Liver Pathology

2/7/11

1. Normal liver: Normal portal tract is triangular-shaped. Branch of hepatic artery, bile duct, and portal vein. Can see outline between connective tissue of portal tract and liver cells nice smooth border. 2. Normal liver: See zone 1 (periportal around portal tract) and zone 3 (central venous). A lot of liver injury occurs in a zonal pattern. 3. Special Stains Trichrome for fibrosis. Normal to have type I collagen in the portal tracts. Not fibrosis here. Fibrosis occurs outside the normal unit. Pattern of liver necrosis: Single cell acidophil body (big pink) councilman body Lytic necrosis Form of ballooning collapsed hepatocytes Confluent necrosis Bridging necrosis Goes from portal tract to central vein Zonal necrosis Massive/sub-massive

4. Hepatitis = Increased AST and/or ALT. Bilirubin may or may not be increased. Some show ballooning, some look necrotic. May or may not see inflammation associated. 5. Cholestasis = increased Alk Phos and/or GGT. Bilirubin may or may not be increased. Cholestasis = Interruption to bile flow. Can be problem w/bile ducts themselves or may be external obstruction. Here, we see lots of lymphocytes attacking bile duct epithelium.
Test q: A 35M has been infected w/hepatitis C virus. Which of the following lab tests is the most direct indicator of ongoing damage to hepatocytes caused by the virus in this patient? Alanine aminotransferase (ALT) (Other choices: Alk phos, GGT, Amylase)

Other Measures of Liver integrity: Detoxification Serum bilirubin Total: unconjugated plus conjugated Direct: conjugated only Delta: covalently linked to albumin Urine bilirubin Serum bile acids Serum ammonia

Synthesis Proteins secreted into the blood (binding proteins, transthyretin, haptoglobin, etc) Serum albumin Prothrombin time (factors V, VII, X, prothrombin, fibrinogen)

Patterns of Injury: Acute Hepatitis Fulminant Hepatitis Chronic Hepatitis Cirrhosis Chronic Cholestatic Disorders Fatty liver Disease Steatohepatitis alcohol NASH Acute Hepatitis: Nausea, vomiting +/- jaundice +/- fever Increased transaminases but usually < 1000 Virus Drug (Tylenol) / toxin (mushrooms) Autoimmune hepatitis Histology - Lobular injury predominates; no fibrosis Acute Hepatitis Viruses:
Agent Hepatitis A Hepatitis B Hepatitis C Hepatitis D Hepatitis E Hepatitis G CMV Herpes ssRNA En dsDNA En ssRNA En ssRNA ssRNA ssRNA dsDNA dsDNA Route Fecal - oral Parenteral Parenteral Parenteral Fecal - oral Parenteral Close contact Close contact Carrier No < 1% < 1% < 10% IDA No < 2% High High Chronic No Yes Yes Yes No No No No

Hemorrhagic fever, SARS, yellow fever also can give you hepatitis. HDV requires HBV infection.

Test q: In addition to hepatitis A, which of the following characteristically has a fecal-oral route of transmission? Hepatitis E virus. (Other choices: HIV, HBV, HCV, HDV) Test q: A persistent carrier state can be seen w/all of the following hepatitis viruses except: HAV. (Other choices: HBV, HCV, HDV [delta agent])

Case: Axel R. a 40y/o male singer noted fatigue and a flu-like illness. A friend noticed his eyes were slightly yellow. 3 months previously he had gotten a rose tattoo at the county fair. There were no other AIDS risk factors, no travel, no dental visits, no raw shell fish, etc. Alkaline phosphatase T. Bili Indirect (uncong.) Bili GGT T. Prot. Alb AST (SGOT) ALT (SGPT) 75 IU/L 2.8 mg/DL 1.8 40 IU/L 6.5 gm/DL 3.8 396 IU/DL 264 IU/DL (25-125) (0-1) (0-1) (12-43) (6.3-8.2) (3.5-5.0) (25-45) (0-35)

Bilirubin is elevated (>2.0, see jaundice in patient). AST and ALT are almost 10x upper limit of normal = hepatitis. IgM anti- HAV IgG anti-HAV HCV antibody HBsAg IgM anti HBc + + IgG anti-HBc Anti HBs HBe Ag IgM anti-delta + -

Diagnostic of acute Hepatitis B virus infection.

Left: Can see where endothelium would be see lots of necrosis, ballooning. Right: Acidophil/councilman bodies. Also see bile stuck in bile canaliculus (circled).

Viral Hepatitis: HAV 99% recover. Does not lead to chronic hepatitis but can lead to fulminant hepatitis. HBV recovery, chronic hepatitis, or fulminant hepatitis. HCV major pathway is chronic hepatitis cirrhosis. Fulminant Hepatitis Similar symptoms to acute hepatitis Transaminases > 1000 Coagulopathy Encephalopathy Jaundice Similar etiology as acute hepatitis plus decompensated cirrhosis, microvesicular fatty liver disorders, ischemia
Test q: A 45F presents w/fatigue and itching of recent onset. Physical exam is significant for jaundice and the patient seems confused and disoriented. Liver disease is suspected and serum transaminases are measured. The AST is 1520 IU/L (normal 25-45) and the ALT is 1290 (normal range 0-35). What conclusion should be drawn from these findings? Fulminant hepatitis should be suspected and liver biopsy is indicated. (Other choices: The transminase elevation is probably due to HAV and the disease will resolve, The result is suspect and probably is elevated due to hemolysis of the specimen, These findings are diagnostic of autoimmune hepatitis.) REPEATED x2 Test q: Over the past 4 days, a previously healthy 38F has become increasingly obtunded. On phys exam, she has scleral icterus. She is afebrile and her BP is 100/55. Lab findings show a prothrombin time of 38s, ALT 1854, AST 1621, albumin 1.8 g/dL, and total protein 4.8 g/dL. Which of the following additional serologic test results is most likely to be reported in this patient? Increased ammonia level. (Other choices: Increased alk phos level, Anti-HCV, Increased amylase, Positive ANA) Robbins explanation: The patients history points to an acute fulminant hepatitis with massive hepatic necrosis. The loss of hepatic function from destruction of 80% to 90% of the liver results in hyperammonemia from the defective hepatocyte urea cycle.

Case: 19 year old pregnant female presents with low grade fever, malaise and right upper quadrant - flank pain. AST/ALT ~ 200s (=hepatitis), normal blood pressure, no proteinuria. Admitted, blood cultures, started on antibiotics. No improvement over several days. Some coagulopathy and increasing LFTs ?HELLP syndrome. Baby delivered, no improvement. Next 3 4 days, Surgical consult no need for surgery. Infectious disease consult recommends different antibiotics. LFTs in 4000 range (=fulminant), coagulopathy worsened, renal failure and respiratory failure develop.

1. Fulminant hepatitis: See blood, lymphocytes, coagulative necrosis. Not zonal. 2. Fulminant herpes hepatitis Cowdry type B inclusions 3. Herpes see characteristic targetoid viral particles, ground glass viral inclusion.

Chronic Hepatitis: Clinical Transaminase elevation for greater than 6 months Histology Marked portal infiltrates of mononuclear cells (lymphocytes, plasma cells and monocytes) predominate Often have fatigue but few other symptoms Etiology of Chronic Hepatitis: Clinical: HBV HCV Autoimmune Wilsons Disease Alpha 1 anti-trypsin Drug Alcohol / NASH Hemochromatosis Portal inflammation: HBV HCV Autoimmune Wilsons Disease Alpha 1 anti-trypsin Drug PBC / PSC Lymphoma Alcohol/hemochromatosis never produce portal inflammation. PBC/PSC/Lymphoma wont cause transaminases to be elevated, so may be hard to catch.

Test q: Chronic hepatitis may be caused by all of the following except: Hepatitis A virus. (Other choices: HBV, HCV, Autoimmune hepatitis) REPEATED x3 Test q: A 55M presents with fatigue and scleral icterus is noted on exam. Serum transaminases (AST and ALT) are elevated. Review of this patients history reveals that the patient also had AST and ALT elevation 8 months ago. Assuming the same process is responsible for the serum transaminase elevation now and 8mo ago, which of the following is NOT in the differential dx? HAV infection. (Other choices: HBV, HCV, Wilsons disease, a-1antitrypsin deficiency)

Chronic HBV: Positive Hepatitis B serologies; + serum HBV DNA Rule out co-infections i.e HCV and or Delta Treated with anti-virals - lamivudine

All figures above: Chronic hepatitis HBV. 1: Inflammation confined to the portal tracts. Instead of triangles, now are irregularly-shaped (maple leaf appearance). Virus causes an immune reaction that attacks these areas eventually may spread out into the lobule itself. 2: HBV clue: ground glass inclusion in the cytoplasm of hepatocytes. Virus gets out of sync with its production build-up of surface antigen gets carried away, stuck in SER. 3: Anti-HBsAg stain. Characteristic inclusions show up. 4: Anti-HBcAg stain. Core antigen almost always located in the nucleus.
Test q: The gross photo below shows an autopsy liver (2007 Exam 2, #22 cant see picture very well). The most likely etiology for the pathologic change seen is: HBV infection. (Other choices: HAV infection, Acute acetaminophen toxicity, Right heart failure)

Chronic HCV Positive serum anti - HCV antibody; + rt PCR for serum HCV RNA Treatment with interferon and ribavirin

HCV is often an incidental finding on an insurance physical. There are 7+ different strains. Mostly 1a in the USA resistant to ribavirin therapy.

1. Chronic hepatitis HCV. Same slide as HBV. Cant tell HBV from HCV histologically there are characteristics of each that may allow you to lean toward one dx or the other, but they are not diagnostic. 2. Chronic hepatitis HCV. Inflammation in portal tract border not smooth anymore irregular. Nodular inflammation. Looks like its trying to make a lymphoid follicle = not specific, but fairly characteristic of HCV. 3. Chronic hepatitis HCV. Injury to bile duct epithelium bile duct nuclei pretty big. Lymphocytes inside, squishing up against the epithelium but do not see elevated alkaline phosphatase/GGT or cholestasis.
Test q: Chronic hepatitis showing nodular lymphocytic infiltrates w/germinal center formation within the portal areas, intraepithelial lymphocytes within the bile ducts, and prominent steatosis is most likely due to: Hepatitis C virus. (Other choices: HAV, HBV, Autoimmune hepatitis) Test q: A 29F presents w/jaundice and a liver biopsy is performed. The biopsy shows a portal area lymphocytic infiltrate and occasional single shrunken hepatocytes w/small dark nuclei and orange cytoplasm. The lymphocytic infiltrate is nodular in some areas and lymphocytes infiltrate the bile duct epithelium. Mild steatosis is also seen. What diagnosis should be suspected? Hepatitis C. (Other choices: alcoholic liver disease, HBV, autoimmune hep) Test q: A 40M w/a history of IV drug abuse presents w/mild jaundice. The patient states that the jaundice has been present for over 1 yr. After serologic studies are performed, a liver biopsy is obtained. The biopsy shows liver w/portal areas which are expanded by nodular lymphocyte aggregates, periportal necrosis of individual hepatocytes, bridging fibrosis, and mild-to-moderate steatosis. Plasma cells and hepatocytes with ballooning degeneration are not seen. These findings are most compatible with which of the following? Hepatitis C virus infection. (Other choices: HAV, HBV, autoimmune hepatitis)

Autoimmune Hepatitis Chronic (90+%) > Fulminant > acute Female > Male May affect children Elevated transaminases and gamma globulins, total protein, +/- jaundice Positive serum marker: ANA, ASMA, LKM o ASMA = anti smooth muscle antibody o LKM liver kidney microsomal antibodies Bx = chronic hepatitis with plasma cells Tx = immunosuppression - steroids Both figures: Chronic hepatitis Autoimmune hepatitis. Left: See dense infiltrate plasma cells mixed in. Right: Eccentric nuclei, clockface appearance, plasma cells
Test q: A 60F reports a yellow discoloration of her skin to her physician. Phys exam confirms the presence of jaundice, but no other abnormalities are noted. Lab studies show elevation of bilirubin, AST, and ALT. An ANA titer is elevated. A liver core needle biopsy is performed. It shows expansion of the portal triads by chronic inflammatory cells, a mixture of lymphocytes and plasma cells. The bile ducts and blood vessels in the portal triads are unremarkable. Away from the portal inflammatory infiltrate, the hepatocytes are unremarkable w/no abnormal pigment visible. The most likely diagnosis is: Autoimmune hepatitis. (Other choices: Chronic viral hep, Hemochromatosis, Wilsons disease) Test q: A 30F presents w/nausea, vomiting, and fever. Upon admission to the hospital, the serum ALT and AST are both over 1000. She develops jaundice and mental status changes. A liver biopsy shows inflammatory infiltrates in the portal tracts that include numerous plasma cells. Which of the following lab tests may be useful in confirming the diagnosis? Anti-nuclear antibody (ANA) or anti-smooth muscle antibody (ASMA). (Other choices: Lipase, Serum alpha-1-antitrypsin, Ceruloplasmin)

Wilsons Disease: Genetic defect - ATP7B (13q14.3) - a transmembrane copper transporting ATPase is defective Liver disease - copper injury in liver (bx = normal liver, fatty change, chronic hepatitis, cirrhosis) Neurologic disease - copper injury in putamen presents before 35 years of age decreased serum ceruloplasmin (enzyme involved in iron metabolism for some reason, its low in Wilsons) Kayser-Fleischer rings Tx = penicillamine Get hepatitic symptoms early, neuro symptoms predominate later
Test q: A 20M w/peripheral discoloration of the iris bilaterally is suspected of having Wilsons disease. Which of the following tests/procedures is most useful in confirming or rejecting this suspected diagnosis? Ceruloplasmin. (Other choices: Anti-smooth muscle antibody, Serum protein electrophoresis, Ferritin, ERCP)

Both figures: Chronic hepatitis Wilsons Disease. Left: Chronic inflammatory infiltrate in portal tract. Right: Hepatocytes retaining copper. May see Mallory bodies condensed collapsed cytoskeleton pink amorphous globule in hepatocyte.
Test q: A 22M presents w/jaundice. He is unemployed and has a several year history of psychiatric problems. Serum AST is 130 (normal 25-45), ALT is 85 (0-35), ferritin is 44ng/mL (29-371), and ceruloplasmin is 3 mg/dL (12-48). A liver biopsy is performed and shows periportal fibrosis and mild-tomoderate steatosis. Light brown pigment is seen in the hepatocytes. What disease should be suspected? Wilsons disease. (Other choices: HBV infection, Hemochromatosis, a-1-antitrypsin deficiency) REPEATED x2 Test q: A 19F is bothered by a tremor at rest, which becomes progressively worse over the next 6mo. She begins to act strangely and is diagnosed w/an acute psychosis. On phys exam, she has slight scleral icterus. A slit-lamp exam shows corneal Kayser-Fleischer rings. Lab findings include total serum protein of 5.9 g/dL (normal: 6.6-7.8), albumin 3.1 g/dL (3.5-5.0), total bilirubin 4.9 mg/dL (0-1), direct bilirubin 3.1 mg/dL (0-0.2), AST 128 U/L (2545), ALT 157 U/L (0-35), and alkaline phosphatase 56 U/L (17-142). Which of the following additional serologic test findings is most likely to be reported in this patient? Decreased serum ceruloplasmin level. (Other choices: Positive HBsAg, Decreased a-1-antitrypsin level, Increased serum ferritin level, Positive anti-mitochondrial antibody)

Alpha 1- antitrypsin deficiency: Genetic defect - chromosome 14; at least 75 alleles - PiMM = normal, - PiZZ = most common abnormality May present at any time, neonate to adult Decreased serum alpha 1- antitrypsin levels Bx = chronic hepatitis or cirrhosis with PAS +, diastase resistant globules Microscopically, see eosinophilic cytoplasmic inclusions of AAT

All figures above: Chronic hepatitis Alpha 1 ATD 1. See lymphocytes. 2. PAS with diastase pre-digestion. Heterozygotes form inclusions but may be ok clinically 3. anti-alpha 1 anti-trypsin (IMPOX)
Test q: A 69F w/a long history of pulmonary emphysema presents w/jaundice and a liver biopsy is performed. The biopsy shows cirrhosis. Within the hepatocytes, eosinophilic, round globules are seen. These globules are positive with a PAS stain. The most likely dx is: Alpha-1-antitrypsin deficiency. (Other choices: Wilsons disease, HBV, Autoimmune hepatitis) Test q: A 35M presents w/nausea and jaundice. Serum transaminases are elevated and a liver biopsy is performed. The biopsy shows a portal triad lymphocytic infiltrate. Some hepatocytes have eosinophilic cytoplasmic inclusions. These stain bright pink on a periodic acid Schiff-diastase stain. What is the dx? a-1-antitrypsin deficiency. (Other choices: Alcoholic liver disease, HBV, Wilsons disease) REPEATED x2 Test q: A 28M has had increasing shortness of breath for the past year. On phys exam, he is afebrile and normotensive. Breath sounds are decreased in all lung fields. His medical history indicates that he developed marked icterus as a neonate, but he has been healthy since then. Because of the family history of liver disease, a liver biopsy is performed. The sections show fibrosis and abundant round eosinophilic granules within damaged hepatocytes. These are positive on a PAS stain. The patient is at very high risk for the development of which of the following conditions? Pulmonary emphysema (Other choices: Diabetes mellitus, CHF, Ulcerative colitis, SLE) Robbins explanation: The PAS-positive globules in the liver seen here are characteristic of AAT deficiency. Approximately 10% of individuals w/the homozygous deficiency (PiZZ phenotype) of AAT deficiency develop significant liver disease, including neonatal hepatitis and progressive cirrhosis. Deficiency of AAT also allows unchecked action of elastases in the lung, which destroys the elastic tissue and causes emphysema.

Drug Induced Chronic Hepatitis: No specific findings process of elimination Numerous drugs including: Methotrexate, INH, Nitrofuratoin, Dantrolene, etc. Chronic Hepatitis: HCV HBV Autoimmune Wilsons Alpha 1 Drug Hemochromatosis Alcohol serum assay serum assay ANA, ASMA, LKM ceruloplasmin, urine Cu serum electrophoresis exclusion, history ferritin, genetic test, biopsy exclusion, history, biopsy

Grading of Chronic Hepatitis: Many different systems Know what your pathologist uses
Grad 0 1 mild 2 moderate 3 severe Portal changes None Patchy interface hepatitis More extensive interface hepatitis in many tracts Circumferential interface hepatitis in most tracts Lobular changes none Occasional patchy foci of liver injury Multiple foci of injury per lobule Bridging necrosis

Staging of Chronic Hepatitis: Many different systems Portal fibrosis and periportal fibrosis often refer to the same thing know what system your pathologist uses Metavir system F 0 = No fibrosis F 1 = Periportal fibrosis F 2 = Focal bridging (septal) fibrosis F 3 = Bridging (septal) fibrosis F 4 = Cirrhosis Staging and Treatment Response:

Chronic hepatitis interface hepatitis:

From First Aid Hemochromatosis: disease caused by hemosiderosis (deposition of iron). Classic triad of micronodular cirrhosis, diabetes mellitus, and skin pigmentation bronze diabetes. Results in CHF and increased risk of hepatocellular carcinoma.
Test q: Common complications of genetic hemochromatosis include all of the following EXCEPT: Neurologic symptoms including ataxia due to damage to the putamen. (Other choices: Diabetes mellitus, Cutaneous hyperpigmentation, Hepatocellular carcinoma)

Cirrhosis: Diffuse process characterized by fibrosis and the conversion of normal liver architecture into abnormal nodules Cirrhosis: Clinical Features: Vascular spiders, asterixis, palmer erythema Large liver Splenomegaly (congestive) o Decreased platelets Where does Cirrhosis come from? Ascites Varices +/- Jaundice

After you injure enough hepatocytes, they secrete cytokines that stimulate the stellate cells they are the bad guys who produce the type I collagen/fibrosis.

Normal:

Periportal fibrosis F1:

Septal fibrosis, Focal bridging, F2:

Lines = fibrous bands Bridging fibrosis F3: Cirrhosis:

Fibrous bands get longer and thicker, connect w/other vascular structures.

Fibrous bands hook up. Lots of hepatocytes but no longer a central vein.

Test q: A liver core needle biopsy shows nodules of hepatocytes that are separated by bands of fibrosis w/a chronic inflammatory cell infiltrate. In order to make the diagnosis of cirrhosis, what additional info do you need? The process is diffuse. (Other choices: The fibrosis has been present for at least 6mo. The ALT and AST are elevated. Steatosis is present)

1. Cirrhosis: Blood flow disrupted, in fibrous bands. Hepatic parenchyma balls up football shape nodules. 2. Micronodular Cirrhosis. 3mm or less 3. Micronodular Cirrhosis. Upper left can see where portal tract was. Structures get incorporated into the fibrous bands. No central vein.

4. Macronodular Cirrhosis. Seen w/congenital Hepatitis B, syphilis, etc had it for so long, it remodels into this. 5. Macronodular Cirrhosis. Light pink areas = nodules. 6. Needle core biopsy.

Cirrhosis: Compensated Fibrosis/rearrangement present but patient still has fair amount of liver parenchyma fibrosis hasnt impinged on the vasculature too much can still perform detoxifying functions Decompensated Hydrostatic problems Synthetic failure Detoxifying failure Chronic hepatitis often progresses to cirrhosis Etiology of cirrhosis may or may not be apparent HCV most common cause of cirrhosis seen at this institution Problems with Cirrhosis: Bleeding Varicies Decreased platelets and clotting factors Ascites Increased venous pressure Decreased oncotic pressure Spontaneous bacterial peritonitis Encephalopathy Decreased detoxifying capacity Jaundice Decreased detoxifying capacity Hepatoma All of the above contribute to high mortality Liver Function Tests (LFTs): Cirrhosis therapy: TX = symptomatic TIPPS relieves increased portal pressure eases ascites, bleeding Lactulose, low protein diet for encephalopathy Albumin, nutrition Transplantation th IU 5 most liver transplants in USA, 2009 Rejection, opportunistic infection, recurrent disease, PTLD = management problems PTLD post-transplant lymphoproliferative disorder

Jaundice: Bilirubin hemoglobin breakdown Conjugated in liver - homeostasis Hyperbilirubinemia (>2 mg/DL) Prehepatic - hepatic - posthepatic Cholestasis: Impairment of bile flow Alk Phos, GGT Bile complex substance made up of bilirubin, bile acids and salts, proteins, electrolytes and water Secreted by hepatocytes, altered by bile ducts Acute or Chronic Hemolytic anemia jaundice but no cholestasis. Too much bilirubin, nothing wrong w/liver, canalicular enzymes are ok.
Test q: Which of the following concerning gamma-glutamyl transferase is true? It is more characteristic of bile duct cell injury than hepatocyte injury. (Other choices: An older name is serum glutamate pyruvate transferase [SGPT], It declines w/increasing ethanol intake, It is usually low [less than 5U/L] in patients taking oral contraceptives or barbiturates.) REPEATED x2

Test q: A 36F has become increasingly icteric for 1 month. In the past 3yr, she has had several bouts of colicky, midabdominal pain. On phys exam, she has generalized jaundice w/scleral icterus. There is tenderness in the RUQ and the liver span is normal. A liver biopsy is done. Micro exam of the specimen shows bile duct proliferation and intracanalicular bile stasis, but no inflammation or hepatocyte necrosis. Which of the following serum lab findings is most likely to be present in this patient? Elevated alkaline phosphatase. (Other choices: Markedly increased antimitochondrial antibody, Postive HCV antibody, Markedly elevated indirect bilirubin level, Increased blood ammonia level) REPEATED x2 Robbins explanation: The findings suggest obstructive jaundice from biliary tract disease (e.g., gallstones). Elevation of the serum alk phos level is characteristic of cholestasis. The alk phos comes from bile duct epithelium and hepatocyte canalicular membrane.

1. Chronic Cholestasis Ductular Reaction. Fluids dont flow well, tend to get edema in the portal tract more space in between cells 2. Chronic Cholestasis Cholate stasis. Feathery degeneration of hepatocytes at the edge of the portal tract. Much is retained bile acids and bile salts get out into serum, patient presents as itchy. 3. Canilicular Cholestasis. May be able to see bile in dilated canaliculi. 4 5 4. Chronic Cholestasis Mallory Denk bodies. MD bodies found in hepatocytes. Also seen in alcohol and Wilsons disease. 5. Chronic Cholestasis Copper Retention. Hepatocytes around the portal tracts can retain copper. Also seen in Wilsons disease

Primary Biliary Cirrhosis (PBC) Peak incidence 40 to 60 years 10 to 15:1 female to male Presenting features: Pruritus = itching Skin pigmentation Hepatomegaly Xanthomas / xanthelasmas (30%) Jaundice (late) Etiology unknown, associated with other autoimmune disorders Symptomatic patients survive 10-15 years after the onset of jaundice Laboratory findings: Anti-mitochondrial antibody (AMA) 90+% M2 (ATP synthase) said to be specific Markedly increased alkaline phosphatase Other LFTs may be elevated; bili late Complications include cirrhosis and osteoporosis Tx Actigall for pruritus; Transplantation Both figures: Chronic Cholestasis PBC Looks similar to chronic hepatitis. Injury to bile ducts. Lots of lymphocytes +/- plasma cells. Poorly formed granuloma see epithelial histiocytes.

Test q: A 52F presents w/itching. Lab investigation demonstrates an increased alkaline phosphatase and gamma-glutamyl transferase. Which of the following would be supportive of a diagnosis of primary biliary cirrhosis? Increased antimitochondrial antibodies. (Other choices: Decreased serum ceruloplasmin, Increased aspartate aminotransferase, Increased serum AFP) Test q: A 50F presents w/itching and mild jaundice. Phys exam is significant for jaundice and multiple cutaneous xanthomas which the patient says, along with a generalized darkening of her skin, have appeared over the last year. Serum AST is 165 (normal 25-45), ALT is 102 (0-35), and alkaline phosphatase is 415 (24-125). Which serum test is most likely to confirm the suspected clinical dx? Antimitochondrial antibodies. (Other choices: ANA, Antiendomysial antibodies, Anticentromere antibodies) Test q: A 44F has noticed increasingly severe generalized pruritus for the past 8mo. Serum level of alkaline phosphatase and cholesterol are elevated, anti-mitochondrial antibody titer is elevated, but ANAs are not present. The serum total bilirubin concentration increases. A liver biopsy is done and the biopsy shows nonsuppurative granulomatous destruction of medium-sized bile ducts. Which of the following conditions is most likely to be present? Primary biliary cirrhosis. (Other choices: a-1-antitrypsin deficiency, Autoimmune hepatits, Choledocholithiasis, Hereditary hemochromatosis) REPETAED x3 Test q: Presence of a serum antimitochondrial antibody (AMA) is most predictive of the presence of which of the following disorders? Primary biliary cirrhosis. (Other choices: SLE, Primary sclerosing cholangitis, Wilsons disease, Hemochromatosis) Test q: A 45F is noted to have hepatomegaly at an office visit for other reasons. Her skin is excoriated in several areas and she gives a history of itching. Lab studies indicate slightly elevated serum transaminases and an elevated alkaline phosphatase. An antimitochondrial antibody (AMA) is positive. The most likely diagnosis is: Primary biliary cirrhosis. (Other choices: Primary sclerosing cholangitis, Wilsons disease, Hemochromatosis)

Primary Sclerosing Cholangitis (PSC): Presents 20 to 50 years 2-3:1 male to female Etiology unknown autoimmune type disorder Vague presentation fatigue, pruritus (itchy), jaundice (late) Pathognomonic lesion of PSC onion-skinning fibrosis Associated with Ulcerative Colitis (50-70%) ~ 5% of UC patients develop PSC Elevated alkaline phosphatase/GGT, No other serum markers Progresses to cirrhosis Risk of cholangiocarcinoma Tx = symptoms + transplantation

ERCP

MR cholangiogram

(ERCP = endoscopic retrograde cholangiography)

Instead of nice smooth tubular dye filling, get beaded pattern sacculations and constrictions (shown above).
Test q: A 41M has experienced progressive fatigue, pruritus, and icterus for several months. A colectomy was performed several years ago for ulcerative colitis. On phys exam, he now has generalized jaundice. The abdomen is not distended. On palpation there is no abdominal pain and no mass. Lab studies show a serum alkaline phosphatase level of 285 U/L. Cholangiography shows widespread obliteration of intrahepatic bile ducts and a beaded appearance in the remaining ducts. Which of the following morphologic features is most likely to be present in this patients liver? Concentric onion skin fibrosis of the bile ducts (Other choices: Copper deposition in the hepatocytes, Granulomatous bile duct destruction, Periportal PAS positive granules, Piecemeal hepatocellular necrosis at the interface of portal tracts.) REPEATED x2 Test q: A 48M w/a history of ulcerative colitis presents w/itching. Serum alkaline phosphatase is elevated and liver biopsy is performed and shows onionskinning fibrosis around the ducts. What other means of evaluation would confirm this patients probably diagnosis? Endoscopic retrograde cholangiography. (Other choices: Hepatitis virus serology, PAS staining of the liver biopsy, Prussian blue staining of the liver biopsy) Test q: A 35M presents w/fatigue and mild jaundice of 1wk duration. ROS is significant for a history of ulcerative colitis beginning 4yr ago that has been minimally active recently. The patient states that he has been very itchy recently. Lab eval is significant for elevation of alkaline phosphatase w/normal ALT and AST. Serologic studies for HBV and HCV are negative. Which of the following should be most strongly suspected? Primary sclerosing cholangitis. (Other choices: Primary biliary cirrhosis, Chronic viral hepatitis, Autoimmune hepatitis, Wilsons disease)

Both figures: Chronic Cholestasis PSC. Hepatic arteries, veins are there. Missing bile ducts. Pathognomonic lesion of PSC onionskinning fibrosis.

Staging Chronic Cholestasis: Stage I = Portal inflammation (florid duct lesion) Stage II = Periportal inflammation / fibrosis Stage III = Bridging fibrosis Stage IV = Cirrhosis Chronic Cholestasis: PSC Men 2-3:1 ERCP Ulcerative colitis Big ducts (spares small ducts) Onion skinning fibrosis PBC Women 6-15:1 AMA + Intermediate ducts Florid duct lesion Secondary Sclerosing Cholangitis Due to mechanical duct obstruction Men ~ Women

Above: Chronic Cholestasis Stage 1-2. See inflammation, swelling in edge hepatocytes, bit of fibrosis.

Alcoholic Liver Disease: 14+ million Americans are alcoholics, M > F Alcohol associated with 200,000 deaths annually Short term ingestion of 80 mg ethanol typically leads to fatty liver Daily intake of 80 mg ethanol leads to significant risk of liver injury Very variable among individuals Only 10-15% of alcoholics develop cirrhosis Etiology of Ethanol Induced Liver Injury: Upregulation of Etoh dehydrogenase and acetalaldehyde dehydrogenase lead to lipid biosynthesis (Increased NADH) GSH decreased leading to oxidative stress Induction of cytochrome P-450 leads to more oxidative stress Millimolar concentrations of ethanol directly toxic to microtubules and mitochondria Acetalaldehyde induces lipid peroxidation and forms adducts disrupting cytoskeleton Adducts may be immunogenic

Alcohol and the liver:

Steatohepatitis: Zone 3 disease Fat usually macrovesicular Hepatocellular injury Ballooning (alcoholic clear cells), acidophil bodies Mallory bodies eosinophilic, pink, zone 3 Giant mitochondria Inflammation often neutrophils Fibrosis early perisinusoidal - chicken wire fibrosis late bridging fibrosis +/- cholestasis

All figures above: Steatohepatitis. 2: See Mallory Denk bodies. 3: Sinusoidal Fibrosis.

Test q: A liver core needle biopsy shows marked macrovesicular steatosis. The portal triads have small numbers of lymphocytes. There are inflammatory cells, predominantly neutrophils, in the lobules, especially in the pericentral zones. At high magnification, enlarged hepatocytes w/clear cytoplasm (ballooning degeneration) are seen. Occasional cytoplasmic rounded granules (giant mitochondria) and irregular, ill-defined eosinophilic inclusions are seen. A trichrome stain shows mild perisinusoidal fibrosis. The most likely diagnosis is: Alcoholic liver disease. (Other choices: a-1antitrypsin deficiency, Chronic viral hep, Autoimmune hep) Test q: Concerning the pathologic differences between viral hepatitis and steatohepatitis, all of the following are true, EXCEPT: The inflammation in viral hepatitis is primarily pericentral (zone 3) and the inflammation in steatohepatitis is primarily in and around the portal area (zone 1). (Other choices: Steatohepatitis typically has macrovesicular steatosis, but steatosis can also be seen in hepatitis C. Giant mitochondria are more characteristic of steatohepatitis. Both can result in fibrosis. The inflammatory cells in viral hepatitis are primarily lymphocytes, but neutrophils may also be seen in steatohepatitis.)

NASH = Non Alcoholic SteatoHepatitis Associated with type II diabetes, hyperlipidemia, and obesity As above increase in population, NASH more common Other causes: jejunal-ileal bypass, drugs i.e. amiodarone May lead to cirrhosis (May be the leading cause of idiopathic cirrhosis) Treatment? Often does poorly after transplantation
Test q: Significant risk factors for NASH include all of the following EXCEPT: Male sex. (Other choices: Obesity, Type II diabetes, Hyperlipidemia) Test q: A liver biopsy shows steatosis, abundant Mallory bodies, pericentral fibrosis surrounding individual hepatocytes, occasional ballooning hepatocytes, and a lobular neutrophil infiltrate. A reasonable differential dx includes all of the following EXCEPT: NASH due to bile duct obstruction. (Other choices: Alcoholic steatohepatitis, NASH due to type II diabetes, NASH due to amiodarone)

NASH Grading: Lobular inflammation (0 = 0; < 2 = 1; 2-4 = 2; > 4 =3, per average lobule @ 20 x) Hepatocyte ballooning (none = 0; few = 1; many = 2) Fatty change (<5% = 0; 5-33% =1; 34-66% = 2; 67-100% =3) NAS score = fat + inflammation + ballooning Score of 5 and above highly correlated with NASH NASH Staging: 1a pericentral fibrosis seen only on special stains 1b obvious pericentral fibrosis 1c periportal fibrosis only 2 pericentral and periportal fibrosis 3 bridging fibrosis 4 cirrhosis 1 2 3

1. Steatohepatitis Zone 3. Inflammation, fat, dropout of hepatocytes, +/- balloon cells, fibrosis 2. Steatohepatitis 3. Steatohepatitis: Electron micrograph. Crystalloid inside mitochondria, fingerprint phagosomes.
Test q: A liver biopsy shows marked steatosis and inflammatory cells including neutrophils infiltrating the lobules, especially in zone 3. A diagnosis of steatohepatitis is made. Which of the following is true concerning the distinction of alcoholic steatohepatitis from nonalcoholic steatohepatitis (NASH)? It is not possible to reliably distinguish the two based on histology. (Other choices: Megamitochondria are seen only in NASH, Asking the patient always provides a reliable estimate of alcohol intake, Mallory bodies are seen only in alcoholic liver disease) Test q: A 48F is noted to have jaundice and lab investigation is significant for elevated serum transaminases (ALT and AST) and gamma-gluatmyl transferase. A liver core needle biopsy is performed and shows abundant intrahepatocytic clear fat vacuoles and neutrophils infiltrating the lobules, particularly in the pericentral regions (zone 3). The differential dx of this finding that should be investigated is: Alcoholic liver disease and nonalcoholic steatohepatitis. (Other choices: Chronic Hep B and chronic Hep C [by serology]. Wilsons and hemochromatosis [by staining the liver biopsy for copper and iron]. Primary biliary cirrhosis and primary sclerosing cholangitis.)

Test q: A 28F, G3P2, is in the 3 trimester of a previously uncomplicated pregnancy when she develops increasing lethargy w/nausea, vomiting, and jaundice over a 10-day period. On phys exam, she has generalized jaundice and scattered ecchymoses over the trunk and extremities. The estimated fetal age is 35wk. Lab studies show total serum bilirubin of 5.8mg/dL, AST of 122 U/L, ALT of 131 U/L, and alkaline phosphatase of 125 U/L. Which of the following histologic features is most likely to be found in a liver biopsy specimen? Marked microvesicular steatosis. (Other choices: Concentric bile duct fibrosis, Periportal PAS-positive hepatic globules, Extensive intrahepatic hemosiderin deposition, Inflammation w/loss of intrahepatic bile ducts) Robbins explanation: This patient has acute fatty liver of pregnancy, an uncommon condition of variable severity. Accumulation of small droplets of fat in hepatocytes (microvesicular steatosis) is the typical histologic finding. This feature is not seen in any of the other conditions listed. The condition may occur because of a defect in intramitochondrial fatty acid oxidation.

rd

Liver Tumors: Bile duct adenoma (hamartoma) Focal Nodular hyperplasia Hepatic adenoma Hemangioma Hepatocellular carcinoma (Hepatoma) Cholangiocarcinoma Metastases Bile duct adenoma Common benign tumor usually found incidentally during abdominal surgery Probable developmental defect Could be confused for metastatic carcinoma Focal Nodular Hyperplasia 2:1 female to male ratio Usually found incidentally, may present as a mass Usually solitary but may be multiple Thought to be a reaction to vascular injury No relationship to OCP Not a precursor to HCCa Central depressed stellate scar Fibrous septae radiate to the periphery

All figures above: Focal Nodular Hyperplasia.

Test q: All of the following are true concerning focal nodular hyperplasia EXCEPT: It is composed of hepatocytes w/solid architecture without fibrous tissue. (Other choices: It is benign and is not thought to be a precursor to hepatocellular carcinoma. It is more common in women. It is usually asymptomatic if small and may be discovered incidentally on CT scan of the abdomen.) Test q: A 48M is involved in a motor vehicle accident and has abdominal pain following the collision. An abdominal CT scan is performed and is negative for evidence of injury related to the collision, but does show an incidental 3cm hepatic mass, just under the capsule of the right lobe of the liver. The nodule is solitary. There is no other evidence or history of liver disease and AST, ALT, and alkaline phosphatase are normal. Several days alter a core needle biopsy is performed and shows hepatic tissue w/nodular architectre, bands of fibrous tissue, and scattered lymphocytes in the fibrous tissue. The most likely diagnosis is: Focal nodular hyperplasia. (Other choices: Bile duct adenoma, Cirrhosis, Hepatic adenoma, Fibromatosis [desmoids tumor]).

Hepatic adenoma: Predominantly females May be seen in certain metabolic disorders Related to OCP and anabolic steroid use Presents as a mass or found incidentally May rupture (hemoperitoneum) so removed surgically May (rarely) give rise to HCCa

All figures above: Hepatic adenoma.

Hepatocellular Carcinoma (HCCa): Most common malignant liver tumor worldwide Usually arises in a background of cirrhosis (70-80%). Other factor implicated: HBV, HCV, hemochromatosis, aflatoxin, etc. o Aflatoxin = any of a class of toxic compounds that are produced by certain molds found in foods Presents with vague symptoms, mass, jaundice, weight loss, metastases Serum alfa-fetoprotein (AFP) level increased (70-80%). Also seen in germ cell tumors Prognosis is poor; tumors with vascular invasion (common 5 cm and above) have 35% five year survival; overall 15% five year survival Mucin-negative

Above: HCCa. Left fine micronodular cirrhosis. Right carcinoma.

Test q: Risk factors for the development of hepatocellular carcinoma include all of the following EXCEPT: Focal nodular hyperplasia. (Other choices: Cirrhosis due to alcoholic liver disease, HBV infection, eating moldy peanuts) Test q: Which of the following is true concerning hepatocellular carcinoma? Prognosis is poor, with <40% 5-year survival. (Other choices: HAV infection is a significant risk factor; Serum AFP is usually elevated in the fibrolamellar variant; If a peritoneal effusion develops in a patient w/a history of cirrhosis, the effusion frequently has metastatic hepatocellular carcinoma cells in the effusion.) Test q: A patient w/a liver mass has a markedly elevated serum alpha-fetoprotein. What is the probable diagnosis? Hepatocellular carcinoma. (Other choices: Cholangiosarcoma, Metastatic signet ring adenocarcinoma of gastric origin, Angiosarcoma) Test q: A 60M has an abdominal CT scan and a 3cm hepatic mass is discovered. Serum a-fetoprotein is 20 ng/mL (normal: 0-25). A core needle biopsy performed. This shows epithelial cells arranged in gland-like groups with pale blue material in the cytoplasm and in the lumens. A mucicarmine stain confirms the presence of intracellular and extracellular mucin. A reasonable differential dx includes all of the following EXCEPT: Hepatocellular carcinoma. (Other choices: Cholangiosarcoma, Metastatic adenocarcinoma of colorectal origin, Metastatic adenocarcinoma of gastric origin) Test q: A 56M from Shanghai, China, has experienced fatigue and a 10kg weight loss over the past 3mo. Phys exam yields no remarkable findings. Lab test results are positive for hepatitis B surface antigen (HBsAg) and negative for anti-HCV and anti-HAV. An abdominal CT scan shows a 10cm solid mass in the left lobe of a nodular liver. A liver biopsy of the lesion indicates hepatocellular carcinoma. Which of the following mechanisms is most likely responsible for the development of this lesion? Repeated cycles of liver cell necrosis and regeneration caused by HBV infection. (Other choices: Insertion of the HBV DNA in the vicinity of the C-MYC oncogene. Inherited mutation in the DNA mismatch-repair genes. Development of a hepatic adenoma that accumulates mutations. Coinfection with Clonorchis sinensis.) Robbins explanation: There is a long-term risk of hepatocellular carcinoma in patients infected w/HBV. This infection is more common (often from vertical transmission) in Asia than in N. America and Europe, and it accounts for more cases of primary liver cancer worldwide than other causes, such as chronic alcoholism. Most likely, neoplastic transformation occurs bc HBV induces repeated cycles of liver cell death and regeneration. This repeated cycling increases the risk of accumulating mutations during several rounds of cell division. Test q: A 61M has had ascites for the past year. After paracentesis w/removal of 1L of slightly cloudy, serosanguinous fluid, phys exam shows a firm, nodular liver. Lab findings are positive for serum HBsAg and anti-HBc. He has a markedly elevated serum a-fetoprotein level. Which of the following hepatic lesions is most likely to be present? Hepatocellular carcinoma (Other choices: Massive hepatocyte necrosis, Marked steatosis, Wilsons disease, Autoimmune hepatitis) Robbins explanation: The elevated alpha-fetoprotein is most suggestive of hepatocellular carcinoma, which arises in cirrhosis. The presence of HBsAg and anti-HBc indicates chronic infection w/HBV, which gave rise to cirrhosis and, ultimately, to liver cell cancer.

1. Incidence of HCCa by region and age: higher incidence in the East. 2. Incidence of HCCa: per 100,000.

3. Incidence of Chronic HBV infection. 4. HCCa HBV and Aflatoxin. If no exposure to either OR one or the other odds are ok. But if you have both things, risk is greatly magnified.

5. Primary liver carcinoma. People at the top have liver flukes get into bile ducts liver cancer. 6. Hepatocellular Carcinoma. Characteristic finding = bile in neoplastic cells.

All figures above: Hepatocellular carcinoma. In middle figure, can see ancillary cells hanging out at the edges. Mets can show these same cells. Characteristic finding = bile in neoplastic cells.

All figures above: Hepatocellular carcinoma. Middle = Reticulin stain. Can see that cells have proliferated and expanded. Right = Anti- alpha feto-protein (IMPOX). HCC will have solid growth or rosette-like architecture. Nuclei may be somewhat enlarged and pleomorphic. Therapy for Liver Cancer: Resection Transplantation Chemoembolization Sclerotherapy Radiofrequency ablation Cryotherapy Chemotherapy

Above: Hepatocellular carcinoma.

Test q: A 60M presents w/a pathologic fracture. CT scan reveals multiple tumors involving the lungs, liver, and bone. A liver core needle biopsy is performed. The biopsy shows poorly differentiated malignant epithelial cells with a moderate amount of eosinophilic cytoplasm and no desmoplastic response. Bile pigment is present within some of the tumor cells. The best dx is: Hepatocellular carcinoma. (Other choices: Metastatic carcinoma, the site of origin cannot be determined. Metastatic non-small cell carcinoma of lung origin. Cholangiosarcoma.) Test q: A 67M w/a long history of Hep C-related liver disease notes weight loss and worsening of his jaundice. A CT scan of the abdomen demonstrates a 4cm mass near the hilum of the liver. An ultrasound-guided core needle biopsy is performed. The biopsy shows cells w/round, mildly enlarged and pleomorphic nuclei and moderately abundant eosinophilic, somewhat granular cytoplasm. They are arranged in solid and pseudoglandular patterns. There is bile in the gland-like spaces in the pseudoglandular areas. A mucin (mucicarmine) stain is performed and it is negative. The most likely diagnosis is: Hepatocellular carcinoma. (Other choices: Cholangiocarcinoma, Metastatic colorectal adenocarcinoma, Angiosarcoma, Hepatocellular adenoma) Test q: A 60M presents w/jaundice and unintentional weight loss. During the eval of this patient, a 6cm solitary liver mass is discovered near the hilum of the liver. A core needle biopsy is performed and shows malignant glands with an invasive growth pattern and moderate to marked nuclear enlargement and pleomorphism. A mucicarmine stain is positive. Which of the following is true? The tumor is not a hepatocellular carcinoma. (Other choices: The tumor cannot be a metastasis because it is a single mass. The positive mucicarmine stain proves that it is metastatic colorectal adenocarcinoma. The patient probably will be cured by excision of the tumor. The tumor might be a hemangioma.)

Staging of Hepatocellular Carcinoma 2009: Primary Tumor (T) TX Primary tumor cannot be assessed T0 No evidence of primary tumor T1 Solitary tumor without vascular invasion T2 Solitary tumor with vascular invasion; or multiple tumors, none more than 5 cm in greatest dimension T3 Multiple tumors more than 5 cm in greatest dimension or tumor involving a major branch of the portal or hepatic veins(s) T3a Multiple tumors more than 5 cm T3b Tumor(s) any size involving a major branch of the portal or hepatic vein(s) T4 Tumor(s) with direct invasion of adjacent organs other than the gallbladder or with perforation of visceral peritoneum Regional Lymph Nodes (N) NX Regional lymph nodes cannot be assessed N0 No regional lymph node metastasis N1 Regional lymph node metastasis Distant Metastasis (M) M0 No distant metastasis M1 Distant metastasis Hepatocellular Carcinoma Survival by Stage: Stage Groupings Stage I T1 N0 M0 Stage II T2 N0 M0 Stage IIIA T3a N0 M0 o IIIB T3b N0 M0 o IIIC T4 N0 M0 Stage IVA any T N1 M0 Stage IVB any T any N M1

Even low stage tumors have bad 5-yr survival rates (55%).

Fibrolamellar Carcinoma: Children and young adults Etiology unknown No cirrhosis No elevated AFP Prognosis curve shifted right by approximately 5 years Tx= surgery
Test q: The fibrolamellar variant of hepatocellular carcinoma differs from the usual type of hepatocellular carcinoma in that: fibrolamellar variant is usually not associated w.an increased serum AFP (Other choices: Fibrolamellar variant only occurs in adults, Fibrolamella variant is always a result of HBV, Fibrolamellar variant always occurs in a background of cirrhosis.)

All figures above: Fibrolamellar Carcinoma.

Cholangiocarcinoma: Adenocarcinoma of intra-hepatic bile ducts Male > female, middle age Presents w/jaundice and weight loss Associated with PSC Prognosis is poor, but data is poor Tx = surgery Ill-defined hilar lesion

Cholangiocarcinoma: Multifocal see ductular reaction. Haphazard arrangement of glands. Irregular shapes. Staging of Intrahepatic Bile Duct Carcinoma 2009: Primary Tumor (T) TX Primary tumor cannot be assessed T0 No evidence of primary tumor Tis Carcinoma in situ (intraductal tumor) T1 Solitary tumor without vascular invasion T2a Solitary tumor with vascular invasion T2b Multiple tumors, with or without vascular invasion T3 Tumor perforates the visceral peritoneum or involves local extrahepatic structures by direct invasion T4 Tumor with periductal invasion Regional Lymph Nodes (N) NX Regional lymph nodes cannot be assessed N0 No regional lymph node metastasis N1 Regional lymph node metastasis Liver Cancer Survival: Distant Metastasis (M) M0 No distant metastasis M1 Distant metastasis Stage Groupings Stage I T1 N0 M0 Stage II T2 N0 M0 Stage III T3 N0 M0 Stage IVA T4 N0 M0 o Any T N1 M0 Stage IVB Any T Any N M1

Metastatic tumors: Most common malignant liver tumor in USA is metastatic Colon most common primary site, breast and lung very common Prognosis is poor Tx = chemo for primary, surgery

Test q: A 68F has multiple tumors in the liver. Assuming that they represent metastatic disease, which of the following is the most likely primary site? Colon and rectum. (Other choices: CNS, Bone, Ovary, Skin) Test q: Which of the following is the most common malignant tumor of the liver in the US? Metastatic carcinoma. (Other choices: Cholangiosarcoma, Hepatocellular carcinoma, Angiosarcoma)

Extra Credit: 64 year old woman with elevated LFTs

Extra credit: T. Bili 0.8 AST 25 ALT 30 Alkaline Phosphatase 325 Viral serologies all negative Ceruloplasmin within normal limits AMA, ANA negative On no medications GGT 23 What diagnostic test was performed? Skeletal survey = Pagets Disease of Bone