Practical session [14]-Pathology of Liver (Objectives) Identify morphological changes (gross and microscopic) in Hepatitis, Alcoholic liver disease and Hepatocellular carcinoma

a cellular infiltrate throughout the hepatic lobule- LIVER BIOPSY: The diagnosis is usually based on the clinical presentation and laboratory results, serologic tests. Acute Hepatitis a cellular infiltrate throughout the hepatic lobule- chronic, inflammatory cellular infiltrate and Kupffer cell hypertrophy and hyperplasia. The hepatic cords are also disrupted with evidence of both hepatocyte necrosis and ongoing hepatocyte regeneration. Regenerating hepatocytes are large, frequently containing multiple nuclei. chronic, inflammatory cellular infiltrate and Kupffer cell hypertrophy and hyperplasia.

Cholestasis& MQ reaction Acute hepatitis- MORPHOLOGY cells injury& ballooning Lobular inflammation Cholestasis& MQ reaction

Councilman, or acidophilic, bodies

Questions ◆ What is the most likely diagnosis? ◆ What are the possible etiologies of this disorder? ◆ What other tests would be appropriate? ◆ What are the possible complications? ◆ Describe the morphologic features of this condition?

Questions ◆ What is the most likely diagnosis? Acute viral hepatitis (hepatitis B virus) ◆ What are the possible etiologies of this disorder? Hepatitis B virus- acute infection ◆ What other tests would be appropriate? PCR ◆ What are the possible complications? Progress to Chronic hepatitis or Fulminant hepatitis with confluent necrosis ◆ Describe the morphologic features of this condition? >>>>………………………………

Acute hepatitis B virus- morphology Lobular hepatitis: a cellular infiltrate throughout the hepatic lobule Chronic, inflammatory cellular infiltrate . Loss of normal architecture .  Ballooning of the cytoplasm in degenerating hepatocyte. Kupffer cell hypertrophy and hyperplasia. Hepatocyte necrosis - individually necrotic or apoptotic hepatocytes= Councilman bodies Regenerating hepatocytes are large, frequently containing multiple nuclei. Cholestasis

Case No 2 Over the past 4 days, a previously healthy, 38-year-old woman has become increasingly obtunded. On physical examination, she has scleral icterus. She is afebrile, and her BP is 110/55 mm Hg. Laboratory findings show a PT of 38 seconds, serum ALT of 1854 U/L, AST of 1621 U/L, albumin of 1.8 g/dL, and total protein of 4.8 g/dL withraised plasma ammonia (> 100 IU/L) “hyperammonemia”? From history what’ the most likely diagnosis? Mention other helpful serological investigations? Describe the expected liver morphologic changes?

Case 2: Fulminant hepatitis: liver is smaller than normal, due to extensive areas of liver necrosis. The surface is soft with a wrinkled capsular surface. Acute fulminant hepatitis with massive hepatic necrosis.

Fulminant Hepatitis morphology FH-indicates that the liver has sustained severe damage (loss of function of 80-90% of liver cells) Location: Entire liver or only random areas may be involved. Severe necrotizing process. Inflammatory response: little inflammatory reaction. Macrophages response: Massive influx of macrophages for phagocytosis Ductular reaction: If pt. survive hepatocytes replication started with ductular reaction

Questions ◆ What is the most likely diagnosis? Fulminant hepatitis with massive hepatic necrosis ◆ What are the possible etiologies of this disorder? Acute hepatitis A, acute HBV (+\- HDV), other viruses. ◆ Can you name some causes, other than hepatotropic virus infections, that can cause a similar clinical picture? 1- Toxin- excessive alcohol intake(severe alcoholic hepatitis. 2- Drugs(paracetamol , Aspirin overdose). 3-Hereditary copper accumulation (Wilson's disease) 4- Infection (bacterial….) ◆ What’s the complications of this condition? Renal failure, coagulopathy, cerebral edema, encephalopathy Haemodynamic distrubance, Adrenal insufficiently-hepatorenal syn ◆ Describe themorphologic features of this condition? There is massive necrosis of hepatocytes throughout the lobules in fulminant hepatitis………….

_____________________________________ Case No 3 A 34-year-old woman known case of Hepatitis C virus- HCV presented with fatigue for month ago. LFT along with liver biopsy done for follow-up, staging and grading: _____________________________________ 1- describe the morphologic features? 2- mention other differentials for similar changes? 3- What’s the commonest complications of this conditions?

Chronic Hepatitis: HCV infection

Liver biopsy- lower power Portal hepatitis + focal steatosis Cells necrosis+ inflammation + focal steatosis Cells necrosis+ inflammation + focal steatosis

Chronic Hepatitis: Piecemeal necrosis

Fibrosis with incomplete septa

Answers-HCV I. Describe the morphologic features? 1- Portal hepatitis with acinar extension (chronic inflammatory cells infiltrates). 2- Cells death. 3-Steatosis (focal, diffuse) (mild, moderate, severe) 4- Interphase hepatitis (piecemeal necrosis). 5- Degree of fibrosis II. Mention other differentials for similar changes? Alcohol, DM, Obesity, Malnutrition, AIH, Idiopathic. III. What’s the commonest complications? Cirrhosis, Liver failure, hepatocellular carcinoma.

Liver biopsy: Chronic viral hepatitis (HBV)

Immune-stain positive for HBsAg (right) : hepatocytes show diffuse granular cytoplasm=(ground glass ) H

Hepatocytes nuclei Immune-stained positive for HBc - HBV Hepatocytes nuclei stained positive for HBc - Hepatitis B virus infection Ground-glass appearance- Hepatitis B virus

Morphologic features of HBV-HDV: 1- Hepatocytes cells injury- necrosis (some time progress to form Fulminant-confluent necrosis). 2- Ballooning hepatocytes degeneration with eosinophilic "councilman body" 3- Inter-phase reaction\necrosis (piecemeal necrosis) 4- Hepatocytes- ground glass appearance, indicate intra-cytoplasmic accumulation of HBsAg 5- Mixed chronic inflammatory cells infiltrates. 6- Fibrosis- varying degree

1- LIVER US? 2- LFT? 3- VIRAL MARKER? 4-LIVER BIOPSY Case No 5 A 41-year-old man has a history of drinking 1 to 2 liters of whisky per day for the past 20 years. He has had numerous episodes of nausea and vomiting in the past 5 years. He now experiences a bout of prolonged vomiting, followed by massive hematemesis. On physical examination his vital signs are: T 36.9°C, P 110/min, RR 26/min, and BP 80/40 mm Hg lying down. His heart has a regular rate and rhythm with no murmurs and his lungs are clear to auscultation. There is NO abdominal tenderness OR distension. Bowel sounds are present. His stool is negative for occult blood. 1- LIVER US? 2- LFT? 3- VIRAL MARKER? 4-LIVER BIOPSY

Gross findings: Liver is enlarged (hepatomegaly) and tender.

Alcoholic Fatty Liver: Lipid droplets accumulate in hepatocytes (around hepatic venule) microvesicular or macrovesicular a macrovesicular steatosis

Fatty change: liver Oil Red O stain for fat Intracellular accumulations of a variety of materials can occur in response to cellular injury. Here is fatty metamorphosis (fatty change) of the liver. Most common cause for fatty change is alcoholism. Lipids , water and glycogen, all appear as clear spaces within cells. Stain for lipid : Oil red O and Sudan IV Stain for glycogen : PAS Water does not stain with any stain. Fall 10 A Jalan 26

Alcoholic Hepatitis: The hallmark is the presence of neutrophils surrounding necrotic hepatocytes + Mallory bodies. Fall 10

Alcoholic hepatitis: Mallory's hyaline (Globular red hyaline material within hepatocytes(

Alcoholic hepatitis Neutrophils Mallory body Figure 18-25. A, The cluster of inflammatory cells marks the site of a necrotic hepatocyte. A Mallory body is present in a second hepatocyte (arrow). Figure 18-25 Alcoholic hepatitis. B, Eosinophilic Mallory bodies are seen in hepatocytes, which are surrounded by fibrous tissue Alcoholic hepatitis Neutrophils Mallory body Fall 10 A Jalan

Perivenular fibrosis

Alcoholic Hepatitis (Alcoholic Steatohepatitis)- Morphology Gross findings: Liver is enlarged (hepatomegaly) and tender. Microscopic findings: Hepatocyte swelling Focal liver cell necrosis. Mallory bodies* -characteristic Damaged cytokeratin intermediate filaments in hepatocytes Fatty change Neutrophilic infiltration Perivenular fibrosis* : fibrosis developing around terminal hepatic venule  by prominent activation of sinusoidal stellate cells and portal tract fibroblasts. Is characterized by liver cell necrosis In the centrilobular region. Mallory body: these inclusions are characteristic but not entirely specific for alcoholic hepatitis

Questions ◆ What is the most likely diagnosis? ◆ What are the possible etiologies of this disorder? ◆ What other tests would be appropriate? ◆ What are the possible complications? ◆ Describe the morphologic features of this condition?

Gross: Post-hepatitis cirrhosis The characteristic diffuse nodularity of the surface reflects the interplay between nodular regeneration and scarring [mixed nodularity= macro& micronodularity].The greenish tint of some nodules is due to bile stasis

Microscopic: Diffuse nodularity [mixed nodularity= macro& micronodularity], varying entrapped in blue-staining fibrous tissue. Bridges extend through sinusoids from central to portal regions as well as from portal tract to portal tract.

Chronic hepatitis/with transition to cirrhosis. Answers ◆ What is the most likely diagnosis? Chronic hepatitis/with transition to cirrhosis. ◆ What are the possible etiologies of this disorder? Most commonly caused by: Progressive Alcohol hepatitis chronic viral infection (HCV, HBV)or; chronic toxin exposure (alcohol), (Drugs), ect.. ◆ What other tests would be appropriate? 1-Hepatitis virus serologies: ICT-rapid, ELISA, PCR. 2- Liver biopsy ◆ What are the possible complications? 1. Hepatic failure, 2.gastrointestinal bleeding, 3. HCC.

Case No 7 A 56-year-old man from China, has experienced fatigue and a 10-kg weight loss over the past 3 months. Physical examination yields no remarkable findings. Laboratory test results revealed increase level of AFP (650 nanograms per milliliter (ng/mL)) and positive for HBsAg& Anti HBs. Negative for HBc Ag, Anti HBc, anti- HCV and anti-HAV. Abdominal CT scan shows a 10-cm solid mass in the nodular liver.

Questions ◆ What is the most likely diagnosis? ◆ What are the possible etiologies of this disorder? ◆ Which of the following mechanisms is most likely responsible for the development of this lesion? ◆ What other tests would be appropriate? ◆ What are the possible complications? ◆ Describe the morphologic features of this condition?

Liver tumor - GROSS Neoplasm is large and bulky and has a greenish cast because it contains bile. To the right of the main mass are smaller satellite nodules, indicate local aggressiveness.

Liver tumor - GROSS Large whitish mass with satellite extension to adjacent tissue Liver: Large whitish mass with satellite extension to adjacent tissue

Hepatocellular carcinoma Microscopic app.: B. well-differentiated tumor cells are arranged in nests\acinar with bile pigmentation Liver tumour - GROSS Hepatocellular carcinoma Hepatocellular carcinoma

Hepatocellular carcinoma Microscopic app.: Section of liver nodule: malignant cells in Branching trabeculae

HCC-Fibrolamellar carcinoma A specimen showing a demarcated hard, Scirrhous nodule B, nests& cords of malignant polygonal hepatocytes separated by dense bundles of collagen

Questions ◆ What is the most likely diagnosis? 1-Hepatocellular carcinoma, 2- Fibrolamellar type ◆ What are the possible etiologies of this disorder? 1- chronic viral hepatitis HBV ◆ Which of the following mechanisms is most likely responsible for the development of this lesion? repeated cycles of liver cell death and regeneration. This repeated cycling increases the risk of accumulating mutations during several rounds of cell division. ◆ What other tests would be appropriate? AFP level ◆ What are the possible complications? ………………………………….. ◆ Describe the morphologic features of this condition? …………………………………