Non-Infectious Pathology of the Liver

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Non-Infectious Pathology of the Liver создатель Mind Map: Non-Infectious Pathology of the Liver

1. Drug-Induced Liver Injury

1.1. Commonly Implicated Drugs

1.1.1. Hepatitis Pattern of Injury Acetaminophen Ketoconazole Valproic acid Isoniazid NSAIDs antidepressants

1.1.2. Cholestasis Pattern of Injury Oral contraceptives Estrongens Tamoxifen Androgens Erythromycin Azathioprine

1.1.3. Cholestatic hepatitis NSAIDs Macrolides Beta-lactam antibiotics Amoxicillin-Clavulanate

2. Liver Failure

2.1. Acute liver failure

2.1.1. 50% DILI

2.1.2. Other causes Acute ischemic injury Acute Budd-Chiari Syndrome Neoplastic infiltration Heatstroke

2.1.3. Clinical Manifestations Encephalopathy Hypotension / Circulatory Dysfunction :arrow_down: blood volume Adrenal gland insufficiency Renal dysfunction Features by Organ

2.2. Decompensation of chronic liver disease

3. Neoplasms

3.1. Hepatic adenoma

3.1.1. Benign Bland heepatocytes No cytological atypia no blie ducts vessesl without associated connective soft tissue Intact reticulin framework Morphology

3.1.2. Risk Factors Orap contraceptives Anabolic steroids Metabolic disorders Reproductive-age women

3.2. Hepatocellular Carcinoma

3.2.1. Risk Factors 20% Noncirrhotic liver Chronic hepatitis malginant transofrmation of hepatic adenoma 80% cirrhotic livers Chronic HCV Steatohepatitis

3.2.2. 40% metastatic disease identified at presentation Lung Bone Abdominal lymph nodes

3.2.3. IHC HepPar1 Arginase Glypican

3.2.4. Morphology Mild to marked cytological atypia Benign Liver Benign fatty liver, loss of reticulin framework Loss of normal reticulin framework

3.3. Intrahepatic cholangiocarcinoma

3.3.1. Malignant Biliary epithelium Morphology Mild to marked cytological atypia Prominent growth pattern

3.3.2. Risk Factors Primary sclerosing cholangitis - 5-15% Other Hepatolithiasis Chronic hepatitis Cirrhosis Liver Flukes Fibropolycystic liver disease Ulcerative Colitis

3.3.3. **Cholangiocarcinoma**: Tumor of the **BIle Ducts** Lab Findings :arrow_up: LFTs Tumor Markers :arrow_up: :question: Bilirubin :arrow_up: :question: ALP :arrow_up: :question: Pancreatic Enzymes Signs / Symptoms Obstructive Jaundice Pruritis (Extrahepatic) Weight loss Pain

3.4. Hepatoblastoma

3.4.1. Malignant Epithelial

3.4.2. Most common liver tumor in infants and children 90% of cases Dx before age 5 Strong a/w premature birth, low birth weight

3.4.3. Marked elevation in serum AFP - 90%

3.5. Angiosarcoma

3.5.1. Malignant Vascular neoplasm High grade

3.5.2. Third most common primary liver malignancy

3.5.3. Catastrophic intra-abdominal bleeding - 25%

3.5.4. Unkown etiology; a/w occupational vinyl chloride exposure

3.5.5. IHC Vascular IHC Markers CD31 CD34

3.6. Liver Metastases

3.6.1. More common than primary liver tumors

3.6.2. often multifocal

3.6.3. most tumor types can metastasize to liver

3.6.4. Most common Colon Pancreas Lung Neuroendocrine Breast

4. Liver Review

4.1. Liver Functions

4.1.1. Detoxification Drugs Toxins

4.1.2. Bile Salt Synthesis and Secretion

4.1.3. Bilirubin Uptake Conjugation Secretion

4.1.4. Production of Coagulation Factors

4.1.5. Glucose Homeostasis

4.1.6. Iron homeostasis

4.1.7. Production of albumin Globulins Transferrin

4.2. Flow of Blood and Bile

4.2.1. Blood flows in Portal Vein (Primary) Hepatic Artery (secondary)

4.2.2. Blood flows out Hepatic vein into IVC

4.2.3. Bile flows out Hepatic bile ducts

4.3. Hepatic Lobule Microanatomy

4.3.1. Portal Triad Blood flows IN Bile flows OUT

4.3.2. Central Vein Blood flows OUT Bile production begins

4.3.3. Functional Zones Zone 1 Most resistant to ischemia Zone 2 Zone 3 most sensitive to metabolic toxins most susceptible to ischemia Site of Bile acid synthesis

4.3.4. Sinusoids Kupffer cells Macrophages Housed in sinusoids Stellate cells (Ito cells) perisinusoidal space Fibrinogenesis - Central role Store vitamin A Incomplete basememnt membrane, intercellular gaps

4.4. Bilirubin Metabolism

4.4.1. Heme Biliverdin (Unconjugated) Bilirubin Biliverdin reductase Heme oxygenase NADPH + H+ CO is released Iron is released

4.5. Hyperbilirubinemia

4.5.1. Increased Bilirubin production Hemolytic diseases processes Ineffective erythropoiesis

4.5.2. Inefficient conjugation Gilbert Syndrome UGT1 mutation Physiologic jaundice of newborn Transient low UGT levels Crigler-Najjar syndrome Type II Type I

4.5.3. Alterations in Excretion of conjugated bilirubin Dubin-Johnson Syndrome ABCC2 Mutation Rotor Syndrome SLCO1B1/3 Mutation

4.5.4. Obstruction of biliary flow Biliary atresia Mechanical obstruction Choledocholithiasis Stricture Mass Viral hepatitis

4.5.5. Causes of elevated bilirubin levels

5. Histological Findings

6. Risk Factors

7. Lab Findings

8. Cirrhosis

8.1. Entire Liver involved

8.1.1. Fibrous septa subdivide parenchyma into nodules

8.2. Mechanism

8.2.1. Kupffer cells activated following injury Release Cytokines Portal fibroblasts activated Stellate Cells stimulated

8.2.2. Normal vs Chronic liver

8.3. Progression

8.3.1. Early-Stage Vascular remodeling Sclerosis of portal tracts Contraction of stellate cells Periventricular fibrosis

8.3.2. Late-Stage Vascular changes Shunting of blood

8.4. Clinical Manifestations

8.4.1. Liver Damage Effects Hepatic insufficiency Hyperestrinism Spider nevi Pectoral alopecia Gynecomastia Altered hair distribution

8.4.2. Portal Hypertension Effects Portal Hypertension per se Hypersplenism

9. Immune-Mediated Liver Diseases

9.1. Autoimmune hepatitis: Type 1: :arrow_up: ANA, ASMA Type 2: :arrow_up: Anti-Liver/-Kidney microsomal-1 *Broad clinical picture from asymptomatic AST/ALT elevations to ALF *

9.1.1. Strong female predominance

9.1.2. Autoantibodies Against hepatocytes

9.1.3. Lab findings ANA :arrow_up: - 80% ASMA :arrow_up: - 70% Polyclonal hypergammaglobulinemia ALP normal or slightly elevated AST and ALT vary

9.1.4. Histologic Features Zone 1 hepatocellular injury Prominent plasma cell population

9.2. **Primary Biliary Cholangitis**: Autoimmune destruction of **Intrahepatic bile ducts** in middle-aged women. *Cholestatic Pattern of Liver Injury * :arrow_up: AMA

9.2.1. Middle-aged female

9.2.2. Lab findings Early Disease Bilirubin, AST, ALT - normal or mildly elevated :arrow_up: ALP :arrow_up: GGT :arrow_up: Cholesterol Advanced disease :arrow_up: Bilirubin (progressive rise in levels) :arrow_up: ALP :arrow_up: GGT :arrow_up: Cholesterol :arrow_up: AMA - 95% Cholestatic Pattern of Liver Function Test

9.2.3. Histological features Florid duct lesion Dense portal lymphoplasmacytic infiltrate Granulomas Hepatic lobules *undamaged *

9.2.4. Continued injury results in bile duct loss cholestasis

9.2.5. Clinical Manifestations (of progressive cholestasis) Pruritis Jaundice Hyperlipidemia Fat-soluble vitamin deficiency Typical Presentation Pruritus + Cholestatic Pattern of Liver Function Test

9.3. secondary biliary Cirrhosis

9.3.1. Uncommon complication of chronic biliary obstruction Resultant biliary cirrhosis

9.3.2. Biliary Fibrosis Portoseptal fibrosis Caused by the ductular reaction with loss of periportal hepatocytes Eventual linking of portal tracts Result of Extension of fibrosis Initial preservation of intrahepatic vascular relationships preserved by portal-portal fibrous links Continued loss of hepatocytes leads to cirrhosis

9.4. **Primary Sclerosing Cholangitis**: Inflammation / Fibrosis of **Intrahepatic and Extrahepatic Bile Ducts** Most patients have IBD (UC > Crohn) *Cholestatic Pattern of Liver Injury *

9.4.1. Adults 20 - 40, even M:F

9.4.2. Strong association with IBD Ulcerative colitis

9.4.3. Increased risk of cholangiocarcinoma

9.4.4. Hallmark clinical finding Abnormal cholangiogram "beaded" appearance of biliary tree on ERCP or MRCP

9.4.5. Lab Findings Liver Biopsy Rule out other diseases Non-specific or normal findings

9.4.6. Typical Presentation Pruritus + Cholestatic Pattern of Liver Function Test

10. Steatohepatitis

10.1. Defined by 3 components

10.1.1. 1. Steatosis Simple Steatosis on its own is a form of NAFLD

10.1.2. 2. Inflammatory activity Pericellular Fibrosis (Trichrome stain)

10.1.3. 3. Cell injury

10.2. Divided into 2 categories

10.2.1. NASH Inflammatory progression of NAFLD Pathogenesis: Two-hit hypothesis 1. Fat accumulation places hepatocytes under stress 2. Second insult results in inflammation, cell death, fibrosis Outcomes vary Remains stable regressing to simple steatosis Progressing to cirrhosis Lab Findings Liver Enzymes? Poor sensitivity for NAFLD ANA Imaging studies Histological Findings Ballooning hepatocytes +/- Mallory-Denk bodies Lobular inflammation Macrovesicular steatosis

10.2.2. Alcohol-related steatohepatitis Alcohol-induced injury is a multifactorial process Primary Mechanism Acetaldehyde Risk factors Amount of alcohol consumed Sex - F > M Central obesity Patterns of consumption Associated medication Coffee intake Genes regulating expression of proinflammatory cytokines and immune response mechanisms Lab findings AST:ALT ≥ 2 Bilirubin disproportionately high compared to ALP Histological Features Identical to NASH "Soft" features

10.3. NAFLD (Non-Inflammatory)

10.3.1. Two Primary categories Simple steatosis Steatohepatitis NASH Alcohol-Related Steatohepatitis

10.3.2. Most common liver disease in western countries

11. Inborn errors of metabolism

11.1. Hereditary Hemochromatosis: Autosomal Recessive Disorder of Increased Iron Absorption :arrow_right: iron overload in tissues.

11.1.1. Autosomal Recessive *HFE* gene mutations C282Y gene

11.1.2. :arrow_down: hepcidin synthesis Dysregulated iron homeostasis

11.1.3. Clinical Manifestations 5th or 6th decades Symptoms manifest 2° to cirrhosis cardiomyopathy / Heart Failure Bronze diabetes Arthritis Lab Findings Transferrin Saturation ≥ 45% Ferritin: > 200 (men); > 150 (women)

11.1.4. Pathogenesis of Iron Accumulation Periportal hepatocytes oxidative damage to hepatocytes from excess iron Cirrhosis, fibrosis

11.1.5. Treatment Weekly Phlebotomy Monitor serum ferritin levels for efficacy

11.2. Wilson's Disease Autosomal Recessive Disorder of Impaired Copper Transport :arrow_right: Copper overload in **Brain** and **Liver**

11.2.1. Autosomal Recessive *ATP7B* gene Transmembrane copper transporting ATPase in hepatocytes

11.2.2. Clinical Manifestations Mean age at Dx: 11-16yo Neuropsychiatric alteration - 40-70% behavioral changes psychosis Parkinsonism Liver disease acute, chronic, or rarely acute fulminant hepatitis In isolation or in tandem

11.2.3. Lab Findings Liver biopsy Copper quantification Screening 24-hour urinary copper excretion Serum Ceruloplasmin? Acute Phase Reactant Can be low in Wilson's but not reliable Slit-Lamp Evaluation Kayser-Fleischer rings

11.2.4. Histological Findings Macrovesicular steatosis Vacuolization of nuclei Foci of hepatocyte necrosis Lobular and portal inflammation

11.3. Alpha-1 antitrypsin deficiency: Autosomal Co-Dominant Inheritance Pattern

11.3.1. Clinical Manifestations 4th to 5th decade Liver disease 80-90% of PiZZ individuals develop chronic liver disease Childhood Presentation cholestatic form of hepatitis in infancy

11.3.2. Autosomal Recessive *SERPINA1* gene Transmembrane copper transporting ATPase in hepatocytes PiM PiZ PiZZ Abnormal protein folding AND defects in protein degradation

12. Major Patterns of Liver Injury

12.1. 1. Hepatocellular Injury Pattern

12.1.1. Mild to moderate elevations of AST and ALT < 500

12.1.2. Marked Elevations of AST and ALT > 750

12.1.3. AST/ALT Ratio

12.2. 2. Cholestatic Pattern