Hello, my name is Meena Bansal, and I'm from the Icahn School of Medicine at Mount Sinai in the Division of Liver Diseases. If you have any questions, please do not hesitate to click on the bottom, ask the forum, where common issues regarding liver diseases are discussed. The title of my module is Outcomes of Patients with Abnormal Liver Tests. At the end of this talk, you will be able to describe the possible outcomes of acute hepatocellular injury, whether that be liver failure, resolution, or chronicity. Recognize the possible outcomes of chronic hepatocellular or cholestatic injury. Understand appropriate methods to assess fibrosis stage, and monitor patients with chronic liver injury. And finally, know that liver fibrosis may be reversible, and recognize those in whom this is more likely to occur. I have nothing to disclose. It is our goal that at the conclusion of the program, you should be able to describe the possible outcomes of acute hepatocellular injury, ranging from liver failure to resolution or chronic liver injury. Recognize the possible outcomes of chronic hepatocellular or cholestatic injury, such as cirrhosis and hepatocellular carcinoma. Understand appropriate methods to assess fibrosis stage, and monitor patients with chronic liver injury. And finally, to know that liver fibrosis may be reversible, and recognize those in whom this is more likely to occur. So when an individual develops acute hepatocellular injury, there are a number of potential outcomes, which largely depend on two key factors. What is the etiology of the injury, and how severe is that injury? In some instances, if the injury is mild and self-limited, there is complete resolution, and the liver returns to normal, such as can be seen with mild cases of hepatitis A or drug-induced liver injury. However, in some cases, the acute insult is so overwhelming that the patient develops acute liver failure, which we will discuss in more detail shortly, but can result in either recovery or death without liver transplant. Lastly, and most commonly, acute liver injury transitions to chronic liver injury. Over time, if the etiology of the chronic liver injury is not treated, it will result in variable rates of fibrosis progression, ranging anywhere from minimal scar to cirrhosis, depending on a number of host, environmental, and genetic factors. Once cirrhotic, patients can remain in the compensated stage or develop decompensated liver disease, along with the risk of developing hepatocellular carcinoma. So acute liver failure is also referred to as fulminant liver failure, and is defined as liver disease that causes encephalopathy within eight weeks of the first symptoms of illness, or within two weeks of the onset of jaundice, or any degree of encephalopathy with an INR greater than 1.5 in a patient without pre-existing liver disease. But irrespective of the etiology, patients with acute liver failure present with, by definition, hepatic encephalopathy, with concomitant coagulopathy, and often jaundice. As these patients do not have underlying chronic liver disease, on physical exam you should not see stigmata of chronic liver disease or signs of portal hypertension. The presence of portal hypertension should raise your index of suspicion for pre-existing underlying liver disease, which has a very different clinical course. There are, however, a few instances where chronic liver disease can have a fulminant presentation, such as the case with fulminant Wilson's disease, autoimmune hepatitis, or reactivation of hepatitis B. In these cases, you may see some signs of portal hypertension even in a fulminant presentation. But no matter what the etiology, a patient with acute hepatocellular injury should be hospitalized in the presence of an INR greater than 1.5 and or altered mental status. And when a patient presents with acute liver failure, you must immediately think about the etiology, because in some cases, disease-specific therapy could be life-saving, such as acyclovir for HSV or n-acetylcysteine for acetaminophen. And on the other side of the spectrum, making certain diagnoses means close to 100% mortality without transplant, such as fulminant Wilson's disease. So if you make the diagnosis of fulminant Wilson's disease, you must list immediately for transplant. While hepatitis B is the most common cause of acute liver failure worldwide, in the United States and in the UK, acetaminophen is the number one cause of acute liver failure, followed by idiosyncratic drug reactions. Interestingly, the most common cause of acetaminophen toxicity is not necessarily in the context of an intentional suicide attempt, but rather from what used to be coined a therapeutic misadventure, where patients are unknowingly taking high doses of acetaminophen in multiple cold and pain medicine preparations. Since they are unaware, they tend to present later than those found after a suicide attempt and therefore have a poor prognosis. This unintentional acetaminophen toxicity can be seen to a greater extent in alcoholics, as alcohol upregulates the cytochrome P450 enzyme responsible for converting acetaminophen into the toxic intermediate napqueen. It can also be seen in those who have decreased glutathione stores, again in patients such as alcoholics or anorectics, glutathione helps conjugate napqueen into a non-toxic excretable metabolite and therefore glutathione deficiency can certainly exacerbate acetaminophen toxicity and actually forms the basis for why NAC is effective. But irrespective of the etiology, I like to think about acute liver failure as two competing processes happening in the liver. On the one hand you have overwhelming hepatocellular necrosis, and on the other hand you have the liver's tremendous regenerative capacity. The outcome of the patient ultimately depends on which process wins out. So when you are seeing a patient with acute liver failure, you need to try to predict whether or not they will actually need a liver transplant or whether you think their native liver would recover. This is obviously critical because you don't want to transplant someone prematurely, making them now having to deal with lifelong immunosuppression and all of the complications that come along with it. And on the other hand, you don't want to wait too long to transplant a patient because donor organs are not always available and the patient may succumb to things like infection, making transplant then contraindicated. So how can we, when we have a patient in front of us, try to make that determination? Are they going to survive without transplant and their native liver will recover? Or do we need to list them for transplant because otherwise they will die? This is a very difficult and humbling process, but multiple prognostic markers have been developed to try to help clinicians predict outcome. One such criteria has really stood the test of time. This is the King's College Criteria. In the King's College Criteria, etiology is considered. For those with acetaminophen toxicity, a pH of less than 7.3, or the presence of all three of the following, grade 3 to 4 encephalopathy, INR greater than 6.5, or CM creatinine greater than 3.4. If these criteria are met, the patient carries an 80% mortality without transplant. For non-acetaminophen-based causes of liver failure, INR is the most important feature. An INR greater than 6.5 or any of the following, age less than 10 or age greater than 40. The etiology of the disease, as we mentioned earlier, Wilson disease carries a 100% mortality rate without transplant when patients present in acute liver failure. Antibiotic drug reactions also carry a poor prognosis. INR greater than 3.8, serum bilirubin greater than 17, and the time of jaundice to encephalopathy. In patients who present actually in a more fulminant course, tend to do better than those who present in a more protean or sub-fulminant course. In summary, most cases of acute liver failure in the United States are due to acetaminophen-induced liver injury followed by idiosyncratic drug reactions. The most common cause of acute liver failure worldwide is hepatitis B. Prognostic criteria are important in determining the probability of survival without transplant. Once liver failure is suspected, hospitalization and transplant centers should be immediate so that workup and therapy where applicable can be initiated and transplant evaluation can be performed. It's important to remember to quickly evaluate a patient for liver transplant because you can always turn down a liver, but if the patient is not on the transplant list, you will not be offered that liver and timing is everything in this disease that can really be devastating very quickly. So as we said earlier, in instances of acute liver failure that resolve, the liver returns fully to normal. However, most causes of elevated liver enzymes persist chronically unless the cause is removed or disease-specific therapy is successful. And there is a variable progression to cirrhosis based on genetic and environmental factors. So when we talk about chronic liver injury, it's important to recognize that no matter what the injury is, whether it be viral hepatitis, alcohol, or fatty liver disease, fibrosis is simply the liver's natural wound healing response to injury. And if that injury is not removed, over time the fibrosis accumulates, ultimately leading to cirrhosis. So how do we know how much fibrosis a patient has? Liver biopsy has been and remains the gold standard, though it has several limitations that we will discuss shortly. However, a number of systems have been developed to stage the amount of fibrosis a patient has. One such system is the Medifier scoring system, which is a four-point scale. Patients with F0 have no fibrosis, but those with F1 have portal tract fibrosis, shown by the darker, thick black line around the portal tract. In F2 fibrosis, there starts to become some septa radiating from the portal tracts. For F3, you now start to see numerous septa and bridging fibrosis. And finally, F4, where you have complete nodule formation, or cirrhosis. Another common scoring system is the Ishak scoring system, which is a six-point scale, where again, zero is no fibrosis, and in this case, six represents cirrhosis. But what we have learned is that patients have variable rates of fibrosis progression. For example, when we look at hepatitis C patients, while most patients will develop cirrhosis over about 30 years, some patients are rapid fibrosis and will develop cirrhosis over a period of 10 years. And some will never develop cirrhosis in their lifetime, and they are considered slow fibrosis. Therefore, understanding who is a rapid fibrosis versus who is a slow fibrosis will help a clinician determine the nature and the timing of their therapy. So briefly, what are the limitations of liver biopsy? We know that it has inherent complications for the patient, such as pain, bleeding, or perforation of another organ. But from a pure fibrosis staging standpoint, sampling error is problematic. Remember, a liver biopsy captures about 1 50,000th of the liver. So if your liver biopsy trajectory was here, and you quantitated the percent of collagen based on morphometry, which is commonly used in clinical trials as well as experimental models since it's more quantitative than assessing fibrosis using a simple staging system. If your liver biopsy trajectory was here, you would say this patient has 65% fibrosis. However, if your needle track was just slightly lower, you might think that the patient has only 15% fibrosis. And thus, sampling error must always be kept in mind when interpreting liver biopsy results. Now in an effort to both avoid the potential patient complications and this issue of sampling error, a number of radiologic and serum tests have been developed and are reviewed in the cirrhosis module. I think the most important point to make is that these assessments are generally very good in identifying patients with no fibrosis and identifying those with cirrhosis. So very good at the two extremes of the spectrum, but less effective in differentiating between the intermediate stages of fibrosis. And therefore, having more than one assessment that are consistent with each other helps increase your confidence in where you think that patient's fibrosis stage may be. In addition, this is a very dynamic process, and so really following an individual patient over time can be more meaningful than simply trying to categorize them or stage them. You want to know with your therapy, is the fibrosis assessment, whether it be a fiber scan or a serum marker, is it going down, is it staying the same, is it going up? If my patient is not on a therapy, how are they progressing? Are they increasing? Are they staying the same? Are they improving? So it's really the dynamic nature of these that I think is important to utilize in patient care rather than simply just trying to categorize a patient as a stage of fibrosis. And what we've realized over the past couple of decades is that hepatic fibrosis is in fact reversible. And while there are no specific antifibrotic therapies, treatment of the underlying disease can be a very effective antifibrotic. Therefore, we want to identify the cause of liver injury as early as possible such that disease-specific therapy can be initiated. We know that not all chronic liver injury evolves to fibrosis and cirrhosis, so close monitoring for progression is critical to tailor the therapy to the individual patient. And while cirrhosis is reversible, the longer a patient is in the cirrhotic stage, the harder it may be to reverse that scar due to the extensive cross-linking that happens between the collagen fibrils, making it harder for that scar to be resorbed. In addition, there are significant architectural changes that occur with long-standing cirrhosis that may not be reversible even with disease-specific therapy or even with potential antifibrotic therapies. But as an example where it has been shown to be reversible, with continued antiviral treatment for hepatitis B, reversal of both fibrosis and cirrhosis has been observed. If you look at the percentage of patients at the various ISHAC scores at baseline and then at 5 years later on antiviral therapy, you can appreciate that there is a percent of patients with high fibrosis scores that decreased with time. 74% with cirrhosis considered an ISHAC score greater than or equal to 5. At baseline, no longer had cirrhosis at year 5. And this is critical as progression to cirrhosis is the most important determinant of mortality from chronic liver disease. For example, in both hepatitis C and NASH, the presence of cirrhosis is significantly associated with decreased survival as was discussed in greater detail in Dr. Kamat's module. Moreover, not all cirrhosis is created equal and should be thought of as a continuum. As discussed by Dr. Garcia-Sau, cirrhosis is classified into two major prognostic stages, compensated cirrhosis and decompensated cirrhosis. So when a patient has chronic liver disease, this can lead to compensated cirrhosis, which may not even be detectable by any clinical or laboratory data. Some patients will then progress to decompensated cirrhosis while others may not. And decompensated cirrhosis is defined by the development of clinical complications, which include variceal hemorrhage, ascites, encephalopathy, and jaundice. Among patients with cirrhosis, hepatocellular carcinoma may develop at any stage, either compensated or decompensated. And therefore, screening for HCC is recommended in all patients with cirrhosis. And fortunately, in some cases, decompensated cirrhosis may revert to a compensated stage with etiologic therapy, such as alcohol abstinence or antiviral therapy. Disease-specific treatments currently exist for a number of liver diseases, though no disease-specific therapy currently exists for primary sclerosing cholangitis or non-alcoholic fatty liver disease, though a number of clinical trials are currently ongoing. So we're hopeful there will be some available soon. So in summary, regardless of the cause of chronic liver disease, fibrosis is the liver's natural wound-healing response. If the injury is removed or treated, fibrosis and cirrhosis are reversible. Cirrhosis can ultimately become irreversible, but that point of no return is not entirely clear and can be variable between patients. Our goal, therefore, should be to treat the underlying disease and monitor for fibrosis progression and regression using various invasive or non-invasive methods. Again, you want to look at the dynamic changes within an individual patient over time to determine their individual fibrosis progression rate so that the timing and the nature of the treatment can be personalized. If signs of decompensation develop, refer for liver transplant evaluation. So in summary, when a patient presents with acute liver disease, some will resolve, but most will go on to develop chronic liver disease. If disease-specific therapy is initiated, many will resolve. If disease-specific therapy is not initiated or not available, patients can go on to develop compensated cirrhosis and then are at risk for the development of decompensated cirrhosis as well as hepatocellular carcinoma. If disease-specific therapy is initiated, even in the stages of decompensated cirrhosis or compensated cirrhosis, one can see reversal. In cases where the acute liver injury is so overwhelming that even the regenerative capacity of the liver cannot keep up, patients can develop acute liver failure and either succumb to death or be rescued by liver transplant. Patients with decompensated and compensated cirrhosis are at risk for the development of acute onchronic renal failure, which can expedite that trajectory to the need for transplant or death without transplant. I hope you've enjoyed this presentation and I invite you to access additional content on liver learning on this topic or any other related topics at your leisure. Thank you.

Fundamentals of Liver Disease

liver diseases

abnormal liver tests

acute hepatocellular injury

chronic liver injury

fibrosis assessment methods

prognostic markers