UC SF. Liver and Gastrointestinal Pathology Update. University of California San Francisco. September 3, 2009

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1 Liver and Gastrointestinal Pathology Update UC SF University of California San Francisco Nonalcoholic Fatty Liver Disease Update in Pathology September 3, 2009 Elizabeth M. Brunt, MD Department of Pathology and Immunology Challenges/Opportunities in NAFLD

2 Challenges in NAFLD Value of Liver Biopsy in NAFLD: Contentious and Controversial The Clinicians The Pathologists The Liver The Disease Itself Value of Liver Biopsy in NAFLD: Contentious and Controversial Pro s Confirm diagnosis exclude other causes of liver dysfunction Value of Liver Biopsy in NAFLD 354 pts with unexplained liver test abnormalities Fatty liver: 66% (SH with fibrosis, 32%) PBC, PSC, sarcoid, AIH, HH: 5.1% Drug-related: 7.6% Cryptogenic: 9% Skelly MM, J Hepatol 2001;35: Bianchi L. J Hepatol 2001;35:290 (Editorial) 2

3 Value of Liver Biopsy in NAFLD 354 pts with unexplained liver test abnormalities Fatty liver: 66% (SH with fibrosis, 32%) PBC, PSC, sarcoid, AIH, HH: 5.1% Drug-related: 7.6% Cryptogenic: 9% Normal liver: 5.9% Value of Liver Biopsy in NAFLD 52 y/o overweight man ALT 77 IU/L (4xULN) negative serologies, no medications negative alcohol hx Skelly MM, J Hepatol 2001;35: Bianchi L. J Hepatol 2001;35:290 (Editorial) US: fatty liver Value of Liver Biopsy in NAFLD 52 y/o overweight man ALT 77 IU/L (4xULN) negative serologies, no medications negative alcohol hx US: fatty liver Value of Liver Biopsy in NAFLD Clinical, histologic features in atypical settings Concurrent with other forms of liver disease Hepatitis C (5-10%) Ong, Liver 2001; Brunt, Mod Pathol 2003; Sanyal, Am J Gastroenterol 2003 Primary Biliary Cirrhosis, AIC, HBV, AIH, α1at (~5%) Brunt, Mod Pathol 2003; Sanyal, Am J Gastroenterol 2003; Sanchez-Munoz, Dig Dis Sci 2004 Some drugs, occupational toxins/exposures Farrell, Semin Liv Dis 2002; Cotrim, Liver 1999; JAMA

4 Value of Liver Biopsy in NAFLD: Contentious and Controversial Pro s Confirm diagnosis Intra-op visuals do not correlate with disease severity ALT in not reliably elevated Normal ALT Entire histologic spectrum: steatosis to silent cirrhosis 12% cirrhosis Mofrad, Hepatology % cirrhosis Sorrentino, J Hepatol % cirrhosis Fracanzani, Hepatology % Stages 1-3 fibrosis (peds): A-Kader, Clin Gastro Hepatol, 2008 Steatosis grade elevated ALT (p= ) Necroinflammation grade elevated ALT (p=0.0002) Normal ALT Fibrosis scores: no signif difference b/w groups Value of Liver Biopsy in NAFLD: Contentious and Controversial Pro s Confirm diagnosis Intra-op visuals do not correlate with disease severity ALT in not reliably elevated Evaluation: Severity of injury Fibrosis/Architecture Fracanzani, Hepatology 2008;48:792 4

5 Value of Liver Biopsy in NAFLD: Contentious and Controversial The Pathologists Pro s Confirm diagnosis Intra-op visuals do not correlate with disease severity ALT in not reliably elevated Biopsy evaluation: Severity of injury Fibrosis/Architecture Con s Invasive, potentially harmful There is no treatment to offer Most suspected patients only have NAFLD Imaging and noninvasive markers are improving Specimen adequacy sampling concerns How good are we? Understand the disease process(es), nuances in histologic diagnoses Problems with Liver Biopsy mm length x 1.2mm diameter ~10 portal tracts ~1/50,000 1/63,000 of liver parenchyma Lee, RG (ed), Diagnostic Liver Pathology, St. Louis, Mosby, 1994, Ch 1. Scheuer PJ and Lefkowitch JH (eds), Liver Biopsy Interpretation, 7 th ed, London, WB Saunders, 2006, Ch 1 Li, Semin Liv Dis 2004;24:21. 17ga Jamshidi suction 16 ga Bard Bx Gun Problems with Liver Biopsy Chronic Hepatitis: Sample size is important in grading, staging Bedossa, Hepatology 2003;38:1449 Colloredo, J Hepatol 2003;39:239 Guido, Semin Liv Pathol 2004;24:89 Fatty Liver Disease: Variability of lesions within the liver alters grade and stage; size (length and width) matters Dixon, Gastroenterol 2001;121:91 Ratziu, Gastroenterol 2005;128:1898 Goldstein, Anatomic Pathology 2005;123:382 Merriman, Hepatology 2006;44:844 Larson, Clin Gastro Hepatol 2007;5:1329 Vuppalanchi, Clin Gastro Hepatol 2009;7:481 5

6 Variability of Findings in NAFLD Sampling Error 59% LL RL 51 patients 2 simultaneous cores processed and interpreted separately Ratziu et al, Gastroenterol 2005;128: % 37% 24% Neuschwander-Tetri, Curr Op Endocrin Diab 2006;13:119 Fibrosis Evaluation Sampling Considerations Intra-operative IntraBiopsy Hierarchy of hepatic portal tracts and bile ducts Bariatric Surgery Almost no steatosis Variability of Portal Tract Size Scheuer and Lefkowitch, 6th ed, 2006 Courtesy Dr. Jay Lefkowitch 6

7 Intra-operative Biopsy Bariatric Surgery Intra-Operative Biopsy Consideration Surgical Hepatitis :? NAS Are studies that compare percutaneous bx with operative bx comparing Apples v Oranges? Percutaneous Bx, Right Lobe The Pathologists Interobserver Variability Studies Specimen adequacy sampling concerns How good are we? Understand the disease process(es), nuances in histologic diagnoses Anonymous Sections of the liver biopsy show. 7

8 Interobserver Variability Studies Interobserver Variability Studies Adult or Pediatric n # Pathologists Steatosis Fibrosis Ballooning Lobular Inflammation Adult or Pediatric n # Pathologists Steatosis Fibrosis Ballooning Lobular Inflammation Younossi, 1998 Adult Biopsies n = 53; 4 pathologists Younossi, 1998 Adult Biopsies n = 53; 4 pathologists Kleiner, 2005 Adult Biopsies n=32; 9 pathologists Kleiner, 2005 Adult Biopsies n=32; 9 pathologists Fukusato, 2005 Adult Biopsies n=21; 8 pathologists Fukusato, 2005 Adult Biopsies n=21; 8 pathologists Kleiner, 2005 Pediatric Biopsies n=18; 9 pathologists Kleiner, 2005 Pediatric Biopsies n=18; 9 pathologists Younossi et al, Mod Pathol 1998;11:560; Kleiner et al, Hepatol 2005;41:1313; Fukusato et al. Hepatol Res 2005;33:122 Younossi et al, Mod Pathol 1998;11:560; Kleiner et al, Hepatol 2005;41:1313; Fukusato et al. Hepatol Res 2005;33:122 Interobserver Variability Studies The Pathologists Younossi, 1998 Kleiner, 2005 Adult or Pediatric n # Pathologists Steatosis Fibrosis Ballooning Lobular Inflammation Adult Biopsies n = 53; 4 pathologists Adult Biopsies n=32; 9 pathologists Specimen adequacy sampling concerns How good are we? Fukusato, 2005 Kleiner, 2005 Adult Biopsies n=21; 8 pathologists Pediatric Biopsies n=18; 9 pathologists Understand the disease process(es), nuances in histologic diagnoses Younossi et al, Mod Pathol 1998;11:560; Kleiner et al, Hepatol 2005;41:1313; Fukusato et al. Hepatol Res 2005;33:122 8

9 Case Review: 58 y/o man Case Review: 58 y/o man Obese, elevated HbA1c (7.7) ALT 59 IU/L, AST 76 Obese, elevated HbA1c (7.7), ALT 59 IU/L, AST 76 IU/L Mild alcohol use Mild alcohol use 76 IU/L Dx: Steatohepatitis, history of obesity, diabetes and alcohol use Marked activity, grade 3 Need trichrome stain for proper staging, but beyond stage 1 ALD and NAFLD a few facts and figures ALD and NAFLD a few facts and figures Develop related liver disease Genetic/familial associations for liver disease Ethnic/Social disparities Age, Gender differences Major risk factors ALD < 15% of heavy drinkers Yes Religious and Cultural Stigmata Not in very young or very old; W>M Amt in past yrs; pattern of consumption (meals v only weekends) (types of beverages); central obesity; acetominophen use; GENES Develop related liver disease Genetic/familial associations for liver disease Ethnic/Social disparities Age, Gender differences Major risk factors ALD < 15% of heavy drinkers Yes Religious and Cultural Stigmata Not in very young or very old; W>M Amt in past yrs; pattern of consumption (meals v only weekends (types of beverages); central obesity; acetominophen use; GENES NAFLD (in obese) 70% have steatosis 20-35% SH; 15-20% cirrh Yes Hispanic>Cauc>Asian>>>AA Increasing in ALL ages; 17% of adolescents have NAFLD adv disease W > M Metabolic syndrome; markers of insulin resistance; some drugs; lipodystrophy; GENES Risk of NASH: female; T2DM; environment, diet, GENES 9

10 Reversibility Morbidity Affects on HCV co-infection Increase fibrosis in HCV; Long-term risk of cirrhosis and complications including HCC Proportion of Chronic Liver Disease in US ALD and NAFLD a few facts and figures ALD Difficult, unlikely Alcoholic hepatitis; complications of cirrhosis Increases progression of fibrosis Yes YES, is #1 indication for OLT ALD cirrh is strong risk for HCC 1-2% 40% of deaths from cirrh NAFLD (in obese) Difficult, unlikely w/out bariatric surgery Many assoc diseases: CVD, sleep apnea, PCOD; Obesityrelated malignancies Co-factor in progression Yes Yes, but incidence of HCC is not clearly established; is considered major cause of cryptogenic cirrh 5-15% Alcoholic Liver Disease ALCOHOL ACETALDEHYDE EF>M Induction of MEOS (CYP2E1) Malnutrition Aberrant lipogenesis Portal endotoxemia Mixed steatosis Shared factors Influence of gender Obesity Cytokines Proinflammatory: high TNFα, ΙL-6 Antiinflammatory: low adiponectin Oxidative stress Mitochondrial iron damage ROS Factors influencing steatosis Metabolic Syndrome Fatty Liver Disease INSULIN RESISTANCE M > F Hepatocytes, macrophages Increased FFA oxidation Dietary, Hepatic lipid processing Body habitus Kupffer cells Immune response? Role of small bowel bacterial overgrowth Fibrosis Hyperinsulinemia, glucose, CTGF, adipose tissue products: leptin, angiotensinogen, norepinephrine Tiniakos and Brunt, in Odze et al, Surgical Pathology of the GI Tract, Liver, Biliary Tract and Pancreas, 2 nd ed, 2009 AFLD v NAFLD Same Pattern.? Subtle Differences in Types of Collagen? Alcoholic Liver Disease Nonalcoholic Steatohepatitis Steatohepatitis, Diabetes Steatohepatitis, Alcohol Nakano, Hepatol Res 2005;33:110 10

11 Patterns of Histologic Lesions Patterns of Histologic Lesions ALD NAFLD Cirrhosis ALD NAFLD Cirrhosis Steatosis, macro or mixed Steatosis, macro or mixed Steatohepatitis Patterns of Histologic Lesions Patterns of Histologic Lesions ALD NAFLD Cirrhosis ALD NAFLD Cirrhosis Steatosis, macro or mixed Steatosis, macro or mixed Steatohepatitis Steatohepatitis Alcoholic Hepatitis No equivalent lesion Alcoholic Hepatitis No equivalent lesion Alcoholic Foamy Degeneration No equivalent lesion No, by definition 11

12 Patterns of Histologic Lesions Steatosis, macro or mixed ALD NAFLD Cirrhosis New Discussions in NAFLD Pathology Steatosis is dynamic Acidophil bodies/apoptosis as marker Steatohepatitis Ballooning: can we better characterize this Alcoholic Hepatitis Alcoholic Foamy Degeneration Burned-Out Cirrhosis No equivalent lesion No equivalent lesion No, by definition Is cryptogenic if underlying etiology is not known Portal inflammation: how does it relate Fibrosis in NAFLD: role of HPC THV THV 12

13 Hepatic Steatosis: Role of PAT Hepatic Steatosis: Role of PAT p<0.01 p<0.01 p<0.01 p<0.01 Straub, Hepatology 2008;47:1936 Straub, Hepatology 2008;47:1936 Hepatic Steatosis: Role of PAT Other Histologic Markers? Perilipin: zone 3; small/medium droplets * * * * * * * = significant Courtesy Dr. M. Charlton FABP-1 IHC Perilipin-3 Perilipin-2 Perilipin-1 Straub, Hepatology 2008;47:1936; Kimmel, JLR, epub, 2009 Courtesy B Straub Charlton, Hepatology 2009;49:1375? Loss of protective effect of FABP-1? Role in FA oxidation, lipogenesis, insulin? New mechanism of FFA lipotoxicity 13

14 Other Histologic Markers? Liver Cell Injury: Ballooning NAFLD 30% 25% p<.001 Courtesy Dr. M. Charlton Charlton, Hepatology 2009;49:1375 * = significant * * * * * * Early and late NASH? marker Stimulated by oxidative stress Partially mediated by NfκB Cirrhosis 20% 15% 10% 5% 0% (0) Type 1 Type 2 Type 3 Type 4 Type 1: Steatosis Type 2: Steatosis plus inflammation Type 3: Steatosis plus ballooning Type 4: Steatosis plus ballooning with Mallory s and/or fibrosis Matteoni, Gastroenterology 1999;116:1413 What is Ballooning? 14

15 K8/18 for Ballooning, MDB Apoptosis Markers of apoptosis NASH > steatosis = controls (p <.01) Correlate with increased fibrosis score, and moderate to severe activity (p <.02) Acidophil body index Lackner et al. J Hepatol :821 Feldstein, Gastroenterology 2003; 125:437 Ribeiro, Am J Gastroenterol 2004;99:1708 Yeh, Hepatol 2008;48:523A Apoptosis: Plasma CK18 Fragments CK18 Fragments:?Plasma Marker to Predict SH p <.001 p <.001 Validity Measure CK18 Fragment Level Cutoff Value 395 IU/l IU/L Specificity Sensitivity PPV n=10 n=8 n=21 Plasma CK 18 n=10 n=8 n=21 Plasma CK 18 NPV Wieckowska, et al. Hepatology 2006;44:27 Wieckowska, et al. Hepatology 2006;44:27 Feldstein, et al. Hepatology 2009;epub August

16 CK-18 Fragment Levels are Increased in the Liver of Patients with NASH Portal Inflammation Normal biopsy Not NASH (Simple Steatosis) Definitive NASH NAS 0 NAS 2 NAS 7 NAFLD Activity Score (NAS) Courtesy of Dr. Ariel Feldstein Wieckowska, et al. Hepatology 2006;44:27 Portal Chronic Inflammation Pediatric NAFLD What are we learning from treatment trials? Concurrent Disease HCV, other forms of CLD (~5-10%) Resolution after treatment Severe NAFLD Clinical parameters Histology Brunt, Mod Pathol 2003;16:49;Neuschwander-Tetri, Hepatology 2003;38:1008;Brunt, Hepatology2009;49:809 Pretreatment Bx Posttreatment Bx 16

17 Post treatment Biopsy: Portal and lobular inflammation Recent Treatment Trials: Primary Histologic Findings Study (n) TX Neuschwander- Tetri, et al Hepatology 2003; 38:1008 Promrat, et al Hepatology 2004;39:188 Kral, et al Surgery 2004;135:48 30 overweight 18 overweight, nondiabetic 689 morbid obese Rosi Pio BPD Post-tx bx (n) wk wk 104 (re-op) wk Histologic Findings Reported 45% no longer NASH; improved grade, steatosis, inflammation, ballooning (p=.004) Shift toward increased portal CI (p=.02) No change in fibrosis score, shift from dense to delicate perisinusoidal fibrosis (p=.02) 67% had histologic response; decreased steatosis, ballooning, lobular inflammation, Mallory s hyaline, fibrosis (p<.05) No change in portal inflammation. Steatosis decreased in all (p <.0001); inflammation gone in 61% of original, developed anew in 10%. 4/10 had features of HCV..?portal inflammation Fibrosis: decreased 28%, increased 42%; no ch 34% Dixon, et al Hepatology 2004;39: morbid obesity; 12 steatosis only LAGB wk 83% no longer NASH; significant improvement in steatosis, inflammation, fibrosis (p <.001). No change in portal inflammation. Fibrosis: Stage > 2: 78% 13% (p <.001) Barker, et al Am J Gastro 2006;101: obese RYGB wk 89% no longer NASH; signif improv steatosis, ballooning, lobular inflamm portal and lobul fibrosis (all p<0.001). No change in portal inflammation. Results: Total Cases Adults: n = 728 Pediatrics: n = 205 NONE v > MILD ADULTS Older ( p < ) Female gender (p = 0.001) Greater BMI (p < ) Elevated serum insulin (p = 0.001) Higher HOMA-IR score (p < ) Hx of Medication for NAFLD ( p = ) Diabetes (p < ) Hypertension (p < ) Brunt, Hepatology2009;49:809 Brunt, Hepatology 2009;49:809 17

18 NONE v > MILD Histology Results: NONE v > MILD ADULTS Older (p < ) Female gender (p = 0.001) Greater BMI (p < ) Elevated serum insulin (p = 0.001) Higher HOMA-IR score (p < ) Hx of Medication for NAFLD ( p = ) Diabetes (p < ) Hypertension (p < ) PEDIATRICS Younger (12 yr v 14 yr) (p=0.01) n.s. Hx of Medication for NAFLD (p=0.03) Diabetes (p=0.03) ADULTS Panacinar or azonal steatosis (52% v 20%) (p<0.0001) Ballooning (many > few, none) (60% v 20%) (p < ) Advanced fibrosis (>2) (60% v 4%) (p<0.0001) PEDIATRICS Panacinar steatosis (41% v 15%) (p=0.008) n.s. Periportal/portal fibrosis (Stage 1c) (p<0.0001) Brunt, Hepatology 2009;49:809 Brunt, Hepatology 2009;49:809 Arterialization of Fibrosed Central Zones What s New in Fibrosis? Ferrell et al (NASH CRN), Hepatology 2007;46:732A p < Zone 3 perisinusoidal fibrosis Periportal fibrosis, ductular reaction 18

19 Replicative arrest in NAFLD Ductular reaction & fibrosis in NAFLD ** p21 Index *** 1.5 *** Steatosis NASH F0/1 + type 2 NAFLD Courtesy Dr. A Clouston NASH F2/3/4 HOMA-IR ** ** 0 0-1% >1% p21 Index Richardson, Gastroenterol 2007;133:80 Ductular Reaction (% Area) A Non-diseased liver ** Steatosis + type 2 NAFLD *** NASH F0/1 * NASH F2/3/4 Courtesy Dr. A Clouston Richardson, Gastroenterol 2007;133:80 Evolution in Scoring in Metabolic FLD Descriptive types related to outcome Type 1: Steatosis Type 2: Steatosis plus inflammation Type 3: Steatosis plus ballooning Type 4: Steatosis plus ballooning with Mallory s and/or fibrosis Types 1-4 Matteoni, % 25% 20% 15% 10% 5% 0% Spectrum of NAFLD (0) Type 1 Type 2 Type 3 Type 4 Evolution in Scoring in Metabolic FLD Separated Activity, Fibrosis Graded each, as in CH Grade Mild, Grade 1 Moderate Grade 2 Steatosis 1-2 (up to 66%) 2-3 (>33%; may be >66%) Ballooning Minimal Present Severe, Grade 3 3 Marked Inflammation L: 1-2 P: None-mild L: 2 P: Mild- moderate L: 3 P: Mild- moderate Stage Brunt Score 1999 Zone 3, peri- sinusoidal 1 Focal or extensive 2 As above 3 Bridging septa Portal- based Focal or extensive Bridging septa Bridging Cirrhosis /- +/- Extensive + 19

20 Evolution in Scoring in Metabolic FLD Created NAS, based on aggregate score maintained division of Activity and Fibrosis Descriptive types related to outcome Component Scoring for Rx Trials NIDDK/Kleiner CRN 2005 Types 1-4 Matteoni, 1999 Grade, Stage Brunt, 1999 Divided Activity, Fibrosis Graded each NIDDK NASH CRN: Pathology Committee NAFLD Scoring System for PIVENS, TONIC NAFLD Activity Score, NAS (0-8) *Pattern of NAFLD Steatosis (0-3) <5%; 5-33%; 33-66%; >66% Lobular Inflam (0-3) 0,<2; 2-4; >4 foci/20x Ballooning (0-2) None, few, many/prominent Fibrosis Score (0-4) Masson strichrome 1a, b: Zone 3 PSF 1c: Portal only 2: Zone 3 + portal/periportal 3: Bridging 4: Cirrhosis Kleiner et al. Hepatology 2005;41:1313 NAFLD Activity Score: Adults NAFLD Activity Score Dx:Steatohepatitis note that the primary purpose of the NAS is to assess overall histological change; it is not intended that numeric values replace the pathologist s diagnostic determination of steatohepatitis. Kleiner et al. Hepatology 2005;41:1319 Modified from Kleiner et al, Hepatology 2005; 41:

21 Sunset in the Okavango Delta, Botswana 21

22 Challenges in NASH 2009 Minimum components for diagnosis of SH What is ballooning? Scoring the lesions Apoptosis: Plasma Marker 44 subjects, suspected NAFLD liver biopsy; CRN scoring and diagnostic criteria ELISA for caspase-3 generated CK18 fragments in plasma (Bantel et al) IHC confirmation in liver biopsies Caspase-3 cleavage product of CK18 Wieckowska, et al. Hepatology 2006;44:27 Arterialization of Fibrosed Central Zones Alcoholic Liver Disease ALCOHOL ACETALDEHYD E F > M Induction of MEOS (CYP2E1) Malnutrition Aberrant lipogenesis Shared factors Influence of gender Obesity Cytokines Proinflammatory: high TNFα, ΙL-6 Antiinflammatory: low adiponectin Concepts of Pathogenesis NAFLD Oxidative stress Mitochondrial iron damage ROS Factors influencing steatosis Metabolic Syndrome Fatty Liver Disease INSULIN RESISTANCE M > F Hepatocytes, macrophages Increased FFA oxidation Dietary, Hepatic lipid processing Body habitus Portal endotoxemia Mixed steatosis Kupffer cells Immune response Fibrosis? Role of small bowel bacterial overgrowth Hyperinsulinemia, glucose, CTGF, adipose tissue products: leptin, angiotensinogen, norepinephrine Ferrell et al (NASH CRN), Hepatology 2007;46:732A p < Tiniakos and Brunt, in Odze et al, Surgical Pathology of the GI Tract, Liver, Biliary Tract and Pancreas, 2 nd ed,

23 Induction of MEOS (CYP2E1) Alcoholic Liver Disease ALCOHOL ACETALDEHYDE F>M Malnutrition Aberrant lipogenesis Portal endotoxemia Mixed steatosis Shared factors Influence of gender Obesity Cytokines Proinflammatory: high TNFα, ΙL-6 Antiinflammatory: low adiponectin Oxidative stress Mitochondrial iron damage ROS Factors influencing steatosis Metabolic Syndrome Fatty Liver Disease INSULIN RESISTANCE M > F Concepts of Increased FFA oxidation Pathogenesis ALD Hepatocytes, macrophages Dietary, Hepatic lipid processing Body habitus Kupffer cells? Role of small bowel Immune response bacterial overgrowth Hyperinsulinemia, glucose, Fibrosis CTGF, adipose tissue products: leptin, angiotensinogen, norepinephrine The Pathologists Specimen adequacy sampling concerns How good are we? Understand the disease process(es), nuances in histologic diagnoses Tiniakos and Brunt, in Odze et al, Surgical Pathology of the GI Tract, Liver, Biliary Tract and Pancreas, 2 nd ed, 2009 True Microvesicular Steatosis in NAFLD Pathology of Fatty Liver Disease Alcoholic Liver Disease Spectrum of Pathology May exist WITHOUT steatosis Alcoholic foamy degeneration Cholestasis, acute or chronic Cholangiolitis Sclerosing hyaline necrosis Veno-occlusive lesions Pseudotumoral foci by CT/US in alcoholic hepatitis with cirrhosis ropy, may be abundant, satellitosis common uncommon Cryptogenic cirrhosis may be seen without features of active steatohepatitis Shared lesions Steatosis, macro>mixed Steatohepatitis, see text Ballooning, acidophil bodies Megamitochondria Lobular, portal inflammation, lipogranulomas Zone 3 Perisinusoidal fibrosis => => Portal fibrosis => => Bridging fibrosis => =>Cirrhosis Mallory-Denk bodies Glycogenated nuclei Iron (hepatocytes/slc) Ductular reaction Metabolic Syndrome Fatty Liver Disease Spectrum of Pathology Steatosis is REQUIRED for diagnosis thin, wispy common Cryptogenic cirrhosis may be seen without steatosis or other features of active steatohepatitis Tiniakos and Brunt, in Odze et al, Surgical Pathology of the GI Tract, Liver, Biliary Tract and Pancreas, 2 nd ed

24 Liver Cell Injury: Ballooning 24

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