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Home , Acute liver failure, Fatty liver disease

Non-profit Org. U.S. Postage PAID Falls Church, VA Permit #118 Center for Inova Fairfax Hospital 3289 Woodburn Road, Suite 375 Annandale,VA 22003-6800

LIVER UPDATE VOL. 6, NO. 4 / FALL 2005

A PUBLICATION OF THE CENTER FOR LIVER DISEASES AND THE INOVA TRANSPLANT CENTER

Inova Health System is a not-for-profit health care Inside this Issue system based in Northern Virginia that consists of hospitals and other health services including I Acute in the : The U.S. ALF Study emergency and urgent care centers, home care, nursing homes, mental health and blood donor I Non-Alcoholic Fatty Liver : Hepatic Manifestation of services, and wellness classes. Governed by a voluntary board of community members, Inova’s I Faculty Presentations at Meetings mission is to improve the health of the diverse Publications and Research Presentations community we serve through excellence in patient I care, education and research. www.inova.org Liver Update is published by the Save the Date: Friday,April 7, 2006 Center for Liver Diseases 3289 Woodburn Road, Suite 375 I Creating the Next Revolution in Molecular : Annandale,VA 22003-6800 The Application of Translational Research Medical Editor in Clinical Medicine Director, Center for Liver Diseases Zobair M.Younossi,MD, MPH Inova Fairfax Hospital 703-208-6650 Physicians Conference Center Managing Editor Details TBA Denise Tatu 703-321-2912 LIVER UPDATE VOL. 6, NO.4 / FALL 2005

A PUBLICATION OF THE CENTER FOR LIVER DISEASES AND THE INOVA TRANSPLANT CENTER

Acute Liver Failure in the United States: The U.S. ALF Study

William M. Lee, MD DEFINITION: The most widely are not particularly helpful since they do Meredith Mosle Chair in accepted definition of not have prognostic significance distinct Division of Digestive and Liver Diseases includes evidence of from the cause of the illness. For UT Southwestern Medical School abnormality, usually an INR ≥ 1.5, and example, hyperacute cases may have a any degree of mental alteration better prognosis but this is because most cute liver failure (ALF) is a () in a patient without are due to acetaminophen toxicity.5 rare condition in which preexisting and with an illness A rapid deterioration of liver of less than 26 weeks duration. Patients ETIOLOGIES: The most prominent function results in altered with Wilson disease or autoimmune causes include drug-induced liver injury, mentation and in may be included in spite of the , autoimmune liver disease previously normal individuals. United possibility of cirrhosis if their disease has and or hypoperfusion; many cases States estimates are placed at only been recognized for less then 26 (~20%) have no discernible cause.2 approximately 2,000 cases per year.1 weeks.A number of other terms have The most common cause in the U.S. Acute liver failure often affects young been used, including hepatic currently is acetaminophen poisoning persons and carries a high morbidity failure and fulminant hepatitis or which accounts for around 50 percent and mortality. Prior to transplantation, .Acute liver failure is a better of all cases each year.The percentage of most series suggested less than overall term that should encompass all cases annually has increased over the last 15 percent survival. Currently, durations up to 26 weeks.Terms used several years from 28 to 53 percent this overall short-term survival with signifying length of illness such as past year.The reasons for so many cases transplantation is greater than hyperacute (< 7 days), acute (7-21 days) L 65 percent.2 and subacute (> 21 days and <26 weeks) see ALF STUDY page 3 Non-Alcoholic : Hepatic Manifestation of Metabolic Syndrome

Zobair M.Younossi, MD, MPH the prevalence of NAFLD has been patients with NAFLD, those with Director, Center for Liver Diseases estimated to be between 3-23 percent. NASH were more likely to die of liver- at Inova Fairfax Hospital In other parts of the world, prevalence related causes as compared to those with Medical Director, Inova Research Center of NAFLD ranges from 9-37 percent. other types of NAFLD. In cohorts of On the other hand, in obese patients NAFLD patients with paired liver onalcoholic fatty liver undergoing bariatric , the biopsies, about a third of patients disease (NAFLD) represents prevalence of NAFLD ranges from showed progression of over a N a spectrum from simple 72-93 percent and that of NASH from follow-up of two to five years. In the hepatic to non- 12-25 percent. Furthermore, the same period of time, 9 percent alcoholic (NASH), prevalence of NASH from the autopsy progressed to cirrhosis.Additionally,a cirrhosis, and hepatocellular and series has been number of studies have reported an carcinoma. NAFLD is increasingly estimated between 1.2- 6.3 percent. association between cryptogenic being recognized as the hepatic cirrhosis and NAFLD. In one study, manifestation of the metabolic The natural history of NAFLD is still syndrome (MS). In the United States, not entirely clear. In a large cohort of see NAFLD page 2 L L NAFLD, from page 1 There are several factors or second The role of liver biopsy in NAFLD in “hits” that have been proposed, routine clinical practice has not been patients with cryptogenic cirrhosis including from reactive fully established.A liver biopsy can resembled NASH patients in that they species produced in confirm the diagnosis and exclude other were more likely to be female, obese, or mitochondria and by cytochrome P- causes of liver disease.Additionally, a have . Another line of evidence 450 enzymes. resistance and liver biopsy is currently the only providing similar support comes from , especially central obesity, can technique to differentiate between post-transplant follow-up of patients also contribute to the simple steatosis and NASH, a distinction receiving hepatic allografts for injury in NASH via free fatty acids, that has prognostic significance. cryptogenic cirrhosis. Several studies the levels of which are increased in However, a liver biopsy does carry a have demonstrated that recurrence of NASH. Increased levels of free fatty small risk of morbidity and mortality NAFLD occurs in the hepatic allografts acids can lead to increased ROS and is expensive. of these patients.All these studies suggest production through increased that some patients with biopsy proven mitochondrial and peroxisomal FFA A number of serum markers of fibrosis NASH can progress to cirrhosis. oxidation. Cytokines, in particular are being developed to replace liver TNF· as well as adipokines biopsy. However, their use in patients Over the past decade, the pathogenesis (adiponectin, leptin and resistin), have with NAFLD has not been established. of NAFLD has been the subject of been implicated as potential second A reasonable approach to a patient intense research. Central to the “hits”. Despite this interesting data, the suspected of NAFLD in clinical practice pathogenesis of NAFLD is insulin exact contribution of each pathway to is consider a liver biopsy in patients who resistance. Insulin resistance is almost be pathogenesis of NASH remains to evidence of metabolic syndrome and in universally demonstrated in patients with be determined. those who have persistently elevated NAFLD. Because insulin resistance can liver enzymes despite optimal be demonstrated in patients with simple In managing patients with NAFLD, it management of the associated metabolic steatosis as well as those with NASH, is important to establish the diagnosis conditions such as obesity, diabetes, or other events are most likely responsible and to understand the limitations of . Regimens used for for progression to steatohepatitis to the currently available data. Diagnosis treatment of patients with NAFLD are cirrhosis.The above findings have given of NAFLD should be considered in summarized in the table below. rise to the “multi-hit” hypothesis.The any patient who has abnormal liver first “hit” is accumulation in the enzymes, hepatomegaly, or “bright” In summary, NAFLD is a common hepatocyte.This is believed to be due to liver on . It is important to cause of chronic liver disease. Most insulin resistance via increased lipolysis exclude other causes of chronic liver patients with NAFLD have conditions and increased delivery of free fatty acids disease especially associated with the metabolic to the liver. Other abnormalities that and HCV infection, both of which syndrome (i.e., obesity, diabetes, and contribute to fat accumulation include can lead to hepatic steatosis. It is also hyperlipidemia) and NAFLD is now decreased synthesis of apolipoproteins important to remember that liver considered the hepatic manifestation of and microsomal transfer protein gene enzymes are not always a sensitive the metabolic syndrome.Although a polymorphism, both leading to marker for NAFLD as some patients large number of agents have been used decreased export of triglycerides out of with NAFLD and normal liver for treatment of NAFLD, there are the liver. Presence of hepatic steatosis is enzymes can have significant liver currently no proven effective treatments. thought to then set the stage for the disease.While most hepatic imaging Nevertheless, interventions improving development of and liver modalities can detect steatosis, they are insulin resistance are promising and cell injury that is characteristic of unable to distinguish between simple prospective studies are currently NASH. steatosis, NASH or fibrosis. underway.

Treatment Intervention Studies (N) Patients(N) Outcomes

Interventions Targeting Components of the Metabolic Syndrome: Medical 5 3-39 Enzymes Surgical Weight Loss 4 15-104 Enzymes, Lowering Agents 7 3-46 Enzymes Thiazolidinediones 4 10-30 Enzymes, Histology Metformin 2 7-20 Enzymes

Interventions Targeting Oxidative Stress and Cytoprotection: Vitamin E 4 11-49 Enzymes, Histology Other Antioxidants 4 1-169 Enzymes Ursodeoxycholic Acid (UDCA) 5 1-166 Enzymes*

* A recent RCT of UDCA 13-15 mg/kg/d for 48 weeks showed similar efficacy to placebo.

2 L ALF STUDY, from page 1 Faculty Presentations at International Meetings Gene Expression of Adipokines in the Adipose of Obese Patients with Insulin occurring remain unclear. In a series I Resistance and NAFLD: 7th International Conference on Cytokines and Chemokines. of 275 patients with ALF due to World Congress of , Montreal, CA. 2005 acetaminophen liver injury,3 unintentional overdoses accounted for I Natural History of Non-alcoholic Steatohepatitis. American College of Gastroenterology. 131 (48 percent) cases, intentional Honolulu, HI. 2005 ( attempts) 122 (44 percent), and 22 (8 percent) were of unknown intent. In the unintentional group, Publications and Presentations 38 percent took two or more Z Younossi, F Gorreta, J Ong M, K Schlauch, L Del Giacco, H Elariny, A Younoszai, acetaminophen preparations I Z Goodman, A Christensen, V Chandhoke, G Grant. Hepatic Gene Expression in simultaneously and 63 percent used Patients with NASH. Liver International 25(4):760-71, 2005 narcotic-containing compounds. Overall, 178 subjects (65 percent) I Baranova A, R Collantes, SJ. Gowder, H Elariny, K Schlauch, A Younoszai, S King, M survived, 74 (27 percent) died without Randhawa, S Pusulury, T Alsheddi, JP. Ong, LM. Martin, V Chandhoke, ZM. Younossi, MD. surgery and 23 subjects (8 percent) Obesity-related Differential Gene Expression in the Visceral . Obes Surg. underwent ; 15(6):758-65, 2005 71 percent were alive at three weeks. J Ong, R Collantes, A Pitts, L Martin, M Sheridan, Z Younossi. High Rates of Uninsured Susceptible acetaminophen patients I Among Positive Patients. Clin Gastroenterol 39(9):826-830, 2005 have concomitant depression, chronic pain, or narcotic use I Z Younossi, T Born, F Gorreta, J Ong M, K Schlauch, L Del Giacco, H Elariny, A Younoszai, and/or take several preparations Z Goodman, A Christensen, V Chandhoke, G Grant. Genomics and Proteomics of simultaneously. Further education of Obesity-Related Non-Alcoholic Fatty Liver Disease. 42(3):665-74, 2005 patients, physicians and pharmacies might help to limit these unfortunate cases.4 Clinical Trials Clinical research protocols for patients with Non-Alcoholic Fatty Liver Disease and THERAPY: All patients with clinical I obesity including a combination regimen for NASH patients after or laboratory evidence of moderate to severe acute hepatitis should have I Clinical research protocols for treatment of Hepatitis C including combination of new immediate measurement of regimens using novel oral protease inhibitors and careful Clinical research protocols for treatment of including the use of novel oral evaluation for subtle alterations in I nucleotide analogues mentation. If the prothrombin time is prolonged by ~4-6 seconds or more (INR ≥ 1.5) and there is any evidence of altered sensorium, the diagnosis of OUTCOMES: Even in the modern era (~65% survival without transplantation) and ALF is established and hospital of transplantation, nearly one-third of those with idiosyncratic drug reactions, admission is mandatory. Since the patients succumb to ALF.The cause of hepatitis B or indeterminate cause have poor condition may progress rapidly, with death is frequently infection, renal failure outcomes (~20% spontaneous survival). changes in consciousness occurring or , a unique hour-by-hour, early transfer to the pathophysiology associated solely with 1. Hoofnagle JH, Carithers RL, Sapiro C,Ascher N. is preferred once ALF.Because of its rarity,ALF has been Fulminant Hepatic Failure: Summary of a difficult to study in depth and very few Workshop. Hepatology 1995; 21:240-252. the diagnosis of acute liver failure is 2. Ostapowicz GA, Fontana RJ, Schiodt FV et al. made.Antidotes are given if controlled therapy trials have been Results of a Prospective Study of Acute Liver Failure acetaminophen poisoning is suspected performed.As a result, standards of at 17 Tertiary Care Centers in the United States. and for . intensive care for this condition have not Ann Intern Med 2002; 137:947-954. Pregnancy-related liver disease is been established.5 There are no accepted 3. Larson AM, Fontana RJ, Davern TJ, Polson J, Lalani treatments for the overall condition. E, et al.Acetaminophen-Induced Acute Liver managed with delivery of the fetus. If Failure: Results of a United States Multi-Center, transplantation is an option, then any Centers vary as to whether lactulose, Prospective Study. Hepatology 2005, In press. patient with encephalopathy should be prophylactic or intracranial 4. Lee WM. Sounding Board:Acetaminophen considered for transfer to a transplant pressure monitors are used. Success in and the U.S.Acute Liver Failure center.Those in a transplant center are predicting outcomes has been limited. Study: Lowering the Risks of Hepatic Failure. Etiology is one of the best guides, with Hepatology 2004; 40:6-9. usually listed for transplantation when 5. Polson J, Lee WM.Acute Liver Failure.AASLC grade 2 is reached. Patients often those with acetaminophen, Position Paper:The Management of Acute Liver deteriorate rapidly. or shock having good outcomes Failure. Hepatology Vol.41 (No.5):1179-1197;2005.

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