During this 20-25 minute pre-recorded lecture, Dr. Scott L. Friedman discusses the topic of alcoholic and nonalcoholic liver disease. This in-depth review will provide an update on this topic for your clinical practice as well as supplement your learning for the ABIM Gastroenterology and Hepatology boards.
Hello. This is Dr scott Friedman. I'm delighted to give you this lecture on alcoholic and non alcoholic fatty liver diseases as part of the G. I. And Hepatology board review course. Let me start with alcoholic liver disease and emphasis that it is really a spectrum that in most patients includes fatty liver but may progress to Seattle hepatitis which involves inflammation fat as well as fibrosis and in severe cases can progress to cirrhosis. It's worth remembering that fatty liver disease per se is not dangerous and it's reversible. But early fiber genic events are already occurring once fat has begun to accumulate in response to alcohol. It's also important to recognise that fat in the liver whether from alcohol or non alcoholic fatty liver disease is recognized as a co factor in liver injury. So that patients, for example who are obese and have viral hepatitis have a more rapid progression because the fat and the liver is a kind of synergize er that accelerates liver entry and fibrosis. And this has been validated in both human obesity and animal models here you see the three of the classic lesions of alcoholic liver disease. When biopsies are performed here you see mostly fatty liver. The fattest in the ePA to sites it's macros the ato sis but the real classic features of alcoholic hepatitis are the presence of polymorphic nuclear Lucas. Sites as well as Mallory's highland and it's important to remember that this is a cell type that's not commonly seen in most forms of chronic liver disease. So polly's tend to implicate alcohol and to a lesser extent nonalcoholic Seattle hepatitis. The other thing to remember is that the fibrosis once it begins to appear occurs around the central vein. And this is thought to be in part because this is where alcohol metabolism has the most severe effects on injury by creating local hypoxia. And so injury tends to start and fibrosis follows in the same region. And so you see perry vehicular disease as opposed to viral hepatitis, which is primarily perry portal. Let me start with an instructive case presentation of a 55 year old man transferred from an outside hospital with several weeks of jaundice, heavy alcohol history history of gall stones. He works as a night watchman and his divorced and distant from his family. His mother drank heavily. His BMI is not elevated but he has multiple stigma of chronic liver disease including spider angio Mata, actress, lethargy and asterix is and he has massive facilities with an elevated white blood cell count on the left shift Marked elevation of Billy Rubin, some synthetic synthetic dysfunction and an STD that's greater than adult and both are less than 500. His creatinine is elevated and rising and he has gall stones, fatty liver, normal duck size and of course societies on his ultrasound but paris synthesis is negative for infection, which findings in this patient are not typical of alcoholic hepatitis. This should say S. T is more than two fold greater than A. L. T. And both are less than 500. that is typical SD greater than adult. He's socially isolated. That's also typical and he works at night. He has a family history of apparent with alcoholic liver disease. That's also quite typical as is the elevated white blood cell count with the left shift and no obvious infection that might suggest severe intra Paddick inflammation that is spilling out into the peritoneum. So the only thing that is not typical of alcoholic hepatitis is the presence of gall stones. All those others a through D are are very commonly associated with uh with alcoholic hepatitis. Clinically we see a number of science and lab symptoms and lab data although none are absolutely specific for alcohol. They include fever of paddle, meagley jaundice anorexia in severe cases as in the case today societies and even encephalopathy. Lab data may indicate anemia, leukocyte, oh sis. Again this elevation of ASD and LT, both of which are 10 are less than 500 cola stasis with an elevated bilirubin and alkaline phosphate station, if there's synthetic dysfunction, I. N. R. May be increased in albumin has decreased. One key pearl is that if you see a patient where you suspect alcoholic hepatitis but the A. S. D. N. A. L. T. Are well in excess 500 and particularly if they're over 1000. You need to think about a second concurrent illness or cause for that liver injury. The most common being either intentional or unintentional overuse of acetaminophen liver patients, particularly alcoholic liver disease patients have heightened sensitivity. Two acetaminophen toxicity. And so even high therapeutic doses of acetaminophen can lead to severe liver injury, particularly if they are in excess of four g per day. So keep that in mind. Otherwise we should csd N. L. T mostly less than 500. When we think about prognosis and alcoholic liver disease, there are really three elements to consider. One is the likelihood and a patient who drinks of developing any alcoholic liver disease at all. The second is what will happen to them, What's their prognosis once they're diagnosed. And the third is what is the prognosis of cirrhosis. And here I'll answer this quickly now and not return to it and that is that the outcome of or prognosis of cirrhosis and patients with alcoholic cirrhosis is determined largely by the child Pugh melts core melt score. Either one is a quantitative or semi quantitative way of assessing liver function and failure and probably the single most important determinant of outcomes in patients who have alcoholic liver disease is whether or not they can abstain from further alcohol use. This is an important take home point. Nothing is more important than abstinence in determining outcomes of patients with alcoholic liver disease. Yeah, so there are some interesting and surprising features about the impact of alcohol and the propensity to develop liver disease and that is that although we know that the risk for alcohol associated liver disease increases in a dose dependent manner, remarkably less than one third of alcoholics or heavy drinkers to develop serious alcohol related liver damage. And as I'll show you the risk thresholds are different between men and women. Let other Let me make another point also about terminology here, I've used the older term of alcoholic liver disease. In fact, the convention now is to really refer to this illness as alcohol associated liver disease. Uh and so you'll hear me use those terms interchangeably. But the more appropriate term is really alcohol associated liver disease to return to the concept of drinking safe drinking limits. That's illustrated here. And it comes from recommendations from the National Institute of alcoholism and alcohol Research or the anti triple A. And it's different between men and women. So for men, they can drink up to healthy otherwise healthy men can drink up to four drinks a day, but no more than uh two drinks a day, on average, or 14 per week. In contrast, women have a lower ability to tolerate alcohol probably because of a lower circulating volume. Uh And so it's recommended that most they have three drinks a day, but they must stay below seven drinks over the course of a week. And this all assumes that the patients have no concurrent liver disease. If they have concurrent viral hepatitis or nash or autoimmune liver disease, then we really strongly recommend to avoid alcohol altogether because you have to synergize NG events or effects that can accelerate or amplify the risk of liver disease based on alcohol consumption, there are other risk factors for alcoholic liver disease. And um, it's interesting that even now, in 2020 we don't have a, an ironclad explanation for how alcohol induces liver disease. So most of the evidence for alcohol induced or alcohol associated liver diseases, epidemiologic, not mechanistic or biochemical, certainly based on a comparable alcohol ingestion, females or higher risk for than men. Again, concurrent liver disease, which may include obesity and non alcoholic fatty liver disease. And there may be some genetic factors that determine both the risk of alcoholism and the likelihood of liver injury after heavy drinking. And if you remember the case that I presented, there was specifically history of family history of a mother who was alcoholic and any individual who has one or both parents who were alcoholic greatly increases the risk that they too will be alcoholic. And it's pretty clear that it's not just because of shared socio economic factors, but there are almost surely genetic determinants of alcoholism that track through the generations. If a patient already has alcoholic or alcohol associated liver disease, we know that again, continue drinking will be the worst predictor, the worst thing they can do in terms of mitigating progressive disease. But if we do biopsy and we don't routinely do biopsy. If the diagnosis is clear, but if we do biopsy um either to rule out other causes or to effectively enroll the patient in a clinical trial that requires biopsy, we know that the degree of inflammation and fibrosis. Again, the presence of coexisting disease whether or not there is iron. And certainly if the patient already has markers of liver failure, these are all indications that the patient will have a poor prognosis. So it's worth keeping this in mind. And let's not forget that the underlying disease here is alcoholism. And so while we treat the acute liver injury and its consequences in the hospital setting, ultimately, alcohol cessation identification of a drinking problem And referral to an appropriate alcohol counseling environment is absolutely critical. Uh currently, uh any 12 step program, particularly alcoholic alcoholic alcoholics anonymous, still remains the gold standard for effectiveness and alcohol cessation programs. But do not forget your patient has a chronic disease known as alcoholism. And this really needs to be addressed as soon as possible. So let's return to our 55 year old night watchman with severe alcohol associated hepatitis. He was treated with penicillin for one week prior to transfer which of the following is the most appropriate management option. Now, should we continue steroids, stop steroids, decrease the dose, increase the dose or switch to predniSONE. Okay. And uh the truth is that because he did not improve and I didn't say this explicitly because he did not improve within seven days meaning his billy Rubin did not improve or go down after seven days of steroids? General recommendation is to stop steroids so that and I'll return to the concept of steroid use an alcoholic associated liver disease in just a moment. All of the following true about alcohol associated hepatitis except what it can be a fatal illness. Yes, that's true. It's always too late for the patient to benefit from abstinence. That's actually not true. So the others are true. The amount or duration of alcohol use do contribute to the risk of alcoholic hepatitis. It may be appropriate to perform liver transplantation and extremely well selected patients. And also Preakness alone therapy is helpful in selected patients. So again, it's never too late for the patient to benefit from abstinence. Both because the liver has an incredible regenerative capacity that may restore liver function if the patient stops drinking. Also, alcohol cessation is critical if the disease is too far advanced and the patient is being considered for liver transplantation, they need to show evidence of insight and awareness of their problem. And there needs to be confidence on the part of a team of providers that the patient has sufficient insight and resources that they will remain abstinent, both before and following a little transplanted one is performed. The principles of management of acute alcohol associated liver disease are really good medical care for the most part abstinence fluids and multivitamins. One needs to be vigilant for infection and port of systemic encephalopathy and watch for evidence of delirium tremens or alcohol withdrawal. Then? What about steroids? So uh the tried and true test of steroid responsiveness was established decades ago by Willis modry and remains really a gold standard for determining the appropriateness Of steroids and whether they should be continued. Um and that is that for patients, all patients should have what's called the discriminate function calculated, it's shown here or one can use meld. So generally a meld of 21 is equivalent to a discriminate function of 32 or greater. In this setting, one can consider steroids for four weeks and then taper. However, those who have elevated creatinine or a gi bleed will not benefit. And perhaps equally importantly, as I already mentioned, an early change in billy Rubin, meaning a decrease after seven days as an important prognostic sign And the absence of improvement or reduction in Billy Rubin within seven days of the pregnancy alone really indicates that they are on the patient is unlikely to benefit and the steroids should be stopped. So, this data shows a landmark study by Philip Mattera and his colleagues in lille France Philippe is a brilliant clinical investigator uh and they undertook a very heroic effort to ultra evaluate or selectively evaluate patients with severe alcohol associated hepatitis who were unresponsive to rennes alone to determine whether they might respond to liver transplantation. Um the overall number of patients that were selected was a small fraction Of those who were initially evaluated. But in those highly selected patients who underwent listing for liver transplant, early liver transplant within 15 days, the outcomes were dramatically improved. As you can see here, comparing 71-plus -9-23% survival. Um, and uh, some of the specifics of this trial are listed here. I don't have time to go through them, but I will say that under the leadership of Jean m, who's on our faculty here, who is a now a national authority and alcohol associated liver disease, the mulsanne experience has been equally good, even more dramatic in showing a survival benefit and early liver transplantation for highly, highly selective patients. Uh again, the the number of patients who are considered Compared to those who are chosen is probably about 9-1. In other words, only one out of nine patients who are considered for early transplant ultimately undergo transplant. So this is clearly not a a treatment option for the large, overwhelming number of patients with alcohol associated Hepatitis. One other very important point in the context of the covid pandemic is the dramatic increase in hospitalizations due to alcohol associated hepatitis. Our own inpatient liver service now is comprised of around 75% of the patients with severe alcohol related liver injury. And we can assume that much of the increase in hospitalizations for alcohol related liver disease is associated with both. The stress of the covid pandemic as well as the lack of adequate access to alcohol rehab programs that patients might ordinarily be enrolled in. So, in the context of the covid epidemic, one should anticipate or have a heightened awareness of the fact that we're going to be admitting more patients than ever before with acute alcohol associated liver disease, which may be severe. Let me pivot now to what's called non alcoholic fatty liver disease and emphasize that this is an emerging terminology. Um, nobody in the field is really like defining this based on what it is not. And so there is a recommendation that is gaining traction internationally to change this name to metabolic associated fatty liver disease or Math Hildy as opposed to Nafta LD. Regardless, let's stick with the older terminology for now and define this as an alcohol like liver disease, but in patients who do not consume excess alcohol, which does suggest that there are many similarities between the liver disease associated with obesity, which I'm telling you about now, and liver disease associated with alcohol excess. Regardless, the prevalence is rising catastrophically, it's estimated that already up to a third of all americans have some element of fat or non alcoholic fatty liver disease and a fraction of those will go on to more advanced disease, which I'm going to talk about a little bit more. So to break down the terminology napoli comprises all patients with fatty liver disease, among whom some have non alcoholic fatty liver alone or nah fill some have a more severe advanced form which is Naff or nash nonalcoholic Seattle hepatitis and among those with Nash a fraction that is rising will go on to progress to cirrhosis. It's important to remember that many patients don't realize they have nash and they show up with liver disease at a time when there so erotic. And traditionally many of these patients were characterized as having crypto eugenics cirrhosis. But in fact, if one looks retrospectively many, if not, most patients with crypto genic cirrhosis had unrecognized Nash probably for years or decades and ultimately present with cirrhosis. It's also important to emphasize that patients with Nash are at risk for hepatitis a lot carcinoma. And because they often don't know they have liver disease. It's not unusual for a patient with Nash, with or without cirrhosis to have their first diagnosis made because they present with liver cancer. So you need to have a high level of vigilance for liver cancer in particular because Nash patients have a higher propensity to develop HCC before there's erotic compared to viral hepatitis. Again, like alcohol, there's no absolute diagnosis diagnostic test. And instead it's a diagnosis of exclusion, which I'll talk about a little bit more. So here's a diagram attic progression of disease. You start with cyanosis. Some patients probably about 20% will progress the Seattle hepatitis uh and that in turn sets them on a path towards cirrhosis and the risk of the peninsula carcinoma. We recognize that in the United States, probably most patients walking around with Seattle hepatitis or even cirrhosis from Nash do not even know they have liver disease, although we know that those with diabetes and obesity and metabolic syndrome. Certainly I have a higher likelihood of developing Nash and should be screened for Nash, even though recommendations are not universal yet. In our practice, up to 70% of patients with Type two diabetes have underlying abnormalities of liver stiffness using fiber scan, which suggests that they may have some element of nash or even cirrhosis. So diabetics should be particularly at risk and screen non invasively for the potential for Nash. Why do we try to distinguish between those who have plain fat versus those who have nash with fibrosis? Those with plain fat have a slower or lower progression rate. Those with Nash based on current estimates have up to a 30% risk of progression to cirrhosis. Again, this doesn't occur in a vacuum. Non alcoholic fatty liver disease is seen most commonly in obese patients who have Type two diabetes in our Disl epidemic. And maybe hypertensive as well. All of this represents typically an insulin resistant state and one that we think also contributes to the pathogenesis of liver disease or non alcoholic fatty liver disease. So let's turn to a case to kind of focus our attention here's a 57 year old woman evaluated for abnormal liver tests who's asymptomatic and has a history of diabetes and hypertension. There's a family history of heart disease and diabetes. A brother has abnormal liver tests and her current meds are treatment for her comorbidities. Metformin, listen, april and aspirin. She has an elevated BMI and waist circumference, but no stigmata, chronic liver disease and an eca genic liver consistent with fatty infiltration, no biliary abnormalities or gall stones. Her lab tests here are fairly typical and modest elevations of S. D. N. L. T. And gamma GT. And elevated hemoglobin A one C. But normal albumin and borderline low played account which is of some concern. So this is a very typical presentation. And for hepatology ist the most common reason we're evaluating or asked to evaluate patients is because they have incidental elevations of there, S. T. And LT picked up and shown to be persistent by their primary providers and or they have an imaging test. Typically an ultrasound that chosen estrogenic liver. The absence of elevation of A. S. D. N. L. T. Or even the presence of modest elevations does not exclude the possibility that they have severe liver disease. So it's really prudent for primary care providers or diabetes. Ologists internists to be highly sensitized to the risk of liver disease, particularly. Again if their patients are diabetic. So which would be which would not be part of the initial work up for this. 50 plus woman who has elevated trans am in eight. So careful history taking to rule out alcohol. Certainly that's useful serum testing for viral hepatitis Absolutely. And a tighter not so much, but probably uh informative to make sure the patient doesn't have autoimmune liver disease iron studies to make sure that she doesn't have concurrent iron overload and liver biopsy. So liver biopsy would really not be part of the initial diagnostic work up. We try to reserve liver biopsy for those patients in whom another cause concurrent or instead is being suspected. And we tend to avoid doing liver biopsy early in the evaluation, in part because if they have a liver biopsy often that is important information to enroll them in a clinical trial and we don't want to deliver biopsies outside of a window of eligibility for a clinical trial. So, we'd rather if the diagnosis of Nash is almost certain, we'll make a presumptive diagnosis clinically and then do a liver biopsy with the hope that we will have a clinical trial that they can be enrolled in. So, overall goals for diagnosis or first of all to confirm that it's non alcoholic fatty liver disease. Um, make sure there's no alcohol to explain the fatty liver and also determine how severe is It is a plain fat is in fact with inflammation and fibrosis and death of the parasites. Or could it even be cirrhosis. Again, I've emphasised this occurs in the context of metabolic syndrome, obesity type two diabetes hypertension display academia fatty liver or eca genic liver on imaging, elevated sTR LT and again uh this uh increasingly appreciated association with crypto eugenics cirrhosis. So here are some of the features of our patients that are typical elevations that are generally less than 10 times the upper limit of normal but may be normal. exclusion of other liver disease Marcus and metabolic syndrome. Uh And we're often asked so how do we know how severe the patient is? So we tend to do two things in our practice. We will calculate a 54 score or an apple D. Score. These are widely available and calculated based on standard laboratory and clinical parameters. Um And uh we increasingly rely at least on liver stiffness test. Although there are other technologies under evaluation I encourage you to review the S. L. D. A. G. A R. A. C. G. Guidelines which are shared for the latest recommendations for the appropriate screening. But in our practice we tend to routinely calculate fit for an apple D. Score and we also look to liver stiffness and I'll say more about that in a minute. Um If you're trying to distinguish between alcohol and non alcohol, it's generally not that hard. What were often struggling to do is determine whether alcohol is contributing to underlying natural D. Um And as I mentioned uh there is in our view no safe alcohol ingestion level and patients who have medical D. Um And so it's really prudent to insist that patients really try to avoid alcohol intake if they already have a diagnosis of Nafta deal, particularly if they have a diagnosis of nash. As I mentioned, experts increasingly argue that because the diseases are so similar uh they really represent in many ways the spectrum of a continuum of diseases known as metabolic associated fatty liver disease. And it's not surprising that many of the treatments that are being tested in napoli are also being envisioned for alcoholic liver disease. So some general principles or messages a clinical prognosis ultimately depends on the histology. If biopsy is performed, fat alone is benign, Seattle hepatitis, increases the risk for cirrhosis. And of course cirrhosis can be lethal and carries a high risk of the paddle cell carcinoma. If you already see evidence of portal hypertension, either by stigma of chronic liver disease or other abnormalities that suggest chronic liver failure than by all means. Uh there needs to be further investigation to make sure the patient is not so erotic. Yeah, in terms of establishing the severity. Uh these imaging tests are not really ironclad useful in terms of distinguishing fatty liver from Seattle hepatitis or early cirrhosis. Again, we use stiffness, mostly bedside fiber scans or MRI last ah graffiti to identify cirrhosis and again, stigmata, portal hypertension. Mace arrest suggests cirrhosis uh imaging is also important because it may detect unsuspected parasailing carcinoma. And although I don't have time to talk about this neo plasm, it's well understood that the best chance for cure or good outcomes for liver cancer is early diagnosis when either a blade of or respective surgical therapy or even liver transplantation can be contemplated for liver biopsy. We look to the brunt kleiner scoring system which comprises three major categories Seattle happened, osteoporosis, ballooning and inflammation uh as well as a separate scoring system for fibrosis. And this leads to a calculated semi quantitative score based on the pathologist grading and staging of these different elements. But there's a lot of sampling variability and liver biopsy. So again, if we have a bona fide or clinical diagnosis of natural D. We only do biopsy to really assess a little bit more accurately the severity as well as um possibly enrolling that patient a clinical trial. I've alluded a couple of times to the availability of stiffness test. We use fiber scan which measures the stiffness of a sound wave that travels through the liver. It's a very straightforward test, patients appreciate it. Providers like to do it because we all got a number. This will help stratify at either end. If the patient has little or no fibrosis or if the patient has advanced fibrosis. The scores in the middle are a little hard to determine and that's the population where a liver biopsy may be most appropriate. So if in a patient with napoli which of the following is not part of the initial management of this patient weight loss. Well that's always a good idea, optimization of glycemic control. That's absolutely important screening for dyslexia. Denia. Yes and management thereof. And I would emphasize status are definitely safe in patients with fatty liver disease. Um and there are no higher increase of liver talks from status and these patients than in otherwise healthy patients is also dial part of the initial management of this patient. Absolutely not. In fact, there is no evidence of versa dial is effective. But on the other hand, dietary counseling to minimize consumption of saturated fats and high fructose is a critical component of dietary change that we really need to educate our patients about the approach at this point is to treat the metabolic syndrome. We do not have approved specialist therapies for national although there are literally dozens of drugs that are in clinical trials. But since this is a board review, you don't really need to be familiar with those drugs yet. Do be aware that they are being tested and in your clinical management or practice patients who have more advanced disease should be contemplated for clinical trials either in your unit or in a neighboring unit that might be conducting clinical trials for Nash. Certainly diet and exercise is critical and remarkably even modest amounts of weight loss can be highly effective, meaning £10 or £15. Can really have a dramatic improvement in liver histology. Of course it needs to be maintained and that's the challenge with weight loss is long term changes in lifestyle that ultimately affect changes in liver histology, sadly, the long term success of most diets is less than 5% and that's why we're trying to develop medications as well. Current therapy certainly can include management of insulin resistance management of Hyperloop academia. There was a new England Journal paper that suggested that vitamin E might be helpful in nine diabetics at 800 units and there's little argument against this but it's worth bearing in mind that vitamin E is over the counter and the activity of that vitamin E is very uneven because these are not effectively regulated by the FDA to ensure that their potent bariatric surgery can actually improve liver disease. But liver disease per se is never a primary indication for bariatric surgery. On the other hand, we have Mount Sinai have a large clinical bariatric surgery practice and our doctors are following those patients again seek clinical trials. I've listed the name of some of our particular our coordinator, MEREDITH Lewis Mark this number because we love to consider evaluating your patients for clinical trials. We have several too many to mention here. This is the only way we're really going to make progress is testing many of these drugs in clinical trials. Um I can just tell you that there are, as I said, dozens of new therapies. I'm not going to go through the slide in any detail but it speaks to the different points of attack different targets that are already being evaluated in the drug development space. And they include changes trying to reduce fat, improve insulin resistance, improve inflammation, improve a parasite oxidant stress as well as direct acting any fiber products. And so all of these are in clinical trials. Stay tuned and we'll be learning much more in the next few years. So let me close with some take home points between these two diseases, alcohol and non alcoholic liver disease. They encompass the spectrum of histological changes from fatty liver to cirrhosis. In the alcoholic high risk drinking behavior must be identified and addressed in alcoholic associated liver disease or alcohol associated liver disease. Their underlying disorder is alcoholism and it must be addressed both of these diseases affect the perry central zones. Histological, they're more prone to develop polymorphic nuclear Lucas sides, particularly alcohol compared to other viral like diseases which typically have mono nuclear Lucas sites and typically affect the perry portal zone. No specific treatments yet for each of these for alcohol. However, abstinence is absolutely critical stories of severe and highly selected patients or the topic liver transplantation for novelty and national particular weight locks exercise, vitamin E. Glitter zones. If they're diabetic bariatric surgery of severe comorbidities and please consider your patients for clinical trials. Um And with that, I'll close and thank you for your attention in this very rapidly moving field of fatty liver disease
