 This is a talk on non-alcoholic fatty liver disease, also known as non-alcoholic steatohepatitis, which is quite a big deal, increasing in the world. In this talk, I have a number of concepts I'd like you to try to latch onto. We'll talk a bit about insulin and its antagonist glucagon, both are your hormones, and a big important concept, insulin resistance syndrome. And it's part of metabolic syndrome. These are very widespread and all are associated with non-alcoholic steatohepatitis, or non-alcoholic fatty liver disease, which I've heard Nuffin used for that acronym. I don't like the sound of that, though. This tends to progress through liver inflammation, fibrosis, cirrhosis, and even hepatic carcinoma, or liver carcinoma, liver cancer. I'm going to talk a little bit about metagenomics and about the gut liver axis and the importance of the GI microbiome and problems with intestinal barrier integrity that leads to fatty change in the liver. Now, I thought I'd begin with a case history. This is John. You may recognize him. We've all seen guys like this. He's a jolly, big guy, lives life to the fullest, living in the western world. Enjoying lots of these. He knows what to do with these. He unhinges his jaws. Let's put that away. He loves plenty of these, which are French fried potatoes, deep fried. He eats lots of these, finishes any he finds left over from other people's boxes, even for breakfast. And he knows what to do with these. Oh, he has a fun approach to food, it may seem. And he's got huge appetites. But after a point, he starts to just not feel quite right. He has a meal feels discomfort in his belly, the abdomen in the right upper quarter or quite right upper quadrant of his abdomen and feels sometimes malaise and fatigue and just doesn't feel as alive as he is used to or accustomed to. So he comes in for a workup. Now, one of the simple things, simply measure the waist circumference. And that's a significant in the discussion we're going to have. His abdominal girth or waist is 102 centimeters or a 40 inch waist. I point out here that that is the lower level of at which 102 or above is the point at which one raises suspicion for patients at risk for non-alcoholic fatty liver disease. And women with a waist measurement of 88 centimeters or 34.6 inches or greater, they're at risk. I'm sorry to tell you that. It doesn't seem like much. Also, body mass index is an important number like hypertension or like blood pressure. Everybody should know their blood pressure numbers. If you keep your blood pressure numbers good, you will not suffer. If they're high, get them get them right medically or by exercise and cut out salt and diet, whatever it takes to get the numbers good. Don't worry about what caused it and you'll you will live without strokes and heart attacks is readily that body mass index is developed by dividing body mass by the total surface area. Of course, you can do their tables and body mass index calculators. You can see where you stand with it. If you're over 25, that's overweight. If you're over 30, that's obese. If you're over 35, that's morbidly obese. I worked in an underserved area here and the percentage of patients that were over 35 was incredible. It's an area with higher poverty and poor education in terms of personal health. In this case, John has a body mass index of 35 and I choose that number just to emphasize that 35 is the cutoff 35 and above is morbidly obese. It does a number of things. It takes a toll on one's skeletal system, on their metabolism and also you are just not structured to accommodate that much extra weight. Patients with that kind of body mass index are at high risk for obstructive sleep apnea because all the tissues thicken. When your throat relaxes, especially if you sleep on your back and your tongue relaxes, this genioglossus muscle that is in the base of the tongue that curves forward to the genu or bend of the jaw holds your tongue forward and allows you to push your tongue out to stick your tongue out at someone. Anyway, if that relaxes too much, your eye on your back, your tongue falls back and corks you like a bottle and you'll have snoring and if you start to have sufficient incidents of episodes of 10 seconds or longer without getting a breath in, that's apnea. More than five of those per hour, I guess, is obstructive sleep apnea. So at any rate, blood pressure, I gave the normal numbers there. That's the same for men or women and it's more stringent than it used to be. And we'll just say that John's blood pressure is pushing a bit over the limits of normal, not severe. Again, in the area where I've worked here, I've had patients that dealt with who were in their 20s with total renal failure because of uncontrolled hypertension. They were on dialysis in their early 20s all because of blood pressure. So this is a serious kind of number. I want to make one more point on this slide before I leave it. Bructose is a key catalyst in the development of non-alcoholic fatty liver disease that's supported in literature and generally ultra-processed food, which John seems to like a lot, high fat, high carbohydrate, fast food, milkshakes, and whatever that sugary sodas seem to be a big part of this diet. For some reason, I went back, sorry about that. So let's look at this food because you're not going to eat it anymore, right? Because you'll end up looking like that. Okay, that's what I wanted to show you. We did some blood tests. Fasting blood sugar was up a little bit. I try to get normal sundies. There's a way to see if someone's had extended, over months, levels of elevated glucose. Glucose tends to glycate or bind to proteins or glycoproteins or complex proteins in the blood if it can. Glycerol doesn't do that, but glucose does. And so you can look at glycated hemoglobin, which is from the blood, 1ac. And someone wrote HbA1c, and I think that's reasonable designation. That's quite a useful assay. Trichlycerides being elevated is important. I give the normals for that, and we'll say that John had elevation of those, and that can be very often diet related. And you have in lipid assays or lipid profiles, high density and low density lipoproteins, along with total cholesterol. These lipoproteins are blood proteins that transport cholesterol. You also have very low density lipoproteins, which are, if those are elevated, those are even more dangerous because there's sort of small particles that felt to be able to release cholesterol into the walls of the vessels for development of arteriosclerosis. One thing I'll point out here, and people that have non-alcoholic fatty liver disease and accelerated development of coronary artery disease and vascular disease, strokes and heart attacks is quite marked, and it's often what kills them. So anyway, in any case, John needs to change what he's doing. This takes a lot of work under part of people that can give him guidance. So he needs to stop eating starchy foods that, you know, if you ever take a slice of potato and try to just stir fry it, it'll burn readily onto the pan unless you have better Teflon than I can find. The reason being that the starchy food like that just is a sponge for bats soaks them up to really cook that you have to deep fry it. So you have starchy potato, which has vitamin C in it, and the peeling, which is generally not noticeable in french fries, that has minerals, and it's not too bad to eat a potato now and then, but you want to be careful about eating too much in the way of starchy vegetables like potatoes and corn, but moderation is okay. But if you fry it, it's loaded with fat, it jacks up the calorie content. And if you have something like meat or schnitzel, you put egg on it and flour, and I guess flour on the schnitzel, and then you dip it in egg batter and then bread it and fry it. It's all that coating is loaded with fat, even if you have a lean piece of meat. I don't actually eat meat. I apologize for the phone. I stuck the phone into a drawer, but the base of it seems to still ring. Anyway, let's talk just to review what this condition is. Steatosis, I guess is a better pronunciation, or fatty change of the liver, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis. These are all pretty much the same thing, although you can have a spectrum that develops. The diagnosis of this, you have to start with some suspicion. You get vague symptoms. You don't get any point tenderness usually. The tenderness or discomfort is there. It's usually intermittent. It makes you think of some presentations of gallbladder disease. I think it's really important that history and physical examination is done well, but it can leave you with just a sense of direction on this without anything definitive. I want to mention that there are liver enzymes. I didn't talk about John's liver enzymes, but there are a number of blood tests for the liver. The one that is most often seen is alkaline phosphatase. That could be from bone or liver. If the liver cells get damaged, they start to leak. You'll have increased levels of these enzymes or proteins from the liver and the blood. If you combine GGT, which is gamma glutamyl transphase, that's another GGT, is the term everyone would use for it. That would help to differentiate from some lesion of the bone, which was causing leakage of alkaline phosphatase from those cells to narrow it down to the liver disease or to some sort of biliary disease. The bile ducts come off the liver cells. We're going to talk a little bit about the anatomy in a bit. Any rate, it's kind of a tough thing to diagnose without getting pushy or invasive. The gold standard is a needle biopsy. That is not too bad, but it hurts. It has some patient discomfort and time down for a day or so, and it can have bleeding, which if you hit a real vessel, that could be nasty. At any rate, there's some other things that are done. One is fatty liver index. I don't know of anyone using it, but it's in the literature. It's an algorithm to develop numbers to determine who's at risk. The algorithm is based on body mass index, waist, girth, triglyceride level, and GGT, the liver enzyme I mentioned. Easier than that is ultrasound. They just put a probe on your side and look at echoes in the liver and try to see if there's fatty change. If there is enough, they might be able to see something. A really brilliant thing that was developed in France around 2002 is the fiber scan, which I described here some. Basically, you put an ultrasound transducer up in the inner space between ribs, and it measures a velocity of a 50 megahertz wave. If there's fibrosis of the liver or change in the consistency of the liver, you'll get some measurements of it in terms of stiffness. If there's inflammation of the liver, it's always going to be stiffer. If there is biliary obstruction, so the bile can't drain from the liver to the GI tract, it will back up and the liver will be stiffer. If there's congestive heart failure or venous congestion from portal hypertension, I'm going to talk about these in a minute, then the liver will be too stiff. And if you have really serious liver disease and it's really scarred up, it seeps. And all the structures that are on the portal circulation seep serum, and your belly will fill with serum, and it's called ascites. And so fibro scan doesn't work so well with obesity or these other conditions, but you can actually combine it in a tertiary center like University of Michigan, and they can do fibro scan MRI. So I think you'll see that sort of thing, non-invasive assessment becoming more and more available, which I think is fantastic that everybody complains about the cost of medicine. This is one of the reasons that you'd rather have a needle. I mean, really, medicine is a growth industry. I don't know why people don't understand that. Not just growth in terms of knowledge, but growth in terms of the range of services and things that can be done for you. Just to step back a second, and it was 1916 in the United States. It was considered Flexner. I think his name was, had gone to Germany and came back, and Americans were training doctors on an apprentice. Pattern or system, and Germany had recognizably modern educational approaches to medical education. So at any rate, that was the point which, as education for physicians in America changed, the average patient after 1916 had a better than 50-50 chance of going in to see a doctor and coming out better than they had been when they entered the door. So things have come a long way, and no one works for free, but I don't think they should work for a rich as either. I think it should be reasonable, but anyway, I wanted to make a point about that. So here's John. We got his attention. He's ready to be told what's going on. And he's telling me he has two problems. One's the better insulin. I have to educate him a little bit about insulin. It's a hormone. It regulates glucose in the blood. Produced by the alpha, actually, I wrote that wrong, the beta cells. That's an error on the slide. It is produced by the beta cells of the islets of Langerhans in the pancreas. There are alpha, beta and delta cells, and the alpha cells produce an antagonistic hormone or a hormone that does sort of the opposite of insulin called glucagon. And his other problem, aside from insulin, he's developing what we call insulin resistance and his liver, this large organ and his right upper quadrant tucked under the rib cage is dysfunctional. And I'll just tell you to do this carefully. You can assess your own liver and if you're lean, it's easier. I can palpate my own liver pretty easily. I have to reach up underneath my rib cage. If I lie in bed or on a flat surface and let my belly relax, I can palpate my abdomen and put my fingers up under my rib cage. If this were a high speed and then you pulled away, it would be a kung fu move. It sounds pretty horrific. But you can assess if you're liver. If you feel the liver edge way up under there, that's okay. If you feel your liver edge at the level of the lower rib cage or beyond it, it might be enlarged. You might be able to feel masses if there were any. I'm not recommending everybody do regular abdominal palpation like breast exams are done by patients on themselves. But I'm just telling you, just saying. So definition, insulin resistance. Just the insulin same amount. It's like being able to say the whiskey ain't working no more. The insulin starts to have less effect and you build up levels of blood sugar. The reason being that the fat cells in the liver are not cooperating. Here's a little diagram. I put this Ying and Yang picture up for parallel principles. You have with increased glucose, glucose is stimulated directly in the beta cells of the islets of Langerhans to release insulin. It acts on the liver and the liver takes up glucose and stores glycogen. It turns the glucose into a polymer for quick energy when it needs it. About 5% of the liver mass in normal livers in someone who's well nourished is glycogen. If you look at the liver histologically under microscope, you'll see a lot of granular quality to it at high power. Then glycogen being stored along with rhizomes, because it has a lot of protein synthesis that goes on the liver. If you understood everything there is to know about the liver's biochemistry and its molecular biology and its physiology, you would be quite a master. It's an extraordinary organ. At a certain rate, it gets the fat cells to take up glucose and fatty acids, and it gets muscle to take up glucose, and the storage of energy is promoted. If you have decreased glucose, the glucagon, on the other hand, in the bottom of the slide, causes the liver to break down its glycogen and release glucose if needed. It's all about keeping the glucose levels in balance. This is an idea I thought that was worth mentioning. Adipose tissues come to be regarded by many in the literature as an intocrine organ, an organ that secretes hormones and it, years ago it used to be just thought of as a warehouse for extra calories. It's the largest intocrine organ. I might get to kind of remember that. There's over 100 factors that it's involved in that mediate or control metabolism. An intocrine function can be autocrine, meaning cells secrete something that acts on itself, or paracrine, where cells secrete mediators, biochemical mediators that act on regional or local cells, or an intocrine proper, which means that the molecules elaborated act systemically. It can be released from your gut and act on your brain, for instance. Okay. And I won't read the slide. I assume you're reading them, but it has a lot of effects on how you feel and how you're functioning. This is just, I thought it was a great slide, and as I borrowed it, when I have information I took from a specific place to get credit, but also to give away for everyone to be able to find more information. I give the source. I thought this diagram just was a beautiful little simplified statement of the complexity of the adipose tissue as an intocrine structure. Leptins are one of those hormones that are produced by the adipose tissue that tell you you're hungry, and leptin resistance, like insulin resistance, you can have resistance, all kinds of signals, in this case leptin resistance, is associated with obesity increasingly. There's rolls of the adipose tissue in the immune system, interacts with the liver and muscle, so we should keep going. All right, so that's insulin resistance. It's quite a big deal, and it's quite widespread, and it's part of a bigger condition called metabolic syndrome, which, seeing a patient like John, one should suspect outright. Insulin resistance is the deadly quartet, the secret killer, and that's pretty well-described because this stuff kills you. Insulin resistance, hypertension, insulin resistance in and of itself tends to promote weight gain and worsening insulin resistance. It's quicksand, high triglyceride levels, and reduced high-density lipoprotein cholesterol. Imagine like an open pickup truck that comes around to pick up the garbage cans, and it just dumps them in the back and drives down the street, and half of it falls on the street. So you have to go out and clean up that garbage, or else you'll be driving through it. That's sort of the way low-density lipoproteins work. They're not very efficient compared in bonding cholesterol and taking it securely to its destination as our high-density lipoprotein carriers or transports. So I just wanted to mention, there's a lot of stuff that goes on, including vascular disease that reflects inflammation. It can be diffuse or systemic, but C-reactive protein is a marker for inflammation that's often looked at. And I wanted to mention it because it's often bound to be elevated in metabolic syndrome, but you may hear of it otherwise as well. C-reactive protein. Okay, so this is a reduced slide just to get us back to our thoughts on it. Non-alcoholic fatty liver disease. It's a spectrum, clinical and histopathological changes that can go from simple fatty change steatosis to steatosis with inflammation to cirrhosis, where you start to get scarring. And cirrhosis is, from whatever cause, it used to be clearly most common from alcoholism and hepatitis, particularly hepatitis C, a viral hepatitis C. You can treat that now. It's quite expensive, but it's less expensive than having people die young and not being productive and able to lead their lives. And it's curable with medications, really. But at any rate, if you get scarring and cirrhosis, you are at greater risk for hepatocellular carcinoma. I'm going to show you what that looks like in a bit. Because these risk factors overweight to obesity, type 2 diabetes, meaning type 1 diabetes is where there's just not enough insulin. It's often basically an autoimmune thing knocks off your insulin producing cells in pancreas, and it occurs in very frequently in teenagers, children. And they become insulin dependent the rest of their lives unless they get a islet cell transplant. And I knew of a person who had struggled with type 1 diabetes all their lives, all their life, and had an islet cell transplant and suddenly did not need insulin anymore. You have worries about rejection of transplanted tissue. It's not from your own. There are distinguishing antigens on the cell surface if it's from another person. So your immune system can kill it, but you still have to take some medicine, but you don't have to be taking insulin all the time. And that individual was depressed by the whole situation, believe it or not, but it's actually quite understandable. So much of their energy and concern the whole life had been staying alive. They may have had a couple of episodes of becoming comatose with excessive insulin or missing doses when they were non-compliant, when they were younger, that sort of thing, but their whole life had been wrapped around that. So type 2 diabetes is where you just start to outstrip the ability of the pancreas to keep up with your needs and your tissues don't respond to the insulin. So you have plenty of insulin that's being produced more than one would think is needed, but it's not working. Like I say, the whiskey ain't working no more. It's like that song. And finally, dyslipidemia or hyperlipidemia, high triclyceride amine, all these are worldwide in distribution. This condition has a prevalence worldwide of about 20%. One in five human beings have non-alcoholic fatty liver disease. So like I say, it's a big deal. So this is just an image of what the liver looks like when it starts to get fatty change. It can get enlarged and its color changes a bit. This is a gross macro-image, not microscopic, but it also has a cut edge there. We can see basically vessels, probably venous vessels as holes. But this is even more so, yellowish looking. So we tell John the diagnosis. He's not too happy. This is difficult for someone who's lived large and suddenly has to learn that they're going to have to change their ways or not going to make it. He goes through five stages of grief, which I throw in here just to share it. It starts with denial. Yeah, he has a beer bottle in his hand. You never believe anyone when they say they don't drink at all. You can always check alcohol level. But I don't want to be like the house, the new Laurie character and say that people always lie, but they always tell you what they want to tell you because they always want to present themselves in the best way. And I had a patient once who told me detail about his alcohol use and I documented it in the notes. And he came in and wanted me to rewrite it and eliminate that from the notes because he had been denied insurance. His insurance company dropped him because they got a hold of those notes and thought he was a risk for alcoholism. And I told him I couldn't change the notes but I could add a statement and I basically added that I had further discussion with him and he had indicated that there was misunderstanding and that his level of alcohol use was moderate, which is what he was insisting and that I had no real reason to doubt his veracity or truthfulness on that. That's the best I could do. We can't change what's documented. We can't go back and erase an injury. So then he got angry. Then he got into a bargaining stage like let's make a deal. He bargained with the great mystery, whatever that is for the individual, and finally sadness and then acceptance. And I liked this guy and I felt like he wouldn't mind being remembered in this lecture. And he wasn't that big. He was kind of a robust fellow, but I don't know that he was morbidly obese, but I just used that for heuristic purposes. So he was not my patient, by the way. He was just somebody I liked. The liver, right up her quadrant, it's got these lobes. It's got a falciform ligament in between these two major lobes and there are a couple of small minor lobes that are sort of historic. Well, I don't know that he had any... He probably had fatty liver when he died, he died of an O.T. And he would have lived many years, might have died of a heart attack or stroke from vascular disease, especially using potent dangerous substances like cocaine. But it was quite sad. Yeah, this is by Netter. He was born I think in 1903 and died in 1992, I believe. He went to medical school, he was an artist, and went to medical school at NYU, New York University. And then he just in 1930, I guess 1933 to 1993, he was active and spent about 60 years doing art, medical art. And there were just fabulous pictures because he had such a good understanding of the anatomy from having studied medicine. And also understanding of what's important to be able to deal with pathology and disease and understand what's normal. I just point out here, on the top view, there's this little string hanging down. It's called the ligament and teres. That runs to your belly button. That is a remnant of an umbilical vein that turns into a fibrous cord. So everything's connected. One of the things that happens if you get real hardened cirrhotic liver is that the blood flow through the liver, what's called the portal circulation in a couple of minutes, the blood flow through the liver is impeded because the liver becomes a high resistance element. The blood from the gut is supposed to flow through the liver and be processed and then drain to the cable system, like the superior and inferior vena cava, actually inferior vena cava, which is the same way blood from your hand drains to the heart. Well, blood from your feet. Blood from your hand would go to the superior vena cava. At any rate, if you get cirrhosis real severely, one of the things you can have is these veins that run along the ligament and teres to the umbilicus become dilated. I'm going to tell you more about that in a minute. But here's some... Oh, let's see. I changed my view here. Hold on one second. I hit my forward key on my computer keyboard rather than on the slide projector here. This is the backside of the liver reflected upwards. This green is the gallbladder. One of the functions of the liver is to produce bile. You have the hepatic cells, the hepatocytes are... Yes, I'm going to point out Kaput Medusa in a minute. You have choline and dino deoxy choline, I think it is, but the main bile salts and mixed with bilirubin that get concentrated in the gallbladder and when the acidic material, like confetti acids or amino acids get to the first section of the duodenum, which is connected to the stomach, you have cholecystokinin released and you get actual contraction of the bile that's stored in the gallbladder and it's excreted into the duodenum, the second portion of the duodenum. Above that place is everything is from the foregut, basically above where the fetus has an umbilicus and everything passed the place where the duodenum's bile and the common duct empties and pancreatic enzymes is from the hindgut. So it's an anatomically important point. It's also marked by the ligament of trides, but just anatomical features. There's also this adipose tissue here, I've touched since the screen, adipose tissue here, a lesser momentum between the underside of the liver and the lesser curvature of the stomach and then this apron greater momentum that hangs off the greater curvature of the stomach and that's belly fat, a lot of the belly fat that people talk about, that's what they're talking about there and that's part of this adipose endocrine tissue. One last point before I go on is this, this liver is sort of suspended from the diaphragm. The diaphragm is like a dome, imagine walking into a dome and looking up, you know, like in Renaissance architecture. The diaphragm is like that and around the periphery of it are muscles that contract to pull the diaphragm down, to expand the lungs and the liver is kind of tucked up in that concavity. So okay, this is an important slide. Portal system, you have mesenteric artery increases blood flow to the gut when you have food being processed and the gut meaning the intestines and so you get absorption and it drains into this portal vein which then percolates through the liver. So the liver actually has this superhighway connection with the intestines. That's what we would call the gut nerve axis and if for some reason you had something affect the GI tract especially the large colon, the large bowel, like dysbiosis, abnormal bacteria and you can have unfavorable biomolecules, lipopolysaccharides, endotoxins, things like that that manage to get into the portal circulation and that's apparently quite related to diet and fructose is a big stimulant like I mentioned. So when you look at all these ultra-processed foods that have high fructose, corn syrup, don't buy it. I won't buy any of that stuff. Every time I see a treat I think, oh, I'll buy this. I start to look at the ingredients and then I never buy it and I know Debbie Downer. So let's see. So remember the portal circulation. The other thing is you see this is a, it's only about a five millimeter on based mercury, millimeters of mercury pressure system. It's a low pressure system and if it encounters this river as a high resistance situation, then there are a couple of places where the portal system can develop better communication with the cable system. One is at the bottom of the esophagus and upper stomach, especially esophageal veins. They'll become dilated, varicose, varicosities, varicose esophageal veins. Also you can get varicosities in the rectum to get blood from that's trapped in the portal system and where you have portal hypertension to get excessive blood pressure in the portal system and so you get hemorrhoids. And the other is you can have this excessive blood develop varicosities along this pathway parallel to the ligament and teres to the umbilical area or umbilicus and you can get distention of veins in the belly wall that you can see that look like hair or snakes of Medusa. That's the kaput Medusa. That's a horrific thing. That's generally in someone with terrible asides where they mostly have muscle wasting and they have a belly that looks like it's been blown up. Unfortunately, Ludwig von Beethoven had this and he had his asides drained a number of times and one of the important functions that delivers is also to detoxify alcohol. Alcohol dehydrogenates. The first step is to make aldehyde which is toxic even more than alcohol is and it's a carcinogen as well which is one reason why in people that drink, whether without smoking they have increased risk of olfaryngeal, esophageal cancers because of the effects of alcohol on those tissues. You get a little bit of end in the stomach as well. So with the esophageal varices I had one patient that I never will forget that I was part of the team taking care of her in training. She was, I'll just say mid-twenties and she appeared to have her entire problem from alcohol abuse and she was a nice person but she was somewhat defiant about quitting alcohol. She's maybe bent on self-destruction or whatever. There were things going on that were beyond what anybody knew how to manage. I'm talking about psychiatric aspects but she developed an esophageal bleed. The esophageal varices are exposed to acid and it's a harsh environment there at the top of the esophagus especially if someone has reflux of acidic material and fear enzymes from the stomach and the surface of these mild-dilated veins can get broken down and start to bleed. People with this terrible liver disease often have, well generally they will always bleed more. They have coagulopathy. You can assess that by doing pro-thrombin type measurement. She wouldn't clot. She wouldn't stop bleeding. She gave nearly a hundred units of packed red blood cells, fresh frozen plasma and platelet transfusions and finally the team, I was not, I was a subordinate. I was very disturbed by this but they gave it up. She wouldn't say she would stop drinking so they basically let her go and she died. There are a lot of cases like that that you experience in this kind of career that you just can't forget. Okay, hope I don't run over too much here and I got a couple more points to make. This is really important. This is a netter picture also, Frank Netter. Those are a bit dated but they are so beautifully informative. Liver lobules are, that's really the functional unit in the liver. You have central veins that's marked by a C here and then you have a portal triad which has a biliary drainage from the side of the liver cells that are producing bile and that drains separately and then you've got a portal vein and hepatic artery and I keep hitting my keyboard here, I'm sorry. So let's present a dysfunction. Here's a couple of pictures I'll just share quickly. It's really elaborate. The down lower left here is the portal triad and here dropping down, this almost looks like a plumbing outlet is the central vein and it has radiating sinusoids that run from the portal triad to the central vein which is in the center of the lobule. So this is a lobule cut sort of from the center so you see the very center of it in the right there. And they used to talk about these in terms of cords and some of the pictures I'm going to show you will show looks like cords of hepatocytes but actually they're plates. The better description of it is plates and this is also from Netter, again this is just so instructive, shows what the hepatic cells look like without all the vascular and ductal structures. By the way, the liver also has an innervation which is synthetic and parasympathetic and has an emphatic drainage, drains to regional mesenteric lymph nodes and such. So if you get a liver cancer, you may get it spreading to adjacent nodes through lymphatic drainage. Now I want you to imagine for a second that you plant three different plants in one pot. In this case, you would have all these root systems that seem to get just intertwined and root bound together. That's sort of what the liver is. If it gets messed up, it's hard to fix. But it's like you've got the portal vein tree and you have the biliary tree. Now the biliary tree represents drainage from the liver to the GI tract. The portal vein is blood going from the GI tract into the liver and the hepatic artery which is from the aorta via the celiac trunk. I won't get into that too much, but about 25% of the blood supply to the liver cells comes in through the hepatic artery. 75% of the blood supply to the liver is through the portal vein. The whole thing drains out through a hepatic vein which goes, you see it coming out at the top there, which goes to the cable system. And this is I actually got from Wikipedia which I usually don't take stuff from, and I get the credit for it, but it's just such a nice explanation of some of the cell types that you have in the liver. It shows these cuboidal cells and on the top there where you have the yellow that's the aspect of the cuboidal cells where they secrete, produce bile and secrete it probably by extravasation of vesicles. On the sinusoid, the lower part is the sinusoid going from, on the left they show this, the portal triad area with the mesentery blood flowing in that's bluish and then hepatic arteriole. And as it hits the liver, the hepatic artery is from the aorta and left heart. That's high pressure, but it loses its mojo as it goes through various levels of resistance and so it actually mixes with the sinusoidal blood that's from the portal vein. So you get richer oxygenation once you get the hepatic arteriole in there. And they drain to the central vein which eventually drains out the hepatic vein. There's a couple cells here. You look at this octopus looking cell that's on the roof of that sinusoid called a coop for cell. That's a macrophage and it's got a lot of surface area and it's sampling for pathogens and damaged red blood cells and it absorbs toxins as well. And you have stellate cells which I think there's a thing called the space of DC which is between these line of hepatocytes pointed out and there's what are called stellate cells. I don't know that they're... Oh, on the lower right there is a stellate cell pointed out. Those are really important. The coop for cells and some T cells including natural killer cells. They're not in high population normally but they reside and the number of natural killer cells delivers pretty well controlled but you got potential for a lot of information and the liver is actually pretty tolerant. It puts up with a lot of insult before it gets angry. But you don't want to abuse it because once it turns on you and you start to get inflammation and you kick up the stellate cells, the stellate cells will lay down fibrosis. They'll lay down scar. You start to get scar in your liver. You get irreversible change. So here's normal human liver. You can see how there seems to be cords and it shows the portal triad lower left and the central vein on the right. They just point about three zones. One point about it, the zone three. I think it's on the next slide. Zone three is the better oxygenated... I'm saying that wrong. I guess zone one is where you get more oxygenated blood and the poorest oxygenation is right before it drains out which makes sense. We're saying it backwards. Zone two is in between. So this area one is where you start to get blood supply from the hepatic artery but still that's only 25% of the blood supply of the liver. And once again, I want to make sure we remember what we're talking about. Non-alcoholic fatty liver disease. It's a spectrum where you get fatty liver and not from alcohol or viral hepatitis and it can go bad on you, become fibrotic, inflamed, fibrotic and cirrhosis and end-stage liver disease. It's soon expected to be maybe by 2020 to be the number one cause to need a liver transplant in the United States. And worldwide it's got a parallel increase in incidence. And liver cancer is also a definite risk as with any cirrhosis and yeah, they've had children two years old that have fatty liver disease. It doesn't spare children. Excuse me. Okay, I want to show some slides quickly. I've run over a bit. If you can give me a couple of minutes, this will be reasonably quick, I think. Stiatatosis in non-alcoholic fatty liver disease. You see all these little clear vesicles. Those are fat collections. Those are basically fat collected in hepatocytes. And I have the source here for that particular slide. That's what it looks like grossly. We saw that a little earlier. And in this one, you see these bluish areas. This is an H and E. Hematoxilin, eosinithin. Hematoxilin is basic. And eosin is somewhat acidic. And it dates back to mid-19th century and particularly in Germany when organic dyes were invented by chemists and they were applied to stain not just textiles but tissues. And it made it possible for a Koch to become the godfather of pathology. At any rate, the smaller bluish gatherings of cells are inflammatory infiltrates. These little blue dots you see generally are nuclei. Hematoxilin being basic tends to bind to nucleic acids. The eosinophiltins, out of the eosin being acidic can show areas where protein is more dominant. So you get a pinkish background. They stain with one rinse and stain with the other one and rinse and let it dry. These are very slim slides created on microtone. There's another with H and E. I guess hepatocellular injury and you get ballooning, which means imminent cell death. And Mallory Dink bodies inside the cell, you have this really fine architecture of prognosis filaments that are submicroscopic. But when you get damage, intercellular damage, you start to get hyaluronization. Hyaluron is kind of a nice term in a way. A lot of things have a hyaluron look, but basically a smear of protein. And these pinkish areas that I guess they're marked out here with the white area. Can you see a white arrow there? Yeah, down here at about five o'clock is a white arrow indicating a Mallory Dink body which shows significant hepatic injury. And if you do a reticular stain, that's an amniated silver stain, which is picked up particularly by Collagen 3. So this is to look for fibers produced by fibrous sites or collagen-forming cells, like those stellate cells in the liver and you get chicken wire patterns with scarring. That's the beginning of real problems. Here you have pretty severe cirrhosis and you have these clumps, these islands and regenerative cells. And a lot of fibrosis around them. The liver will try to heal itself. It does have the potential to regenerate and it'll last you a lifetime if you're careful with it. Here's what the liver grossly looks like and this is pretty severe. Like they say, macronodular cirrhosis because you see clumpiness. And here's a picture with carcinoma and I don't know if you can tell there's fatty change and there's inflammatory change, but also there's total loss of architecture and the cell morphology is varied and I have a close-up of it. And if you look here, just left of center, for instance, that's a nice clump with, you know, the nucleolus is area of RNA production, ribosome production in the nucleus and liver cells tend to have that. But these liver cells, none of them is sort of like listening to Hilberry play a bluegrass tune and never play it the same way twice. And these cells all look different. They have slight distinctions and so you have varied morphology. You don't have uniform structure to the cells and the organization of the tissue has been lost. So here's another one. This actually shows some normal hepatocytes on the left and this is infiltrating carcinoma on the right. At one time I did a long rotation as a medical student at the Mayo Clinic in Rochester, Minnesota in pathology. This is one of the most wonderful places to do pathology. I actually love this kind of stuff, but I'm not a pathologist. This is a hepatocellular carcinoma. It's a big one up right there in the center. And that's, it's sort of greenish because of his bile. These things happen and biliary function gets disrupted and bile tends to build up. So fast food, forget about it. No more of this stuff. Take one last good look. Say bye-bye. Buh-buh. This may be a couple of times a year. I mean, we're only human. So metagenomics was one point I wanted to make when you look at, because I have one last quick, I think it would be quick thing to bring up. You look at the microbiome of the GI tract. It's easier to determine what's there than it is to determine how much. To determine how much, the traditional ways was to take smears and on cultures, street cultures and see what cells grew out and what quantity. Or to look at smears and if you could count the times of specific cells by staining. But in this, you take a whole, a sample of all the life structures in a specific sample or from a particular environment and you look at some marker. And this is, I just wanted to mention, 16S ribosomal RNA gene sequencing is a nice way to do this. And they can tell a lot about what bacteria are present in the gut. So the gut has actually in the more recent literature about the equal number of, we have about 35, 3.5 times 10 to the 13th cells in the body, 35 trillion. And actually the recent numbers on the concentrate or the number of bacteria in the large bowel are about the same number as the total number of cells in the body. Some people consider in the literature the microbiome of the GI tract to be an organ. Some talk about it as being the, an integrated organ. And there is a list here of bacteria that get pathogens and there you know it pretty well and that's probably the results of having a pathogen together or salmonella or something of this sort is probably part of how the Greeks came up with the black bile as being a, one of the humors. Another possibility with that is an upper GI bleed. It gets, the blood gets digested and on excretion the blood is black tarry stools or maybe unformed black tar. Any rate, basically too, most of what I read it's, it's hard to simplify the changes in microbiome with bad diets and good diets but it's very responsive to diet. If you have a lousy microbiome that's associated with non-alcoholic steatohepatitis and you go on a healthy diet and maybe with probiotics, with permitted foods it'll shift and become more, the simplest terms I could find were a little bit less of the bacterial rotiides, bacterial rotiides phylum and more of the fermicudis phylum. I make my own yogurt. It's a micro, it's a bacterial culture of milk and I enrich it with some milk powder and it's got no extra sugars in it and I eat some every day. I eat it on cereal or oatmeal. Bifidobacterium is also good healthy bacteria but this is a probiotic package. I took a picture just to show the sorts of bacteria listed and I would also point out fiber, aside from probiotics, prebiotics are non-digestible stuff that helps promote the effectiveness of a probiotic or like the organisms that will benefit you. You really want to look for soluble fermentable fiber. Fiber is stuff that goes through undigested. If you have healthy microbiome in your lower GI tract it will digest fermentable fibers and make beneficial molecules. For one thing the lining cells in the lower GI tract like butyrate and one of the breakdown products from these bacteria is butyrate. So close to the end I want to encourage some healthy stuff to eat. One rule of thumb I always use to try to teach people when you buy food, get natural food as well as you can and as many different colors. Those colors are pigments, plant pigments or phytochemicals. They generally have antioxidant qualities and felt to be beneficial that way. The more natural colors of food and the better it's ripened like if you have a garden of your own versus if you're buying tomatoes picked green in a distant place that ripen without being attached to the vine and without sunlight they turn reddish. They don't taste the same as... I grew up on a farm and I used to eat a tomato now and then right off a vine just as a snack and I had never tasted tomatoes since those days that taste like that. They were just wonderful. I tried to grow them myself. My father would grow tomato vines that were like about four meters tall, 12-15 feet. So there's more healthy stuff and stir-fry and don't deep fry and use olive oil, canola oil, something like this. Don't use saturated fat. And hummus is a wonderful thing. If you talk about grains, hummus with tahini and garbanzo beans, I guess, chickpeas. And I generally eat hummus with celery rather than crackers. And whole grains and beans, legumes. And I don't eat meat or chicken but I thought I'd put it out there at least. Get me, I wouldn't eat the skin on chicken because it has lots of fat. And finally, once again, the terms to remember insulin, glucagon, insulin resistance syndrome, metabolic syndrome in our NASH and MAF-LD, liver inflammation arising from fatty liver change, becoming fibrotic, cirrhosis, and maybe even developing carcinoma or need for liver transplant. Metagenomics we talked about with looking at ribosomal DNA, ribosomal RNA and gut liver axes and GI microbiome. And if you have healthy bacteria, you may not have the leaky gut, which I think really exists, which lets toxins reach the liver and starts to cause problems in the liver and also may be a catalyst for developing insulin resistance. So all these things work together. So this is a big lifestyle thing. I wanted you to know that so you can live long and prosper. And I'll finish by saying these are the best sources I know of for medical information. Now I see a question, where in the body is adipose tissue located? Well, the abdominal fat, particularly I think the olyntum or apron, that thing that hangs down, and there's a minor one that's your curvature, the stomach and the underside of the liver, that's reactive adipose tissue. Also you have subcutaneous adipose tissue. And you have visceral adipose tissue. We have kind of padding around the heart and a lot of places that let's see. Any questions? By the way, I'm happy to share these slides. I made a PDF where someone was impressed with PDF. So on one of the earlier talks and learning quietly how to do these presentations better. I went over a bit and I had quite a bit I guess. I'm sorry. But I hope this has been helpful and I made my slides work for me this time better than I ever had before. I don't think fat, I think fat is necessary in food. I think high-fat diets are the problem. High-fat, particularly saturated fats with these high carbohydrate, high-fat salt and sugar. And these ultra-processed foods. I think in eating lean animal sources of food and vegetables, fruit, nuts, and nuts have a lot of calories. I love eating nuts, and I eat about 12 different kinds of nuts a day and I spread it out so I get to enjoy them. But because they would probably put weight on me if I didn't, but having fat in the diet and moderation, as do the French, is not such a problem. Especially if you don't end up developing insulin resistance or type 2 diabetes or metabolic syndrome. I think France is starting to see more of that as well, though. Well, the French, I thought, tend to have a lot of courses of food and they're none of them so large. That was my experience with what I've eaten with French families. Well, sugar, but high-fat diet is associated with this disease process. Alcohol-related changes in the liver, that's different. That's alcohol toxicity, which can cause inflammation and fibrosis and cirrhosis. And it's associated also with hepadol, cellular carcinoma. I wrote down a note for myself. Most literature recommends keeping the alcohol intake to a max of about... Well, let me say it this way. One glass of alcohol has 14 grams of pure alcohol. One dose, I suppose I should say. If you had 8 ounces of beer... I'm sorry, 12 ounces of beer. That's about 14 grams of alcohol. So the upper limit of beer that one might consume per day is recommended around 18 ounces or 532 milliliters. For wine, 8 ounces of wine or 236 milliliters is the limit. Some write 12 ounces for men, 8 ounces for women. That was probably written by a man. Then for spirits, for hard alcohol, 2 ounces or 60 milliliters is the max. And beyond that, then you can start to get effects. Another aspect of the metabolism of alcohol is that it feeds into the acetyl-CoA system, the citric acid breakout where fat synthesis occurs. Alcohol shunts right into fat synthesis. It's like ingesting pure fat, metabolically. I think in studying NASH, they try to exclude patients. So it's a reductionist approach. Exclude patients who consume more alcohol than what I listed verbally. There are a minute ago because it becomes multifactorial otherwise. And NASH already is a multi-hit disease. It's associated with the insulin resistance and high triglycerides and obesity or increased abdominal girth and that sort of thing. So I think if you are drinking too much, you're going to have toxicity to the liver just from the alcohol and the aldehyde that's produced from it. It's also neurotoxic. I see a lot of people with great talent who seem to hang on to their intellectual abilities a long time despite their alcohol abuse, but it does take a toll on neural function. I don't think there's any question on that. High blood cholesterol, that's really a good question. If you have high levels of high-density lipoproteins, so you have efficient transport, then not necessarily. And you don't have high blood pressure and family history. I'm sorry about the phone again. Or smoking of tobacco. All those promote vascular disease. I got to figure a better way to deal with the phone the next time. I got the actual phone stuck in a drawer. I didn't realize the base was what rang. So any other questions? I think that's a good question about VMI when someone's muscular. I think that one has to, if you have an athlete, you have to take that into account. And that's where there are other assessments for fat. You can do assessment of subcut fat by measurement under the arm and that sort of thing. And there are ways of looking at weight and height and impedance to determine the total body fat. So I think if somebody is very muscular but has a low body fat, then I think the BMI is probably not so applicable to them if it's high. I don't know, Arianna, about that. If everyone has potential to develop non-alcoholic steroid hepatitis without obesity, maybe. And some people, I think there's certainly genetic predispositions that some people handle certain things better than others and certain lifestyles better than others. I mean, look at Keith Richards. He should have been dead a long time ago. But most people would have been. There are people that are lean who have it. So certainly you can have it without having obesity. I don't know that everyone has the potential to get it without obesity, though. Any other, okay, thank you very much. I appreciate your attention and hope this helps you live a long, healthy life.