The Liver: A ‘Blob’ That Runs the Body

https://www.nytimes.com/2017/06/12/health/liver-bodily-function.html

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To the Mesopotamians, the liver was the body’s premier organ, the seat of the human soul and emotions. The ancient Greeks linked the liver to pleasure: The words hepatic and hedonic are thought to share the same root.

The Elizabethans referred to their monarch not as the head of state but as its liver, and woe to any people saddled with a lily-livered leader, whose bloodless cowardice would surely prove their undoing.

Yet even the most ardent liverati of history may have underestimated the scope and complexity of the organ. Its powers are so profound that the old toss-away line, “What am I, chopped liver?” can be seen as a kind of humblebrag.

After all, a healthy liver is the one organ in the adult body that, if chopped down to a fraction of its initial size, will rapidly regenerate and perform as if brand-new. Which is a lucky thing, for the liver’s to-do list is second only to that of the brain and numbers well over 300 items, including systematically reworking the food we eat into usable building blocks for our cells; neutralizing the many potentially harmful substances that we incidentally or deliberately ingest; generating a vast pharmacopoeia of hormones, enzymes, clotting factors and immune molecules; controlling blood chemistry; and really, we’re just getting started.

“We have mechanical ventilators to breathe for you if your lungs fail, dialysis machines if your kidneys fail, and the heart is mostly just a pump, so we have an artificial heart,” said Dr. Anna Lok, president of the American Association for the Study of Liver Diseases and director of clinical hepatology at the University of Michigan.

“But if your liver fails, there’s no machine to replace all its different functions, and the best you can hope for is a transplant.”

And while scientists admit it hardly seems possible, the closer they look, the longer the liver’s inventory of talents and tasks becomes.

In one recent study, researchers were astonished to discover that the liver grows and shrinks by up to 40 percent every 24 hours, while the organs around it barely budge.

Others have found that signals from the liver may help dictate our dietary choices, particularly our cravings for sweets, like a ripe peach or a tall glass of Newman’s Own Virgin Limeade — which our local supermarket chain has, to our personal devastation, suddenly stopped selling, so please, liver, get a grip.

Scientists have also discovered that hepatocytes, the metabolically active cells that constitute 80 percent of the liver, possess traits not seen in any other normal cells of the body. For example, whereas most cells have two sets of chromosomes — two sets of genetic instructions on how a cell should behave — hepatocytes can enfold and deftly manipulate up to eight sets of chromosomes, and all without falling apart or turning cancerous.

That sort of composed chromosomal excess, said Dr. Markus Grompe, who studies the phenomenon at Oregon Health and Science University, is “superunique,” and most likely helps account for the liver’s regenerative prowess.

Scientists hope that the new insights into liver development and performance will yield novel therapies for the more than 100 disorders that afflict the organ, many of which are on the rise worldwide, in concert with soaring rates of obesity and diabetes.

“It’s a funny thing,” said Valerie Gouon-Evans, a liver specialist at the Mount Sinai School of Medicine. “The liver is not a very sexy organ. It doesn’t look important. It just looks like a big blob.

“But it is quietly vital, the control tower of the body,” and the hepatocytes that it is composed of “are astonishing.”

The liver is our largest internal organ, weighing three and a half-pounds and measuring six inches long. The reddish-brown mass of four unevenly sized lobes sprawls like a beached sea lion across the upper right side of the abdominal cavity, beneath the diaphragm and atop the stomach.

The organ is always flush with blood, holding about 13 percent of the body’s supply at any given time. Many of the liver’s unusual features are linked to its intimate association with blood.

During fetal development, blood cells are born in the liver, and though that task later migrates to the bone marrow, the liver never loses its taste for the bodywide biochemical gossip that only the circulatory system can bring.

Most organs have a single source of blood. The liver alone has two blood supplies, the hepatic artery conveying oxygen-rich blood from the heart, the hepatic portal vein dropping off blood drained from the intestines and spleen. That portal blood delivers semi-processed foodstuffs in need of hepatic massaging, conversion, detoxification, storage, secretion, elimination.

“Everything you put in your mouth must go through the liver before it does anything useful elsewhere in the body,” Dr. Lok said.

The liver likes its bloodlines leaky. In contrast to the well-sealed vessels that prevent direct contact between blood and most tissues of the body, the arteries and veins that snake through the liver are stippled with holes, which means they drizzle blood right onto the hepatocytes.

The liver cells in turn are covered with microvilli — fingerlike protrusions that “massively enlarge” the cell surface area in contact with blood, said Dr. Markus Heim, a liver researcher at the University of Basel.

“Hepatocytes are swimming in blood,” he said. “That’s what makes them so incredibly efficient at taking up substances from the blood.”

As the master sampler of circulating blood, the liver keeps track of the body’s moment-to-moment energy demands, releasing glucose as needed from its stash of stored glycogen, along with any vitamins, minerals, lipids, amino acids or other micronutrients that might be required.

New research suggests the liver may take a proactive, as well as a reactive, role in the control of appetite and food choice.

Humans are famously fond of sweets, for example, presumably a legacy of our fruit-eating primate ancestors. But to gorge on sugar-rich foods, even in the relatively healthy format of a bucketful of Rainier cherries, could mean neglecting other worthy menu items.

Reporting in the journal Cell Metabolism, Matthew Gillum of the University of Copenhagen and his colleagues showed that after exposure to a high-sugar drink, the liver seeks to dampen further sugar indulgence by releasing a signaling hormone called fibroblast growth factor 21, or FGF21.

The effort is not always successful. For reasons that remain unclear, the hormone comes in active and feeble varieties, and the researchers found that people with a mutant version of FGF21 confessed to a lifelong passion for sweets.

The scientists are searching for other liver-borne hormones that might influence the hunger for protein or fat.

“It makes sense that the liver could be a nexus of metabolic control,” Dr. Gillum said. “At some level it knows more than the brain does about energy availability, and whether you’re eating too many pears.”

The liver also keeps track of time. In a recent issue of the journal Cell, Ulrich Schibler of the University of Geneva and his colleagues described their studies of the oscillating liver, and how it swells and shrinks each day, depending on an animal’s normal circadian rhythms and feeding schedule.

The researchers found that in mice, which normally eat at night and sleep during the day, the size of the liver expands by nearly half after dark and then retrenches come daylight. The scientists also determined the cause of the changing dimensions.

“We wanted to know, is it just extra water or glycogen?” Dr. Schibler said. “Because that would be boring.”

It wasn’t boring. “The total gemish, the total soup of the liver turns out to be different,” he said. Protein production in mouse hepatocytes rises sharply at night, followed by equivalent protein destruction during the day.

Evidence suggests that a similar extravaganza of protein creation and destruction occurs in the human liver, too, but the timing is flipped to match our largely diurnal pattern.

The researchers do not yet know why the liver oscillates, but Dr. Schibler suggested it’s part of the organ’s fastidious maintenance program.

“The liver gets a lot of bad stuff coming through,” he said. “If you damage some of its components, you need to replace them.” By having a rhythm to that replacement, he said, “you keep the liver in a good state.”

Adding to the liver’s repair protocol, Dr. Grompe of Oregon Health and Science University said, is the extreme plasticity of hepatocytes.

He and others have shown that, through their extraordinary ability to handle multiple sets of chromosomes and still perform and divide normally, liver cells become almost like immune cells — genetically diverse enough to handle nearly any poison thrown at them.

“Our ancestors didn’t have healthy refrigerated food,” he said. “They ate a lot of crap, probably literally, and the liver in prehistoric times was continuously bombarded with toxins. You need every mechanism there is to adapt to that.”

The liver rose to the evolutionary challenge. So yes, I’m chopped liver — and proud.