−58%) despite an increase in NEFA concentrations (+35%). These changes were attributed to increased net hydrolysis of IHTG and partitioning of the resulting fatty acids toward ketogenesis (+232%) due to reductions in serum insulin concentrations (−53%) and hepatic citrate synthase flux (−38%), respectively. The former was attributed to decreased hepatic insulin resistance and the latter to increased hepatic mitochondrial redox state (+167%) and decreased plasma leptin (−45%) and triiodothyronine (−21%) concentrations. These data demonstrate heretofore undescribed adaptations underlying the reversal of NAFLD by KD: That is, markedly altered hepatic mitochondrial fluxes and redox state to promote ketogenesis rather than synthesis of IHTG.

Source: Effect of a ketogenic diet on hepatic steatosis and hepatic mitochondrial metabolism in nonalcoholic fatty liver disease | PNAS

Steve Parker, M.D.

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Stages of liver damage. Healthy, fatty, liver fibrosis, and finally cirrhosis

A recent article in Gastroenterology Clinics suggests this one:

•Prioritize intact starches such as brown rice, quinoa, and steel-cut oats, and limit or avoid refined starches such as white bread and white rice

•Replace some of the CHO [carbohydrate], especially refined CHO, in the diet with additional protein from a mixture of animal or vegetable sources, including chicken, fish, cheese, tofu, and pulses

•Include a variety of bioactive compounds in the diet by consuming fruits, vegetables, coffee, tea, nuts, seeds, and extra virgin olive oil

•Get most fat from unsaturated sources, such as olive oil (ideally extra virgin), rapeseed oil, sunflower oil, safflower oil, canola oil, or nuts and seeds

•Limit or avoid added sugars, whether sucrose, fructose, maltose, maltodextrin, or any syrups. If any of these words appear in the first 3–5 ingredients of any food item, it is best to avoid that item and choose a no-sugar version instead. Examples are yogurts and commercial cereals•In particular, avoid liquid sugar such as carbonated sugary drinks/sodas, lemonade, any juices, smoothies, and added sugar to tea and coffee

Source: Nutrition and Nonalcoholic Fatty Liver Disease – Gastroenterology Clinics

See the article for a typical daily menu. Looks like a Mediterranean diet to me. I’m not aware of the paleo diet being used to combat NAFLD.

Excessive fructose and saturated fatty acid consumption appear to be particularly harmful to the liver.

The authors also seem to endorse exercise: 150 t0 300 minutes per week of moderate- to vigorous intensity aerobics exercise, performed at least thrice weekly.

And all experts recommend loss of excess fat weight.

If you really want to get into the weeds, read about how fat deposits in liver and muscle lead to metabolic inflexibility, resulting in insulin resistance and mitochondrial dysfunction, which alters lipid metabolism, releasing free fatty acids (some of which are lipotoxic), leading to lipotoxic molecules (like ceramides), causing inflammation and fibrosis.

Steve Parker, M.D.

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Stages of liver damage. Healthy, fatty, liver fibrosis and cirrhosis. Vector illustration

I’ve written before about fatty liver here, here, and here, for example. Fatty liver by itself may not be very harmful but sometimes it progresses to liver inflammation called steatohepatitis. Which can lead to cirrhosis. Non-alcoholic fatty liver disease is the second leading cause for liver transplantation in the U.S., after viral hepatitis.

You only have one liver, so be nice to it.

How common is fatty liver in the U.S. among those with T2 diabetes? From Diabetes Care:

The overall prevalence of NAFLD [non-alcoholic fatty liver disease] was >70% (47% with NAFL [non-alcoholic fatty liver] plus 26% with NASH [non-alcoholic steatohepatitis], for a total of >18 million patients with T2D having NAFLD (not including patients in the U.S. with undiagnosed T2D).

Source: Time to Include Nonalcoholic Steatohepatitis in the Management of Patients With Type 2 Diabetes | Diabetes Care

Steve Parker, M.D.

PS: One way to get fat out of your liver is to lose excess fat body weight. Let me help you.

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Stages of liver damage: Healthy, fatty liver, fibrosis, and cirrhosis

From Dr Bret Scher at DietDoctor:

Fortunately, we have emerging evidence that low-carb and ketogenic diets improve fatty liver while also helping with glycemic control and weight loss, an impressive combination rarely seen with medications. As we reported earlier, studies have shown that carbohydrate restriction changes liver metabolism, stimulating the breakdown of liver fat. Another study mentioned in the same post showed that when children substitute complex forms of starch to replace sugar, they experience reduced amounts of liver fat.

Yet another impressive study found that despite equal weight loss, a low-carb Mediterranean diet was better than a low-fat diet for reversing liver fat and signs of NAFLD. And finally, Virta Health published a subset of its data showing that one year on a ketogenic diet improved non-invasive tests for NAFLD and liver scarring.

Source: Limiting Carbs Likely Better Than Drugs for Fatty Liver — Diet Doctor

Steve Parker, M.D.

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