5/26/2017 CURRENT ISSUES IN ANATOMIC PATHOLOGY 2017 PITFALLS IN THE DIAGNOSIS OF MEDICAL I HAVE NOTHING TO LIVER DISEASE WITH TWO DISCLOSE CONCURRENT ETIOLOGIES Linda Ferrell Linda Ferrell, MD, UCSF � Entities such as non-alcoholic steatohepatitis and THE PROBLEM for liver pathology in 2017 HCV are relatively common � Many patients with chronic liver disease history are IDEAL versus REAL living longer due to more advanced therapies (HCV, HBV, PBC) IDEAL = one disease only to consider � Risk of acquiring a 2 nd etiology is likely increased REAL = more than one entity is increasingly of over time concern � Separation of entities enables better treatment with etiology- specific therapies 1
5/26/2017 Major Patterns of Disease: Portal-based Injury typically in portal/periportal areas � Chronic viral hepatitis, other chronic hepatitides � HBV, HCV, alpha-1-antitrypsin, Wilson’s, AIH � Biliary tract obstructive disease: � Obstruction, primary biliary cholangitis, primary sclerosing cholangitis � Hemochromatosis Portal-Based: Chronic biliary disease (PBC) with Portal Based: Chronic Hepatitis ductular reaction in portal zones 2
5/26/2017 Portal-based: Hemochromatosis Major Patterns of Disease: Central -based Injury typically in centrizonal areas Iron overload � Steatohepatitis begins in periportal � Nonalcoholic (NASH), Alcoholic zone. � Chronic ischemic injury and/or chronic vascular Results in outflow obstruction periportal � Budd-Chiari syndrome, congestive heart failure fibrosis due � Some mild to moderate acute drug/toxic to FE toxicity injuries � Acetaminophen, mushroom toxicity NASH, Trichrome: Centrizonal NASH, Trichrome: Centrizonal NASH, Trichrome: Centrizonal NASH, Trichrome: Centrizonal Central-based: pericellular and sinusoidal fibrosis pericellular and sinusoidal fibrosis pericellular and sinusoidal fibrosis pericellular and sinusoidal fibrosis Chronic Venous Outflow Obstruction Chronic Heart Failure Chronic Budd Chiari Syndrome 3
5/26/2017 Central based: Toxic (one-hit) event Central-Based Pattern: Pitfalls Example: Acetaminophen Chronic changes of centrizonal region that can mimic portal tracts, so called “portalization of central zones” Centrizonal necrosis � Arterialization within centrizonal scar � Ductular reaction/metaplasia of injured hepatocytes and/or progenitor cells Arrows highlight centrizonal arteries Central Vein Artery DON’T CONFUSE WITH PORTAL ZONE NASH, Trichrome: Centrizonal Fibrosis (1b) NASH, Trichrome: Centrizonal Fibrosis (1b) NASH, Trichrome: Centrizonal Fibrosis (1b) NASH, Trichrome: Centrizonal Fibrosis (1b) 4
5/26/2017 Budd-Chiari Syndrome: Centrizonal Fibrosis and Ductular Metaplasia DON’T CONFUSE WITH PORTAL ZONE Acute or Chronic Injury Hepatocytic Panlobular Injury � Inflammatory (hepatitic) panlobular Major Patterns: � ACUTE hepatitis (Notable examples: HAV, HEV, AIH, � Hepatocyte panlobular injury idiosyncratic drug or “herbal” reactions) � Ongoing/active chronic hepatitis (Examples: AIH, � Inflammatory (hepatitic) panlobular HBV, HCV) � Necrotic panlobular � Necrotic panlobular: acute injury with minimal � Fatty change inflammation � Alcohol, Non-alcoholic steatohepatitis, other causes � Toxic (one-hit, as with acetaminophen) � Ischemic (Example: shock) � Fibrosis versus Necrosis � Combination of Inflammatory and Necrotic � Biggest issue is CIRRHOSIS versus SEVERE ACTIVE HEPATITIS � SEVERE acute to subacute hepatitis (more variable with regenerative nodules and intervening necrosis stages of necrosis + inflammatory changes usually with ductular reaction) 5
5/26/2017 Fibrosis versus Necrosis Severe Acute Hepatitis, Inflammatory Pattern Routine histochemical stains can be helpful Generally presents as fulminant liver failure � Trichrome: Two-toned color and two textures Typically correlates with submassive to massive � Scar: darker blue color and dense fibers necrosis of the liver � Necrosis: Lighter blue color and more delicate fibers � Early stage — necrosis, Kupffer cell reaction � Reticulin: collapsed or not � Subacute stage — hepatocyte regeneration, early � Orcein/EVG: Used for elastic fibers: formation starts collapse of reticulin framework about 12 weeks after injury � Late stage — nodule formation; fibrosis and/or Ferrell L, Greenberg M. Special Stains Can Distinguish Hepatic Necrosis cirrhosis with Regenerative Nodules from Cirrhosis Liver International 27:681- 686, 2007. EARLY Severe Acute Hepatitis: EARLY Severe Acute Hepatitis: Necrosis Necrosis and Kupffer Cell Reaction and Kupffer Cell Reaction Trichrome: No hepatocytes; Reticulin stain: Centrilobular Panlobular necrosis and Immunostain for CD68 to Centrilobular zone, two colors and zone, framework still intact congestion confirm as Kupffer cells textures Intact plates, No necrosis Light and delicate = necrosis Dark and Dense = Normal structures or scar Intact plates: Necrosis 6
5/26/2017 Subacute Severe Hepatitis: Subacute Severe Hepatitis Regeneration and collapse Reticulin stain: Collapse of Nodular regeneration, congestion of Trichrome framework between regenerative necrotic centrilobular zones nodules stain: Regenerative nodule Lighter blue with congestion, ductular reaction = zones of recent necrosis NODULAR regeneration and DUCTULAR REACTION Collapse: Thinner plates, Congested central zone indicates subacute wavy fibers process Late Stage: Established Cirrhosis Late Stage: Established Cirrhosis Trichrome: Dark, dense blue Trichrome: Dark, dense blue Orcein: Elastic (black) fibers Orcein: Elastic fibers in scar scar as sign of chronicity Cirrhosis 7
5/26/2017 In contrast: Acute Necrosis, <12 weeks In contrast: Subacute injury approaching 12 weeks in duration Orcein: Elastic (black) fibers limited to portal zones, central Orcein: Elastic (black) fibers present in residual portal tracts veins; rare small fibers in early scar and central veins; ductular reaction present Regenerative nodule Late Stage: Established Cirrhosis Late Stage: Established Cirrhosis Elastic (EVG) stain: Black elastic Elastic (EVG) stain: Black elastic Trichrome: Dark, dense blue scar Trichrome: Dark, dense blue scar fibers fibers and pale grey zones (Elastic fibers) and pale grey zones (Elastic fibers) Orcein stain: Black elastic fibers 8
5/26/2017 Mixed etiology: Acute on Chronic Question: Fibrosis or Necrosis CASE 1 Is this centrizonal fibrosis or necrosis on trichrome � 31 year old man, history of ulcerative colitis stain? � Clinical diagnosis of primary sclerosing cholangitis in 2001, no liver biopsy A. Fibrosis � No signs of cirrhosis 3 months prior to his 88% B. Necrosis presentation of subacute liver failure with high levels AST, ALT � Transplanted at UCSF � Clinical diagnosis: Possibly end-stage PSC, but an 12% unusual rapid hepatitic pattern of progression over 3 months s s i i s s o o b r c r e F i N Acute on Chronic Acute on Chronic Large zones of panacinar necrosis, with ductular Trichrome stain: Trichome: zones of collapse, but no reaction and inflammatory infiltrates dark bands of fibrosis Two toned, light and dark 9
5/26/2017 Acute on Chronic Acute on Chronic Trichrome: No fibrosis Focal regenerative nodules ORCEIN: no elastosis Acute on Chronic Question: What is your best diagnosis? A. Cirrhosis due to HCV and primary sclerosing Trichrome: Hilar duct sclerosis Periduct sclerosis cholangitis (PSC) 93% B. Acute hepatitis and PSC C. Chronic hepatitis C and PSC D. Fatty liver disease (NASH) and PSC 3% 3% 0% C C . . . S S . . P P S d n A d d a N n n V a a ( e C s C s H t i a i s o t i e a t s t i i p t d e e a u p r h d e e e h v s t l i s i u c i y o c n t h A o t a r r r h F i C C 10
5/26/2017 Mixed Etiology: Acute on Chronic Mixed etiology: Acute on Chronic DIAGNOSES Case 2 � Chronic changes of early stage PSC � 50 year old obese man, diabetic and heavy drinker � Periduct fibrosis and hilar duct sclerosis � No previous liver biopsy � Superimposed acute hepatitis of unknown etiology � Presented in liver failure and ascites for liver � Zones of panacinar necrosis, without fibrosis transplantation � Clinical diagnosis: End-stage liver disease, possibly due to severe steatohepatitis Case courtesy of Dr A Paul Dhillon, Royal Free Hospital, London Acute on Chronic Acute on Chronic Trichrome: nodular, with necrosis, Focal bridging fibrosis involving Two toned; and swollen, ballooned Two toned; with ductular reaction, two toned centrizonal areas, mild fatty change hepatocytes focal fat, ballooned hepatocytes 11
5/26/2017 Acute on Chronic: Acute on Chronic: Inflammation Regenerative nodule Question: What is your best diagnosis? Mixed etiology: Acute on Chronic � Chronic steatohepatitis with bridging fibrosis, indistinguishable for NASH or ASH A. End-stage cirrhosis due to steatohepatitis � Overlying acute hepatitis, not specific for etiology, B. Steatohepatitis with fibrosis, with overlying plasma cells seen acute injury 98% � Differential diagnosis: AIH, Drug, HAV, HEV � Workup: negative for autoimmune markers, HAV, and drug/herbal/other nutritional agents � Final Diagnosis : 2% Hepatitis E (HEV) and chronic steatohepatitis . . . . . . o o t r b e u f i d h t s i s i w o s h r t i r i i t c a p e e g a h o t s t - a d e n t E S 12
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