Patologia sistematica V Gastroenterologia Prof. Stefano Fiorucci. Approach to patient with liver disease Alcoholic liver disease NAFLD & NASH

Transcription

1 Patologia sistematica V Gastroenterologia Prof. Stefano Fiorucci Approach to patient with liver disease Alcoholic liver disease NAFLD & NASH Harrison s Principles of Internal Medicine 18 Ed. 2012

2 Liver anatomy

3 Hepatic lobules by Coinaud

4 Liver functional anatomy

5 Portal vein anatomy and pathology

6 Hepatic artery

7 Hepatic veins

8 Liver cirrhosis causes portal hypertension Ascites

9 Biliary system

10 Liver histology Chronic liver disorders can be discriminated by liver biopsy Viral B and C Autoimmune hepatitis Genetic Drugs-induced hepatitis NASH Alcohol

11 Liver fibrosis Liver fibrosis a pathological state that occurs in crhonic liver disorders and is associated with increased risk of progression toward liver cirrhosis. Liver fibrosis is caused by activation of hepatic stellate cells (or Ito cells) and mesenchymal cells in repsonse to liver injury.

12 Sources of fibrogenic cell types in hepatic fibrosis Friedman, S. L. (2010) Evolving challenges in hepatic fibrosis Nat. Rev. Gastroenterol. Hepatol. doi: /nrgastro

13 Liver fibrosis Assessment of liver fibrosis could be obtained by: - Biochemistry (fibro test) - Transient elastography - MR - Liver biopsy

14 Transient elastography

15 Liver biochemistry Enzymes that detect liver fibrosis Fibro test or others The test incorporate : Haptoglobin, bilirubin, γgt, apolipoprotein A1 and α2 -macroglobulin

16 Liver biochemistry Test that indicate damage to hepatocytes Aspartate aminotransferase (AST), formerly called SGOT. The AST enzyme is also found in muscles and many other tissues besides the liver. NV <40UI/L Alanine aminotransferase (ALT), formerly called SGPT. ALT is almost exclusively found in the liver. NV < 40UI/L AST/ALT >1000 UI/L occurs in extensive acute liver injury AST/ALT a ratio of 2-4 folds of normal occurs in chronic hepatitis AST:ALT ratio 2:1 is suggestive of alcoholic liver disease

17 Liver biochemistry Tests that indicate a reduced liver mass (reduced biosynthetic activity) Prothrombin time (PT): A test of the time it takes for a blood sample to clot, under specific conditions in a lab. If low levels of clotting factors are present, the prothrombin time is longer. NV % International normalized ratio (INR): a standardized way for all labs to report PT, so their results can be compared accurately with each other. >1.3 Serum Albumin levels are low in severe chronic liver diseases, because reduced protein synthesis. NV >3.5 g/l Bilirubin(see below)

18 Liver biochemistry Test reflecting detoxification and excretion Bilirubin Indirect or unconjugated bilirubin mg/dl Direct bilirubin or conjugated mg/dl Total bilirubin <1.2 mg/dl Jaundice may be noticeable in mucosas at levels of 2 to 3 mg/dl and in the skin at higher levels. Urine urobilinogen (see below)

19 Liver biochemistry Test reflecting detoxification and excretion Ammonia is produced in the body during normal protein metabolism and by colon bacteria and recycled in the liver to generate urea. Increased blood levels of ammonia associates to hepatic encelophathy

20 Liver biochemistry Enzymes that reflect cholestasis Alkaline phosphatase NV < UI/L Gamma-glutamyl transpeptidase (γgt) NV<50UI/L Bilirubin (also indicates reduced detoxification ability) Urine bilirubin (dark urine) urobilinogen 1-3 mg/dl

21 Cirrosis:classification scores

22 Cirrhosis:classification scores

23 Jaundice Jaundice (icterus) is a yellowish discoloration of the skin and other membranes including sclerae and mucus membrane caused by hyperbilirubinemia. Hyperbilirubinamia is a sign of liver diseases or less frequently of a hemolytic disorder Harrison s Principles of internal medicine. 18 ed Ch42

24 Bilirubin metabolism

25 Bilirubin metabolism Hepatocellular bilirubin transport. Albumin-bound bilirubin in sinusoidal blood passes through endothelial cell fenestrae to reach the hepatocyte surface, entering the cell by both facilitated and simple diffusional processes. Within the cell it is bound to glutathione-s-transferases and conjugated by bilirubin-udpglucuronosyltransferase (UGT1A1) to mono- and diglucuronides, which are actively transported across the canalicular membrane into the bile. ALB, albumin; UCB, unconjugated bilirubin, UGT1A1, bilirubin-udp-glucuronosyltransferase; BMG, bilirubin monoglucuronide; GST, glutathione-s-transferase; MRP2, multidrug resistance associated protein 2; BDG, bilirubin diglucuronide; BT, proposed bilirubin transporter.

26 Jaundice Approach to the Patient: Bilirubin The bilirubin present in serum represents a balance between input from production of bilirubin and hepatic/biliary removal of the pigment. Hyperbilirubinemia may result from (1) overproduction of bilirubin; (2) impaired uptake, conjugation, or excretion of bilirubin; (3) regurgitation of unconjugated or conjugated bilirubin from damaged hepatocytes or bile ducts.

27 Approach to the Patient: Bilirubin Jaundice An increase in unconjugated bilirubin in serum results from either overproduction, impairment of uptake, or conjugation of bilirubin. An increase in conjugated bilirubin is due to decreased excretion into the bile ductules or backward leakage of the pigment.

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29 Fatty liver diseases

30 Fatty liver diseases: Terminology ALD: Alcoholic Liver Disease Significant alcohol consumption* > 40 g/10 years for males > 20 gr/ 10 years for females NAFLD: Non-Alcoholic Fatty Liver Disease steatosis without hepatocyte injury NASH: Non-Alcoholic Steatohepatitis steatosis with inflammation, hepatocyte injury with or without fibrosis *Sanyal, et al Hepatology 2011

31 Alcoholic liver disease (ALD) Chronic and excessive alcohol ingestion is one of the major causes of liver disease. The pathology of alcoholic liver disease comprises two major lesions, with the injury rarely existing in a pure form: (1) fatty liver (steatosis and steatohepatitis) (2) cirrhosis.

32 Alcoholic liver disease (ALD)

33 Alcoholic liver disease natural history Fatty liver is present in >90% of binge and chronic drinkers. A much smaller percentage of heavy drinkers will progress to alcoholic hepatitis, thought to be a precursor to cirrhosis. The prognosis of severe alcoholic liver disease is dismal; the mortality of patients with alcoholic hepatitis concurrent with cirrhosis is nearly 60% at 4 years. Although alcohol is considered a direct hepatotoxin, only between 10 and 20% of alcoholics will develop alcoholic hepatitis (comorbid factors such as gender, heredity and immunity)

34 Alcoholic liver disease natural history Risk threshold of alcohol consumption for liver cirrhosis An important aspect of public health policy concerning alcohol has been the attempt to establish a safe threshold for consumption. This revolves primarily around the extent to which moderate alcohol consumption is cardioprotective. This positive effect of alcohol, if real, can then offset the large array of negative health consequences of even moderate alcohol consumption. In a meta-analysis of daily consumption levels in relation to cirrhosis, patients taking 25 g of ethanol a day were at higher risk of cirrhosis than non-drinkers. A recent meta-analysis found increased risks of mortality from liver cirrhosis among men and women drinking g of ethanol per day. Indeed, among women, a significant increase was also seen for those drinking up to 12 g/day. These levels of consumption (<25 g/day) are appreciably lower than most public health recommendations for overall safe levels of consumption. The human evidence to date therefore suggests that if a threshold exists, it is very low, and may in fact be difficult to detect because of limitations in measuring consumption below g per day.

35 Alcoholic liver disease Etiology and Pathogenesis Quantity and duration of alcohol intake are the most important risk factors involved in the development of alcoholic liver disease The roles of beverage type(s), i.e. wine, beer, or spirits, and pattern of drinking are less clear. Progress of the hepatic injury beyond the fatty liver stage seems to require additional risk factors that remain incompletely defined. Women are more susceptible to alcoholic liver injury when compared to men. They develop advanced liver disease with substantially less alcohol intake.

36 Alcoholic liver disease-pathogenesis Alcohol is a direct hepatotoxin, but ingestion of alcohol initiates a variety of metabolic responses that influence the final hepatotoxic response. The hepatic metabolism of alcohol initiates a pathogenic process involving production of toxic protein-aldehyde adducts, endotoxins, oxidative stress, immunologic activity, and pro-inflammatory cytokine release.

37 Alcohol related diseases

38 Alcohol oxidation to acetaldehyde may occur through cytosolic alcohol dehydrogenase (ADH), cytochrome P-450 2E1, or peroxisomal catalase (in that order of importance) by American Physiological Society

39 Alcohol oxidation to acetaldehyde may occur through cytosolic alcohol dehydrogenase (ADH), cytochrome P-450 2E1, or peroxisomal catalase (in that order of importance). Patricia E. Molina Am J Physiol Endocrinol Metab 2008;295:E1-E by American Physiological Society

40 Alcoholic liver disease-pathogenesis The complex interaction of intestinal and hepatic cells is crucial to alcohol-mediated liver injury. Tumor necrosis factor (TNF-α) and intestine-derived endotoxemia facilitate hepatocyte apoptosis and necrosis. Stellate cell activation and collagen production are key events in hepatic fibrogenesis. The resulting fibrosis determines the architectural derangement of the liver following chronic alcohol ingestion.

41 Alcoholic liver disease-risk factors Risk Factor Quantity Comment In men, >25 g/d of ethanol produces fatty liver; 160 g/d for years causes hepatitis or cirrhosis. Only 15% of alcoholics develop alcoholic liver disease. Gender Women exhibit increased susceptibility to alcoholic liver disease at amounts g/d; two drinks per day probably safe. Hepatitis C Genetics Malnutrition HCV infection concurrent with alcoholic liver disease is associated with younger age for severity, more advanced histology, decreased survival. Gene polymorphisms may include alcohol dehydrogenase, cytochrome P4502E1, and those associated with alcoholism (twin studies). Alcohol injury does not require malnutrition, but obesity and fatty liver from the effect of carbohydrate on the transcriptional control of lipid synthesis and transport may be factors. Patients should receive vigorous attention to nutritional support.

42 Alcoholic liver disease and HCV infection Chronic infection with hepatitis C (HCV) is an important comorbidity in the progression of alcoholic liver disease to cirrhosis in chronic and excessive drinkers. Even moderate alcohol intake of g/d increases the risk of cirrhosis and hepatocellular cancer in HCV-infected individuals. Patients with both alcoholic liver injury and HCV infection develop decompensated liver disease at a younger age and have poorer overall survival. Increased liver iron stores can occur as a consequence of the overlapping injurious processes secondary to alcohol abuse and HCV infection. In addition, alcohol intake of >50 g/d by HCV-infected patients decreases the efficacy of interferon-based antiviral therapy.

43 Alcoholic liver disease- histopathology Fatty liver is the initial and most common histologic response to hepatotoxic stimuli, including excessive alcohol ingestion. The accumulation of fat within the perivenular hepatocytes coincides with the location of alcohol dehydrogenase, the major enzyme responsible for alcohol metabolism. Continuing alcohol ingestion results in fat accumulation throughout the entire hepatic lobule. Despite extensive fatty change and distortion of the hepatocytes with macrovesicular fat, the cessation of drinking results in normalization of hepatic architecture and fat content within the liver. Alcoholic fatty liver has traditionally been regarded as entirely benign, but similar to the spectrum of nonalcoholic fatty liver disease the appearance of steatohepatitis and certain pathologic features such as giant mitochondria, perivenular fibrosis, and macrovesicular fat may be associated with progressive liver injury.

44 Alcoholic liver disease-histopathology progression The transition between fatty liver and the development of alcoholic hepatitis is blurred. The hallmark of alcoholic hepatitis is hepatocyte injury characterized by ballooning degeneration, spotty necrosis, polymorphonuclear infiltrate, and fibrosis in the perivenular and perisinusoidal space of Disse. Mallory bodies are often present in florid cases but are neither specific nor necessary to establishing the diagnosis. Alcoholic hepatitis is thought to be a precursor to the development of cirrhosis. However, like fatty liver, it is potentially reversible with cessation of drinking. Cirrhosis is present in up to 50% of patients with biopsy-proven alcoholic hepatitis and its regression is uncertain, even with abstention

45 Alcoholic liver disease Clinical presentation

46 Alcoholic liver disease Clinical Features The clinical manifestations of alcoholic fatty liver are subtle and characteristically detected as a consequence of the patient's visit for a seemingly unrelated matter. Previously unsuspected hepatomegaly is often the only clinical finding. Occasionally, patients with fatty liver will present with right upper quadrant discomfort, tender hepatomegaly, nausea, and jaundice. Differentiation of alcoholic fatty liver from nonalcoholic fatty liver is difficult unless an accurate drinking history is ascertained.

47 Alcoholic liver disease Clinical Features Most patients with moderate forms of ALD are asymptomatic and it can only be detected by appropriate screening methods. Some patients can show signs suggestive of harmful alcohol drinking such as bilateral parotid gland hypertrophy, muscle wasting, malnutrition, Dupuytren's sign, and signs of symmetric peripheral neuropathy. In patients with cirrhosis, most physical findings are not specific of the etiology. However, some signs such gynecomastia and extensive spider angiomas may be more frequently seen in those with alcohol as the main cause of liver disease.

48 Alcoholic liver diseases On physical examination, the liver and spleen may be enlarged, with the liver edge being firm and nodular. Other frequent findings include scleral icterus, palmar erythema & spider angiomas parotid gland enlargement, digital clubbing, muscle wasting, or the development of edema and ascites. Men may have decreased body hair and gynecomastia Testicular atrophy, which may be a consequence of hormonal abnormalities or a direct toxic effect of alcohol on the testes. In women with advanced alcoholic cirrhosis, menstrual irregularities usually occur, and some women may be amenorrheic. These changes are often reversible following cessation of alcohol 48

49 Alcoholic liver disease Laboratory Features Patients with alcoholic liver disease are often identified through routine screening tests. The typical laboratory abnormalities seen in fatty liver are nonspecific and include: 1. modest elevations of the aspartate aminotransferase (AST), alanine aminotransferase (ALT), 2. glutamyl transpeptidase (γgt), 3. Increased MCV 4. aaccompanied by hypertriglyceridemia, hypercholesterolemia, and occasionally hyperbilirubinemia. In alcoholic hepatitis and in contrast to other causes of fatty liver, the AST and ALT are usually elevated two- to sevenfold. They are rarely >400 IU, and the AST/ALT ratio >1

50 Alcoholic liver disease Laboratory Features Test AST Comment Increased two- to sevenfold, <400 U/L, greater than ALT ALT AST/ALT (GT/GPT) γgt MCV Increased two- to sevenfold, <400 U/L Usually 2:1 As the measurement of GGT is easy and inexpensive, it remains the most frequently used marker for early detection of chronic alcohol misuse. GGT is usually higher in ALD patients compared with those who have other liver diseases. Serum GGT activity loses its specificity for alcohol in more advanced liver disease. Serum GGT activity is influenced not only by the amount of alcohol consumed but also by body mass index (BMI) and sex >95 uc3

51 Alcoholic liver disease Laboratory Features Serum markers of liver fibrosis Aspartate aminotransferase (AST) to platelet ratio index (APRI) has been evaluated in heavy drinkers. FibroTest is a serum biomarker of fibrosis combining alpha-2- macroglobulin, haptoglobin, GGT, ApoA1, and bilirubin, corrected for age and sex. FibrometerA, combining PT, alpha-2-macroglobulin, hyaluronic acid, and age has similar diagnostic accuracy in ALD. Hepascore combines bilirubin, GGT, hyaluronic acid, alpha-2- macroglobulin, age, and sex.

52 Alcoholic liver disease Liver fibrosis Liver stiffness measurement (LSM) has been demonstrated to be a reliable tool for assessing hepatic fibrosis in patients with ALD In patients with ALD, liver stiffness correlates with the degree of fibrosis. Several studies have shown that patients with alcoholic cirrhosis had significantly higher values of liver stiffness than patients with viral cirrhosis, suggesting that the etiology may strongly affect the amount of fibrosis at the same stage. A recent study indicated that coexisting ASH markedly increases LSM in patients with ALD independent of fibrosis stage

53 Alcoholic liver disease Ultrasonography is useful in detecting fatty infiltration of the liver and determining liver size. The demonstration by ultrasound of portal vein flow reversal, ascites, and intraabdominal collaterals indicates serious liver injury with less potential for complete reversal of liver disease. In clinical practice, ultrasonography should be proposed to heavy drinkers as a screening procedure for steatosis. Ultrasonography can also be useful in detecting signs of advanced stages of ALD such as liver cirrhosis, portal-systemic collaterals and splenomegaly

54 Alcoholic hepatitis Alcoholic hepatitis (alcoholic steatohepatitis) Alcoholic hepatitis is a clinical syndrome, i.e. recent onset of jaundice and/or ascites in a patient with ongoing alcohol misuse. Historically, it was referred to as acute alcoholic hepatitis. Although the clinical presentation may present abruptly, the term acute is not recommended, since it is an exacerbation of an underlying chronic liver disease and usually follows an extended course.

55 Alcoholic hepatitis Prognosis Critically ill patients with alcoholic hepatitis have short-term (30 day) mortality rates >50%. Severe alcoholic hepatitis is heralded by coagulopathy (prothrombin time > 5 s), anemia, serum albumin concentrations <25 g/l (2.5 mg/dl), serum bilirubin levels > 137 mol/l (8 mg/dl), renal failure, and ascites. A discriminant function calculated as 4.6 x [prothrombin time control (seconds)] + serum bilirubin (mg/dl) can identify patients with a poor prognosis (discriminant function > 32). The presence of ascites, variceal hemorrhage, deep encephalopathy, or hepatorenal syndrome predicts a dismal prognosis. The pathologic stage of the injury can be helpful in predicting prognosis. Liver biopsy should be performed whenever possible to confirm the diagnosis, to establish potential reversibility of the liver disease, and to guide the therapeutic decisions.

56 Alcoholic hepatitis Predicting the evolution Why is a prognostic score important? 1. Patients with mild disease improve spontaneously upon cessation of alcohol 2. Patients with severe disease need a semiintensive-intensive care 3. Patients with severe disease might benefit from initiation of specific therapy

57 Alcoholic hepatitis

58 Alcoholic hepatitis Lille model Day 0: presence of encephalopaty + mdf (PT-PT control) + bilirubin Day 7: Bilirubin A value >0.5 predict 80% mortality whitin 6 months

59 Alcoholic liver disease Treatment (1) Regardless of the severity, abstinence is the cornerstone of therapy and early management of alcohol abuse or dependence is warranted in all patients with ASH. Malnutrition is frequent and nutrition status should be evaluated. Considering the potential risk of Wernicke's encephalopathy, supplementation with B-complex vitamins is recommended. Independent from hepatic encephalopathy, a daily protein intake of 1.5 g/kg of body weight should be ensured. Liposoluble vitamins (A,D,E K) deficiency should be compensated.

60 Alcoholic liver disease Treatment (2) Patients with symptomatic forms of ASH often develop acute renal failure which negatively impacts survival. The most frequent causes of acute renal failure are Type 1 hepatorenal syndrome. Severe forms of ASH should be considered as a risk factor of radiocontrast-induced nephropathy. Measures aimed at preventing the development of renal failure are recommended. They include volume expansion if needed and early treatment of hepatorenal syndrome. Infections are frequent and difficult to diagnose in these patients since SIRS criteria is common at admission and could reflect either the inflammatory state associated with the ASH episode or an ongoing bacterial infection.

61 Alcoholic hepatitis Treatment (3) Patients with severe alcoholic hepatitis, 40 mg/d, or prednisolone, for 4 weeks followed by a steroid taper. Exclusion criteria included active gastrointestinal bleeding, sepsis, renal failure, or pancreatitis. Women with encephalopathy from severe alcoholic hepatitis may be particularly good candidates for glucocorticoids. TNF inhibition as an alternative to glucocorticoids for severe alcoholic hepatitis. The nonspecific TNF inhibitor, pentoxifylline, recently demonstrated improved survival in the therapy of severe alcoholic hepatitis

62 Alcoholic hepatitis Treatment (4) Most studies indicate that only a limited proportion of patients with severe forms of ASH benefit from corticosteroids. Thus, early identification of non-responders to corticosteroids is important to define stopping rules and limit unnecessary exposure. For example, after 7 days on corticosteroids, a Lille score above 0.45 predicts poor response. In poor responders, the interruption of corticosteroids is recommended particularly in those classified as null responders (Lille score >0.56). In poor responders, an early switch to pentoxifylline or the use of a molecular adsorbent recirculating system (MARS) appears not to modify the outcome. In these patients, early liver transplantation may be considered after a careful selection process.

63 Alcoholic hepatitis Treatment (4) Liver transplantation (1) The conviction that alcoholism is self-inflicted must be reconciled with the strong evidence supporting genetic and environmental influences on alcohol dependence diagnosed by the DSM-IV diagnostic system. Graft and patient survival rates among alcoholics after LT are similar to those seen after transplantation for other aetiologies of liver disease. A significant increase in the proportion of patients transplanted for alcoholic liver disease was observed between the periods and in Europe

64 Alcoholic hepatitis Treatment (5) Liver transplantation (2) The classical opinion of European and North American experts considering ASH as a contraindication for transplantation has been recently challenged by a case controlled study showing an unequivocal improvement of survival in patients who received early transplantation. These results support future evaluation of LT in carefully-selected patients with severe AH who do not respond to medical therapy. However, early LT is relevant only in a very small minority of patients.

65 Alcoholic hepatitis Treatment (5) Liver transplantation (3) In Child Pugh stage B alcoholic cirrhosis, immediate listing for LT did not show a survival benefit compared with standard care. In most centers, the MELD score is mainly used to prioritize patients awaiting LT. Previous studies have failed to demonstrate that other clinical manifestations of liver decompensation, such as variceal hemorrhage, hepatic encephalopathy, new onset ascites or spontaneous bacterial peritonitis, were independent predictors of survival over and above the MELD score. Nonetheless, the onset of any of these features in an abstinent alcoholic should prompt the managing physician to consider referral to a transplant center.

66 Algorithm for the treatment of alcoholic liver disease (EASL 2016)

67 Alcoholic liver cirrhosis Excessive chronic alcohol use can cause several different types of chronic liver disease, including alcoholic fatty liver, alcoholic hepatitis and alcoholic cirrhosis. Furthermore, use of excessive alcohol can contributes to liver damage in patients with other liver diseases, such as hepatitis C, hemochromatosis, and fatty liver disease related to metabolic syndrome. 67

68 Alcoholic liver cirrhosis Chronic alcohol use can produce fibrosis in the absence of accompanying inflammation and/or necrosis. Fibrosis can be centrilobular, pericellular, or periportal. 68

69 Alcoholic liver cirrhosis When fibrosis reaches a certain degree, there is disruption of the normal liver architecture and replacement of liver cells by regenerative nodules. In alcoholic cirrhosis, the nodules are usually <3 mm in diameter; this form of cirrhosis is referred to as micronodular. With cessation of alcohol use, larger nodules may form, resulting in a mixed micronodular and macronodular cirrhosis 69

70 Alcoholic liver cirrhosis Clinical Features The diagnosis of alcoholic liver disease requires an accurate history regarding both amount and duration of alcohol consumption. Patients with alcoholic liver disease can present with nonspecific symptoms such as vague right upper quadrant abdominal pain, fever, nausea and vomiting, diarrhea, anorexia, and malaise. Alternatively, they may present with more specific complications of chronic liver disease, including ascites, edema, or upper gastrointestinal (GI) hemorrhage or jaundice or encephalopathy. The abrupt onset of any of these complications may be the first event prompting the patient to seek medical attention. Other patients may be identified in the course of an evaluation of routine laboratory studies that are found to be abnormal. 70

71 Alcoholic liver cirrhosis On physical examination, the liver and spleen may be enlarged, with the liver edge being firm and nodular. Other frequent findings include scleral icterus, palmar erythema & spider angiomas parotid gland enlargement, digital clubbing, muscle wasting, or the development of edema and ascites. Men may have decreased body hair and gynecomastia Testicular atrophy, which may be a consequence of hormonal abnormalities or a direct toxic effect of alcohol on the testes. In women with advanced alcoholic cirrhosis, menstrual irregularities usually occur, and some women may be amenorrheic. These changes are often reversible following cessation of alcohol 71

72 Alcoholic liver cirrhosis The diagnosis, however, requires accurate knowledge that the patient is continuing to use and abuse alcohol. Liver biopsy can be helpful to confirm a diagnosis, but generally when patients present with alcoholic hepatitis and are still drinking, liver biopsy is withheld until abstinence has been maintained for at least 6 months to determine residual, nonreversible disease. In patients who have had complications of cirrhosis and who continue to drink, there is a <50% 5-year survival. In contrast, in patients who are able to remain abstinent, the prognosis is significantly improved. In patients with advanced liver disease, the prognosis remains poor. However, in individuals who are able to remain abstinent, liver transplantation is a viable option. 72

73 Alcoholic liver cirrhosis The cornerstone to treatment is cessation of alcohol use. Complete abstinence from alcohol is the cornerstone in the treatment of alcoholic liver disease. Improved survival and the potential for reversal of histologic injury regardless of the initial clinical presentation are associated with total avoidance of alcohol ingestion. Referral of patients to experienced alcohol counselors and/or alcohol treatment programs should be routine in the management of patients with alcoholic liver disease. Attention should be directed to the nutritional and psychosocial states during the evaluation and treatment periods. 73

74 Proposed algorithm for the treatment of alcoholic hepatitis Altamirano, J. & Bataller, R. (2011) Alcoholic liver disease: pathogenesis and new targets for therapy Nat. Rev. Gastroenterol. Hepatol. doi: /nrgastro

75 Fatty liver

76 Fatty liver: Terminology ALD: Alcoholic Liver Disease Significant alcohol consumption* NAFLD: Non-Alcoholic Fatty Liver Disease steatosis without hepatocyte injury NASH: Non-Alcoholic Steatohepatitis steatosis with inflammation, hepatocyte injury with or without fibrosis *Sanyal, et al Hepatology 2011

77 *<25 gr/day male; <15 gr/day female Non-Alcoholic Fatty Liver Disease Histopathology Alcohol-like liver disease in individuals who do not consume excessive alcohol* Histologic spectrum of liver damage NAFLD - fatty liver (steatosis) NASH fatty liver + increased hepatocyte death (steatohepatitis) Cirrhosis regenerative nodules + fibrosis

78 Few symptoms / signs of liver disease NAFLD Benign course? <10% evolves into cirrhosis Risk factor for cirrhosis in HCV & ALD Decreases efficacy of HCV anti-viral therapy NASH

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80 Fatty liver disease: epidemiology Alcoholic liver disease million people abuse/overuse ETOH in EU 90% of those will develop fatty livers Moderate use with another risk factor Non-alcoholic liver disease Second common chronic liver disease in Europe (First USA) 4 th most common reason for liver transplant Projected to be the most common in yrs

81 NAFLD and NASH prevalence in the near future

82 Male gender, Age, Obesity, NAFLD epidemiology Risk factors for NAFLD insulin resistance and the cardiometabolic alterations that define the metabolic syndrome. Prevalence in the general population is 10-12% The prevalence of NAFLD is 80-90% in obese adults, 30-50% in patients with diabetes and up to 90% in patients with hyperlipidemia. The prevalence of NAFLD among children is 3-10%, rising up to 40-70% among obese children. Moreover, pediatric NAFLD increased from about 3% a decade ago to 5% today, with a male-to-female ratio of 2:1.

83 Diagnostic criteria for metabolic syndrome Parameter Impaired glucose tolerance High blood pressure Elevated triglyceride levels Low high-density lipoprotein level Abdominal obesity Waist: Value Fasting blood glucose level 110 mg/dl 130/85 mm Hg >250 mg/dl <40 mg/dl for men; <50 mg/dl for women >102 cm for men; >88 cm for women *Metabolic syndrome is diagnosed by the presence of 2 or more of these parameters.

84 Risk factors

85 NAFLD: risk factors for progression Middle age Female gender Over-weight or obese Viral hepatitis Iron overload Drugs Rapid weight loss Starvation/refeeding syndrome Reye s syndrome Auto-immune disease Malnutrition Abetalipoproteinemia Overgrowth of bacteria in small intestines TPN Acute fatty liver of pregnancy Hereditary

86 Risk factor: drugs Estrogens Tamoxifen Valproic acid Methotrexate Isoniazide Corticosteroids Vitamin A l-asparaginase Amiodarone Calcium channel blockers Nucleoside analogues HAART (Anti-retroviral therapy)

87 NASH Risk factors: Established association Obesity Type 2 DM Dyslipidemia Metabolic syndrome

88 Risk factors: Emerging association Polycystic ovary syndrome Hypothyroidism Obstructive sleep apnea Hypopituitarism and Hypogonadism Pancreatic-duodenal resection

89 NAFLD-NASH: two hits model Obesity Diabetes Overweight FATTY liver NASH FIBROSIS Cirrhosis Intestinal microbiota Adipose tissue SECOND HIT

90 NAFLD-NASH diagnosis Incidental finding on imaging for some other reason Abnormal liver enzymes Symptoms of liver disease (rule out other causes: alcohol, medications, viral hepatitis, etc.)

91 Fatty liver : Clinical evaluation Symptoms Malaise, fatigue, upper right adbomen discomfort Snores, disturbed sleep, nocturnal apnea Physical exam Abdominal obesity Enlarged liver RUQ tenderness on palpation Labs Consistent with metabolic syndrome Elevated bilirubin, AST, ALT, AP, GGT Diagnostic images - US (bright liver grade I-IV)

92 Clinical & laboratory Factor predicting NASH Age > 50 Diabetes Obesity AST/ALT >1 ALT >2 times normal TG & CHO elevated

93 NASH Risk factors: Established association Obesity Type 2 DM Dyslipidemia Metabolic syndrome

94 Clinical staging Staging liver fibrosis

95 NAFLD/NASH fibrosis score* 1. NAFLD typically develops based on various metabolic disorders such as obesity, diabetes mellitus, and dyslipidemia; 2. the prognosis and outcome of the patients with advanced liver fibrosis are predominantly determined by the liver disease-related clinical events, including hepatic failure and hepatocellular carcinoma. 3. Therefore, physicians are required to accurately differentiate NASH from NAFLD and evaluate the severity of liver fibrosis in order to determine the prognosis and optimal treatment. Age BMI Hyperglycemia Platelet count Albumin AST ALT < : predictor of absence of significant fibrosis (F0-F2 fibrosis) to 0.675: indeterminate score > 0.675: predictor of presence of significant fibrosis (F3-F4 fibrosis) *Angulo P, Hui JM, Marchesini G, Bugianesi E, George J, Farrell GC, Enders F, Saksena S, Burt AD, Bida JP. The NAFLD fibrosis score: a noninvasive system that identifies liver fibrosis in patients with NAFLD. Hepatology. 2007;45:

96 NAFLD/NASH and fibrosis evaluation Elastography

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99 Lifestyle Interventions Weight loss by lower caloric intake and increased physical exercise led to improvement in biopsy. 9.3% weight loss: improvement in steatosis, necrosis, and inflammation; not fibrosis 3-5% weight loss improves steatosis but more is needed to improve inflammation Alcohol consumption: heavy intake should be avoided light intake (<1/day) may have benefits**, may not***

100 Insulin sensitizing agents Metformin reduction in IR and enzymes, no improvement in histology Thiazolidinediones Pioglitazone causes weight gain, but improvement in hepatocellular injury Pioglitazone can be used to treat certain patients with biopsy-proven NASH who do not have DM but long term safety and efficacy has not been established

101 Forest plots of improvement in histological variables are shown. (A) Steatosis; (B) inflammation; (C) hepatocellular ballooning and (D) fibrosis. Forest plots of improvement in histological variables are shown. (A) Steatosis; (B) inflammation; (C) hepatocellular ballooning and (D) fibrosis.adverse events were poorly reported. Current information indicates that metformin improves liver function, HOMA-IR and BMI to some extent, but not histological response in NAFLD patients

102 Statins CVD common cause of death for NAFLD and NASH Stratify risks and treat accordingly No RCTs with histological end points using statins to treat NASH Chalasani, et al. Am J Gastro 2012

103 Vitamin E Vitamin E 800 IU/day improves liver histology in NASH patients Not recommended to treat NASH in those with other chronic liver diseases, diabetics, those with NASH cirrhosis or cryptogenic cirrhosis, NAFLD without biopsy Risk Meta-analysis* including 136,000 participants found taking Vitamin E supplements > 400 IU/day had a higher risk of all cause mortality Vitamin E** > 400 IU/day increases risk of prostate cancer in relatively healthy men *Miller et al Annals of Internal Medicine 2005 ** Klein, et al, JAMA 2011

104 Other treatments for NASH Ursodeoxycholic acid No histologic benefit Omega-3 fatty acids Effective in treating hypertriglyceridemia in pts with NAFLD Evidence for treatment of NASH inconclusive to date Large multi-center trial on-going now

105 Recommendations on Bariatric Surgery Premature to consider bariatric surgery as an option to specifically treat NASH Bariatric surgery is not contra-indicated in otherwise eligible pts with NASH or NAFLD WITHOUT cirrhosis For those with cirrhosis: type, safety and efficacy of bariatric surgery is not established

106 Pediatric Issues NAFLD reported as early as 2 y/o NASH-related cirrhosis as early as 8 y/o Independent predictors of FLD in adolescence Obesity Older age Male gender Dyslipidemia IR Schwimmer, et al. Pediatrics 2006 Schwimmer, et al. Hepatology 2005 Schwimmer, et al. Gastroenterology 2009

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108 Pediatric Recommendations Intensive lifestyle behavior modification, including dietitian consultation, is first line treatment Metformin 500mg BID offers no benefit Vitamin E 800 IU/d offers histological benefit but confirmatory studies are needed before it can be recommended in clinical use.

109 NASH recommendations Vitamin E 800 IU/day improves liver histology in NASH patients Not recommended to treat NASH in those with other chronic liver diseases, diabetics, those with NASH cirrhosis or cryptogenic cirrhosis, NAFLD without biopsy Risk Meta-analysis* including 136,000 participants found taking Vitamin E supplements > 400 IU/day had a higher risk of all cause mortality Vitamin E** > 400 IU/day increases risk of prostate cancer in relatively healthy men *Miller et al Annals of Internal Medicine 2005 ** Klein, et al, JAMA 2011