Hello, my name is Manal Abdul-Malik and I'm from Duke University. If you have any questions, please do not hesitate to click on the button, ask the forum, where common issues regarding liver disease are discussed. The title of my module is Chronic Hepatocellular Injury. During this talk, I will discuss the recognition of chronic etiologies of chronic hepatocellular injury, help you to understand the approach to evaluation based on clinical history, examination, laboratory investigation, and when to consider a liver biopsy. We'll also review the alarm signs and evaluation of progression to cirrhosis. These are my disclosures. I receive grant and research support from several industry sponsors. I have no conflict of interest pertaining to the content of this presentation. There will be no discussion of any unapproved, off-label, or investigational uses of a product during this presentation. At the conclusion of the program, you should be able to recognize the common etiologies of chronic hepatocellular injury, understand the approach of evaluating the patient with chronic elevation of liver immunotransferases, by assessment of clinical history, physical examination, laboratory investigations, and further, to assess when to consider a liver biopsy. And lastly, to understand the alarm signs and evaluation of progression to cirrhosis. Chronic hepatocellular injury, or chronic hepatitis, is defined as elevation in AST and or ALT for six months or more. So what represents an elevated AST and or ALT? A true normal liver immunotransferase for women is less than 20 units per liter, and for men, less than 30 units per liter. While the true normal AST and ALT may be at lower thresholds for men and women, the upper limits of normal for many clinical labs is approximately 40 units per liter. What is normal remains ambiguous and depends on the clinical setting and on the persistence of the abnormality by repeat testing. Specifically, one must look at previous levels in the same patient and assess change from baseline, evaluate the risk factors for underlying liver disease, and consider whether those liver immunotransferases are potentially normal in the context of a routine check-up or in the context of symptom-driven evaluations. There are several causes of chronic hepatocellular injury. The most common causes are steatohepatitis, both nonalcoholic and alcoholic, viral hepatitis, and drug-induced liver injury. Other considerations for chronic hepatocellular injury include autoimmune hepatitis, Wilson's disease, and alpha-1 antitrypsin deficiency. When evaluating chronic elevation of AST and ALT, one must first consider the potential for alcohol-induced injury. A careful alcohol history is important for defining the at-risk patient. At-risk alcohol use for women may be as little as one to two drinks a day, and for men, greater than two drinks a day. Clinicians should utilize the DSMB-5 definition for alcohol use disorder. This is a series of 11 questions which will facilitate your ability to ascertain whether a patient has mild, moderate, or potentially severe alcohol use or abuse. Lastly, there are laboratory clues which may help discern potential alcohol-induced liver injury. Specifically, the AST is typically higher than the ALT in a ratio of two to one. There may be an increased MCV on the hematology panel. There could also be fluctuations in the liver aminotransferases that are related to the timing of binge drinking. Higher elevations of liver aminotransferases associated with jaundice may indicate superimposed alcoholic hepatitis. Typically, these elevations are less than 300 IU per liter. Consider an evaluation of non-alcoholic fatty liver disease, or NAFLD, if there is the presence of metabolic syndrome. Specifically, the presence of diabetes, hypertension, hyperlipidemia, or low HDL are all associated with non-alcoholic fatty liver disease. The majority of patients with NAFLD are overweight or obese with prominent truncal obesity. By definition, the diagnosis of NAFLD entails no to very little alcohol use. A laboratory clue for NAFLD may be an ALT and AST that is usually less than 150 IU per liter. Of note, patients do not have to be obese to have NAFLD, especially in unique ethnic populations where NAFLD may develop at lower body mass indexes, as has been reported in the Asian or Indian populations. Consider the evaluation of chronic viral hepatitis, specifically hepatitis B or C, in the presence of risk factors. Such risk factors include a history of sexual practices which may increase the risk for blood-borne infections. These include men who have sex with men, high-risk sexual practices, or a history of multiple sexual partners. Consider drug use that may carry risk for blood-borne infections, such as intranasal cocaine use or intravenous drug use, a history of tattoos, or occupational exposures to blood-borne infection, and particularly health care workers, emergency response teams, law enforcement officials, or those with a past or active history of military service. Baby boomers, those born between 1945 and 65, are also at risk for hepatitis C and should be tested irrespective of risk factors. Patients who are born in a hepatitis B endemic area, specifically Asia and Africa, should also be considered at high risk for hepatitis B infection. Lastly, consider the diagnosis of possible hepatitis B in any patient with a family history of liver disease or liver cancer. The evaluation of chronic hepatitis also includes an evaluation and consideration for drug and toxin-induced liver injury. In order to further assess this possibility, one must first obtain a thorough medication history. Consider current medications and any medications taken in the past six months. Also consider and ask your patient about over-the-counter medications. Herbal, nutritional, or dietary supplements may be a source for drug-induced liver injury. And of course, when evaluating or considering the diagnosis of drug-induced liver injury, exclude other causes of chronic liver disease. A valuable resource to investigate whether a specific drug your patient may be taking can cause an elevation of AST and ALT is the NIH-sponsored website entitled Liver Tox. All medications known to cause potential hepatotoxicity are noted on this website. Consider a potential diagnosis of autoimmune hepatitis if your patient has a personal or family history of autoimmune disorders. Such disorders can include Hashimoto's thyroiditis or Graves' disease, systemic lupus erythematosus, rheumatoid arthritis, or celiac disease. Laboratory clues for autoimmune hepatitis can include a positive antinuclear antibody, typically in titers of greater than 1 to 160, a positive anti-smooth muscle antibody, increased serum immunoglobulins, and increased serum protein. Clues to the presence of chronic hepatitis may also be noted on physical examination. Look for evidence of cirrhosis, specifically signs of jaundice, temporal or proximal muscle wasting, palmar erythema, or spider angiomata. A palpable left lobe of the liver may also be suggestive of well-established cirrhosis. Patients who have portal hypertension will have splenomegaly or ascites on examination. Patients who have portal systemic encephalopathy could have altered mental status, complaint of impaired memory, chronic fatigue, hypersomnolence, or altered sleep patterns. Patients may also have evidence of asterixis on examination. Noted here is a link to Dr. Patrick Kamath's module on cirrhosis, which you may wish to review at your leisure. When evaluating patients with chronic hepatitis, obtain the necessary laboratory and imaging evaluations looking for evidence of cirrhosis. Laboratory studies should include an assessment of platelet count, as a low platelet count may be suggestive of hypersplenism and portal hypertension. Low serum albumin may suggest diminished liver synthetic function, as does a prolongation of the prothrombin time, or INR. Increased bilirubin may be seen in patients with impaired hepatic clearance. Increased globulin levels may also be noted. And lastly, in patients with viral hepatitis, a change in the ALT to AST ratio where a previously elevated ALT, when compared to AST, switches to a pattern where the AST is higher than the ALT. Imaging studies may also be utilized to evaluate for the presence or absence of cirrhosis. Features of a nodular appearing liver, splenomegaly, or venous collaterals on cross-sectional imaging would suggest the presence of cirrhosis. A stiff liver, as assessed by transient elastography, such as FibroScan, may also help in the evaluation of cirrhosis. Please be aware of the alarm signs in your evaluation of patients with chronic hepatitis and the timing of referral to a specialist for further evaluation. If your patient has any evidence of decompensated cirrhosis, such as ascites, variceal bleeding or hemorrhage, hepatic encephalopathy, or jaundice, refer to a specialist for consideration in evaluation of liver transplantation. If the presence or absence of cirrhosis is unclear with methods that are currently available in your practice, refer to a specialist for consideration of a liver biopsy. For further detail regarding the evaluation and the alarm signs of patients with advanced liver disease, please link to the module by Dr. Patrick Kamath for further details. First-line testing for the evaluation of patients with chronic hepatitis should include serologies for viral hepatitis, a screen for hemochromatosis, and evaluation and consideration of fatty liver disease. Tests for chronic hepatitis should include an antibody to hepatitis C virus, a hepatitis B surface antigen, a total antibody to hepatitis B core antigen, and an antibody to hepatitis B surface antigen. In evaluating and screening for hemochromatosis, obtain a serum iron and total iron binding capacity. The total iron binding capacity is typically greater than 45% in patients with hemochromatosis. And also check the serum ferritin. As you evaluate for fatty liver, consider the presence of metabolic syndrome and obtain an ultrasound which may show a hyperechoic or bright appearing liver. Resort to second line testing if the first line tests are normal or negative. Investigate autoimmune hepatitis and obtain the antinuclear antibody, smooth muscle antibodies, and serum protein electrophoresis. Exclude Wilson's disease and obtain a cerebral plasmid level. Consider celiac disease. Evaluation of celiac disease can be facilitated with an anti-endomysial IgA antibodies or anti-tissue transglutaminase IgA antibodies, particularly if there's a history of diarrhea or unexplained iron deficiency. Second line testing may also include an alpha 1 antitrypsin phenotype, especially in patients with a history of emphysema out of proportion to their age or smoking history. Third line testing for the evaluation of chronic hepatitis can then be considered if first and second line tests are normal or negative. At this point, exclude muscle disorders and obtain a creatinine kinase or aldolase level. Obtain thyroid function testing. Assess the TSH if hypothyroidism is suspected. Otherwise, obtain a full set of thyroid function tests. And consider the potential for adrenal insufficiency. As muscle disorders, such as myositis or mitochondrial disease of the muscle or endocrinopathies may cause elevation of liver aminotransferases. This next slide depicts an algorithm for the evaluation of chronic mild elevations of AST and ALT. And what I define as mild are elevations that are typically less than 200 international units. If there is persistent elevation of AST and ALT up to 200 international units, obtain a thorough history and physical examination. Have your patient discontinue alcohol and any potential hepatotoxic medications. And then reevaluate, after several weeks, the AST and ALT abnormality. If the AST and ALT are still abnormal, at that point, check liver chemistry, prothrombin time, albumin, complete blood count with platelets, evaluate chronic viral serologies, and an iron profile. Evaluate and treat positive results accordingly. If the viral serologies are negative, then go on to additional testing and obtain an anti-nuclear antibody, an anti-smooth muscle antibody, ceruloplasmin level, alpha-1 antitrypsin level, and tissue transglutaminase level. If such results are negative, consider the evaluation of non-alcoholic fatty liver disease and advise patients on lifestyle modification with the goal of gradual weight loss. Advise them to continue to avoid alcohol use and stop all hepatotoxic medications. And optimize and control diabetes. If such serologic testing is positive, treat those results accordingly. And of course, refer to a specialist if needed in managing either concerns of fatty liver disease or any positive serologic markers that may suggest autoimmune hepatitis, Wilson's disease, alpha-1 antitrypsin, or celiac disease. If managing patients for alcohol or non-alcoholic fatty liver disease, having lended appropriate counseling and guidance, have the patient return for repeat testing in approximately six months to reassess the AST and ALT. If the levels at that point are normal, continue conservative care and observation. However, if the levels remain elevated, consider referral to a specialist for the potential of a liver biopsy, both for diagnosis and staging of hepatic fibrosis in the setting of chronic hepatitis. The next slide depicts a proposed algorithm for elevation of serum ALT and AST when the levels of elevation are greater than 200 international units. Under such circumstances, obtain a history and physical examination and ensure that your patient discontinues alcohol use and any potential hepatotoxic medications. However, if the ALT and AST are elevated at thresholds above 200 international units, consider possible acute liver injury and diagnoses such as acute alcoholic hepatitis, autoimmune hepatitis, hepatitis B reactivation, or the potential of acute onchronic liver injury, such as acetaminophen toxicity in the context of having underlying chronic hepatitis B or hepatitis C. For evaluation of a potential acute or acute onchronic liver injury, obtain liver chemistry, prothrombin time, albumin, and a complete blood count with platelet count. Evaluate acute viral serologies, which would include a hepatitis B RNA, hepatitis B surface antigen, anti-hepatitis B core, hepatitis B antigen, and a hepatitis B viral DNA. Obtain autoimmune serologies and evaluation of liver architecture with an ultrasound. Evaluate and treat any positive results accordingly. Let's review and discuss a few cases. Case one is a 45-year-old Asian man. He's married and an army officer. His mother died of jaundice and liver cancer. He is noted on routine physical examination to have a mildly elevated AST and ALT. He denies any history of known liver disease, jaundice, or ascites. And he's currently not taking any medications with the exception of a daily multivitamin. His laboratory tests demonstrate an ALT of 65 units per liter and an AST of 60 units per liter. Repeat liver enzymes are performed a month later and confirm an ALT of 59 units per liter and an AST of 55 units per liter. So again, mildly elevated. His anti-hepatitis C antibody is negative, and the hepatitis B surface antigen is positive. The platelet count is normal, as are his bilirubin, his INR, and his albumin. Further evaluation of the hepatitis B demonstrates a hepatitis B antibody, which is negative, a hepatitis B antigen, which is positive, and a positive hepatitis B core antibody. The ultrasound of his liver reveals normal echo texture and is not nodular. The alpha-fetoprotein level is normal, and the liver enzymes over the next six months, however, remain elevated. The hepatitis B viral DNA level is persistently elevated at 10 to the fifth international units per mL. The patient has started on tenofovir with normalization of liver aminotransferases. The hepatitis B DNA, six months after initiation of tenofovir, is now undetectable. The patient is maintained on long-term antiviral therapy, and he's followed for many years and remains clinically stable. Case one has some important points to consider. First, in a patient with chronic abnormalities in AST and ALT, chronic hepatitis B could have been suspected because of his Asian ethnicity and the family history, noting that his mother died with liver cancer. Second, the diagnosis of chronic hepatitis B is established by a positive hepatitis B surface antigen and a hepatitis B DNA of greater than 4 to the 10th international units per mL. The patient had no evidence of cirrhosis. He had normal liver synthetic function and a normal appearing liver without any nodularity on imaging studies. And lastly, early identification and treatment with viral suppression will greatly reduce his risk of cirrhosis or liver cancer. Case two is a case of a 43-year-old Caucasian woman who presents with vague right upper quadrant abdominal pain with no other associated gastrointestinal symptoms. The patient works long hours and admits to a poor diet and has a relatively sedentary desk job. Her mother has adult-onset diabetes, and she reports a history of gestational diabetes with her pregnancies. Her past medical history is significant for being overweight with a body mass index of 28 and diet-controlled diabetes, in addition to her history of gestational diabetes. She's currently not on any medication, and she reports rare alcohol consumption of 20 grams once monthly. Laboratory studies demonstrate her AST to be 45 units per liter and ALT 50 units per liter. The glycosylated hemoglobin is mildly elevated at 6.3%. Total cholesterol is 200 milligrams per deciliter. HDL cholesterol, 25 milligrams per deciliter. LDL cholesterol, 110 milligrams per deciliter. Triglycerides, 190 milligrams per deciliter. And she has both a negative hepatitis B surface antigen and a negative hepatitis C antibody. Ultrasound of her liver demonstrates an echoic heterogeneous appearing liver with no nodularity and no evidence of splenomegaly. A comprehensive serologic evaluation of autoimmune liver disease, hemochromatosis, Wilson's disease, celiac disease, and alpha-1 antitrypsin was unrevealing. The patient is counseled on lifestyle modification with routine exercise and a low-calorie, low-carbohydrate diet. She's effective at gradual weight loss and achieves a 10% reduction in her body weight over 12 months. The follow-up AST has decreased to 24 units per liter, and the ALT also decreased to 22 units per liter. She's referred to a nutritionist and is able to maintain long-term weight loss goals. Follow-up ultrasound now demonstrates a normal liver. So there are important points to consider about case 2. First of all, non-alcoholic steatohepatitis, or NASH, is a seronegative chronic hepatitis in patients who do not drink alcohol. NASH is strongly associated with overweight or obese status. The Western diet, a sedentary lifestyle, and features a metabolic syndrome. Patients with a family history of diabetes, or with prediabetes, or diabetes themselves, are at increased risk for NASH. NASH is a diagnosis of exclusion of other causes of chronic liver disease. First-line therapy for NASH includes lifestyle modification and gradual weight loss. So in summary, chronic hepatitis is defined as an increased liver enzymes, the AST, and or the ALT of at least six months duration. Evaluation necessitates a thorough history, physical examination, and a review of social and environmental risks, as well as medication use. A stepwise diagnostic approach, as otherwise dictated by risks, is appropriate in your evaluation of patients with chronic hepatitis. And remember that chronic hepatitis may progress to cirrhosis and its associated complications. Therefore, the presence or absence of cirrhosis should be evaluated in every patient with chronic hepatitis. 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.

chronic hepatocellular injury

cirrhosis

steatohepatitis

viral hepatitis

Fundamentals of Liver Disease