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

1.1.1.1. Acetaminophen

1.1.1.2. Ketoconazole

1.1.1.3. Valproic acid

1.1.1.4. Isoniazid

1.1.1.5. NSAIDs

1.1.1.6. antidepressants

1.1.2. Cholestasis Pattern of Injury

1.1.2.1. Oral contraceptives

1.1.2.2. Estrongens

1.1.2.3. Tamoxifen

1.1.2.4. Androgens

1.1.2.5. Erythromycin

1.1.2.6. Azathioprine

1.1.3. Cholestatic hepatitis

1.1.3.1. NSAIDs

1.1.3.2. Macrolides

1.1.3.3. Beta-lactam antibiotics

1.1.3.4. Amoxicillin-Clavulanate

2. Liver Failure

2.1. Acute liver failure

2.1.1. 50% DILI

2.1.2. Other causes

2.1.2.1. Acute ischemic injury

2.1.2.2. Acute Budd-Chiari Syndrome

2.1.2.3. Neoplastic infiltration

2.1.2.4. Heatstroke

2.1.3. Clinical Manifestations

2.1.3.1. Encephalopathy

2.1.3.2. Hypotension / Circulatory Dysfunction

2.1.3.2.1. :arrow_down: blood volume

2.1.3.2.2. Adrenal gland insufficiency

2.1.3.3. Renal dysfunction

2.1.3.4. Features by Organ

2.2. Decompensation of chronic liver disease

3. Neoplasms

3.1. Hepatic adenoma

3.1.1. Benign

3.1.1.1. Bland heepatocytes

3.1.1.2. No cytological atypia

3.1.1.3. no blie ducts

3.1.1.4. vessesl without associated connective soft tissue

3.1.1.5. Intact reticulin framework

3.1.1.6. Morphology

3.1.2. Risk Factors

3.1.2.1. Orap contraceptives

3.1.2.2. Anabolic steroids

3.1.2.3. Metabolic disorders

3.1.2.4. Reproductive-age women

3.2. Hepatocellular Carcinoma

3.2.1. Risk Factors

3.2.1.1. 20% Noncirrhotic liver

3.2.1.1.1. Chronic hepatitis

3.2.1.1.2. malginant transofrmation of hepatic adenoma

3.2.1.2. 80% cirrhotic livers

3.2.1.2.1. Chronic HCV

3.2.1.2.2. Steatohepatitis

3.2.2. 40% metastatic disease identified at presentation

3.2.2.1. Lung

3.2.2.2. Bone

3.2.2.3. Abdominal lymph nodes

3.2.3. IHC

3.2.3.1. HepPar1

3.2.3.2. Arginase

3.2.3.3. Glypican

3.2.4. Morphology

3.2.4.1. Mild to marked cytological atypia

3.2.4.2. Benign Liver

3.2.4.2.1. Benign fatty liver, loss of reticulin framework

3.2.4.3. Loss of normal reticulin framework

3.3. Intrahepatic cholangiocarcinoma

3.3.1. Malignant

3.3.1.1. Biliary epithelium

3.3.1.2. Morphology

3.3.1.2.1. Mild to marked cytological atypia

3.3.1.2.2. Prominent growth pattern

3.3.2. Risk Factors

3.3.2.1. Primary sclerosing cholangitis - 5-15%

3.3.2.2. Other

3.3.2.2.1. Hepatolithiasis

3.3.2.2.2. Chronic hepatitis

3.3.2.2.3. Cirrhosis

3.3.2.2.4. Liver Flukes

3.3.2.2.5. Fibropolycystic liver disease

3.3.2.2.6. Ulcerative Colitis

3.3.3. **Cholangiocarcinoma**: Tumor of the **BIle Ducts**

3.3.3.1. Lab Findings

3.3.3.1.1. :arrow_up: LFTs

3.3.3.1.2. Tumor Markers

3.3.3.1.3. :arrow_up: :question: Bilirubin

3.3.3.1.4. :arrow_up: :question: ALP

3.3.3.1.5. :arrow_up: :question: Pancreatic Enzymes

3.3.3.2. Signs / Symptoms

3.3.3.2.1. Obstructive Jaundice

3.3.3.2.2. Pruritis (Extrahepatic)

3.3.3.2.3. Weight loss

3.3.3.2.4. Pain

3.4. Hepatoblastoma

3.4.1. Malignant

3.4.1.1. Epithelial

3.4.2. Most common liver tumor in infants and children

3.4.2.1. 90% of cases Dx before age 5

3.4.2.2. Strong a/w premature birth, low birth weight

3.4.3. Marked elevation in serum AFP - 90%

3.5. Angiosarcoma

3.5.1. Malignant

3.5.1.1. Vascular neoplasm

3.5.1.2. 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

3.5.5.1. Vascular IHC Markers

3.5.5.1.1. CD31

3.5.5.1.2. 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

3.6.4.1. Colon

3.6.4.2. Pancreas

3.6.4.3. Lung

3.6.4.4. Neuroendocrine

3.6.4.5. Breast

4. Liver Review

4.1. Liver Functions

4.1.1. Detoxification

4.1.1.1. Drugs

4.1.1.2. Toxins

4.1.2. Bile Salt Synthesis and Secretion

4.1.3. Bilirubin

4.1.3.1. Uptake

4.1.3.2. Conjugation

4.1.3.3. Secretion

4.1.4. Production of Coagulation Factors

4.1.5. Glucose Homeostasis

4.1.6. Iron homeostasis

4.1.7. Production of

4.1.7.1. albumin

4.1.7.2. Globulins

4.1.7.3. Transferrin

4.2. Flow of Blood and Bile

4.2.1. Blood flows in

4.2.1.1. Portal Vein (Primary)

4.2.1.2. Hepatic Artery (secondary)

4.2.2. Blood flows out

4.2.2.1. Hepatic vein into IVC

4.2.3. Bile flows out

4.2.3.1. Hepatic bile ducts

4.3. Hepatic Lobule Microanatomy

4.3.1. Portal Triad

4.3.1.1. Blood flows IN

4.3.1.2. Bile flows OUT

4.3.2. Central Vein

4.3.2.1. Blood flows OUT

4.3.2.2. Bile production begins

4.3.3. Functional Zones

4.3.3.1. Zone 1

4.3.3.1.1. Most resistant to ischemia

4.3.3.2. Zone 2

4.3.3.3. Zone 3

4.3.3.3.1. most sensitive to metabolic toxins

4.3.3.3.2. most susceptible to ischemia

4.3.3.3.3. Site of Bile acid synthesis

4.3.4. Sinusoids

4.3.4.1. Kupffer cells

4.3.4.1.1. Macrophages

4.3.4.1.2. Housed in sinusoids

4.3.4.2. Stellate cells (Ito cells)

4.3.4.2.1. perisinusoidal space

4.3.4.2.2. Fibrinogenesis - Central role

4.3.4.2.3. Store vitamin A

4.3.4.3. Incomplete basememnt membrane, intercellular gaps

4.4. Bilirubin Metabolism

4.4.1. Heme

4.4.1.1. Biliverdin

4.4.1.1.1. (Unconjugated) Bilirubin

4.4.1.1.2. Biliverdin reductase

4.4.1.2. Heme oxygenase

4.4.1.2.1. NADPH + H+

4.4.1.2.2. CO is released

4.4.1.2.3. Iron is released

4.5. Hyperbilirubinemia

4.5.1. Increased Bilirubin production

4.5.1.1. Hemolytic diseases processes

4.5.1.2. Ineffective erythropoiesis

4.5.2. Inefficient conjugation

4.5.2.1. Gilbert Syndrome

4.5.2.1.1. UGT1 mutation

4.5.2.2. Physiologic jaundice of newborn

4.5.2.2.1. Transient low UGT levels

4.5.2.3. Crigler-Najjar syndrome

4.5.2.3.1. Type II

4.5.2.3.2. Type I

4.5.3. Alterations in Excretion of conjugated bilirubin

4.5.3.1. Dubin-Johnson Syndrome

4.5.3.1.1. ABCC2 Mutation

4.5.3.2. Rotor Syndrome

4.5.3.2.1. SLCO1B1/3 Mutation

4.5.4. Obstruction of biliary flow

4.5.4.1. Biliary atresia

4.5.4.2. Mechanical obstruction

4.5.4.2.1. Choledocholithiasis

4.5.4.2.2. Stricture

4.5.4.2.3. Mass

4.5.4.3. 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

8.2.1.1. Release Cytokines

8.2.1.1.1. Portal fibroblasts activated

8.2.1.1.2. Stellate Cells stimulated

8.2.2. Normal vs Chronic liver

8.3. Progression

8.3.1. Early-Stage

8.3.1.1. Vascular remodeling

8.3.1.1.1. Sclerosis of portal tracts

8.3.1.1.2. Contraction of stellate cells

8.3.1.1.3. Periventricular fibrosis

8.3.2. Late-Stage

8.3.2.1. Vascular changes

8.3.2.1.1. Shunting of blood

8.4. Clinical Manifestations

8.4.1. Liver Damage Effects

8.4.1.1. Hepatic insufficiency

8.4.1.2. Hyperestrinism

8.4.1.2.1. Spider nevi

8.4.1.2.2. Pectoral alopecia

8.4.1.2.3. Gynecomastia

8.4.1.2.4. Altered hair distribution

8.4.2. Portal Hypertension Effects

8.4.2.1. Portal Hypertension per se

8.4.2.2. 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

9.1.2.1. Against hepatocytes

9.1.3. Lab findings

9.1.3.1. ANA :arrow_up: - 80%

9.1.3.2. ASMA :arrow_up: - 70%

9.1.3.3. Polyclonal hypergammaglobulinemia

9.1.3.4. ALP normal or slightly elevated

9.1.3.5. AST and ALT vary

9.1.4. Histologic Features

9.1.4.1. Zone 1 hepatocellular injury

9.1.4.2. 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

9.2.2.1. Early Disease

9.2.2.1.1. Bilirubin, AST, ALT - normal or mildly elevated

9.2.2.1.2. :arrow_up: ALP

9.2.2.1.3. :arrow_up: GGT

9.2.2.1.4. :arrow_up: Cholesterol

9.2.2.2. Advanced disease

9.2.2.2.1. :arrow_up: Bilirubin (progressive rise in levels)

9.2.2.2.2. :arrow_up: ALP

9.2.2.2.3. :arrow_up: GGT

9.2.2.2.4. :arrow_up: Cholesterol

9.2.2.3. :arrow_up: AMA - 95%

9.2.2.4. Cholestatic Pattern of Liver Function Test

9.2.3. Histological features

9.2.3.1. Florid duct lesion

9.2.3.2. Dense portal lymphoplasmacytic infiltrate

9.2.3.3. Granulomas

9.2.3.4. Hepatic lobules *undamaged *

9.2.4. Continued injury results in

9.2.4.1. bile duct loss

9.2.4.2. cholestasis

9.2.5. Clinical Manifestations (of progressive cholestasis)

9.2.5.1. Pruritis

9.2.5.2. Jaundice

9.2.5.3. Hyperlipidemia

9.2.5.4. Fat-soluble vitamin deficiency

9.2.5.5. Typical Presentation

9.2.5.5.1. Pruritus + Cholestatic Pattern of Liver Function Test

9.3. secondary biliary Cirrhosis

9.3.1. Uncommon complication of

9.3.1.1. chronic biliary obstruction

9.3.1.1.1. Resultant biliary cirrhosis

9.3.2. Biliary Fibrosis

9.3.2.1. Portoseptal fibrosis

9.3.2.1.1. Caused by the ductular reaction with loss of periportal hepatocytes

9.3.2.2. Eventual linking of portal tracts

9.3.2.2.1. Result of Extension of fibrosis

9.3.2.3. Initial preservation of intrahepatic vascular relationships

9.3.2.3.1. preserved by portal-portal fibrous links

9.3.2.4. Continued loss of hepatocytes leads to

9.3.2.4.1. 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

9.4.2.1. Ulcerative colitis

9.4.3. Increased risk of

9.4.3.1. cholangiocarcinoma

9.4.4. Hallmark clinical finding

9.4.4.1. Abnormal cholangiogram

9.4.4.1.1. "beaded" appearance of biliary tree on ERCP or MRCP

9.4.5. Lab Findings

9.4.5.1. Liver Biopsy

9.4.5.1.1. Rule out other diseases

9.4.5.1.2. Non-specific or normal findings

9.4.6. Typical Presentation

9.4.6.1. Pruritus + Cholestatic Pattern of Liver Function Test

10. Steatohepatitis

10.1. Defined by 3 components

10.1.1. 1. Steatosis

10.1.1.1. Simple Steatosis on its own is a form of NAFLD

10.1.2. 2. Inflammatory activity

10.1.2.1. Pericellular Fibrosis (Trichrome stain)

10.1.3. 3. Cell injury

10.2. Divided into 2 categories

10.2.1. NASH Inflammatory progression of NAFLD

10.2.1.1. Pathogenesis: Two-hit hypothesis

10.2.1.1.1. 1. Fat accumulation places hepatocytes under stress

10.2.1.1.2. 2. Second insult results in inflammation, cell death, fibrosis

10.2.1.2. Outcomes vary

10.2.1.2.1. Remains stable

10.2.1.2.2. regressing to simple steatosis

10.2.1.2.3. Progressing to cirrhosis

10.2.1.3. Lab Findings

10.2.1.3.1. Liver Enzymes? Poor sensitivity for NAFLD

10.2.1.3.2. ANA

10.2.1.3.3. Imaging studies

10.2.1.4. Histological Findings

10.2.1.4.1. Ballooning hepatocytes

10.2.1.4.2. +/- Mallory-Denk bodies

10.2.1.4.3. Lobular inflammation

10.2.1.4.4. Macrovesicular steatosis

10.2.2. Alcohol-related steatohepatitis

10.2.2.1. Alcohol-induced injury is a multifactorial process

10.2.2.1.1. Primary Mechanism

10.2.2.1.2. Acetaldehyde

10.2.2.2. Risk factors

10.2.2.2.1. Amount of alcohol consumed

10.2.2.2.2. Sex - F > M

10.2.2.2.3. Central obesity

10.2.2.2.4. Patterns of consumption

10.2.2.2.5. Associated medication

10.2.2.2.6. Coffee intake

10.2.2.2.7. Genes regulating expression of proinflammatory cytokines and immune response mechanisms

10.2.2.3. Lab findings

10.2.2.3.1. AST:ALT ≥ 2

10.2.2.3.2. Bilirubin disproportionately high compared to ALP

10.2.2.4. Histological Features

10.2.2.4.1. Identical to NASH

10.2.2.4.2. "Soft" features

10.3. NAFLD (Non-Inflammatory)

10.3.1. Two Primary categories

10.3.1.1. Simple steatosis

10.3.1.2. Steatohepatitis

10.3.1.2.1. NASH

10.3.1.2.2. 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

11.1.1.1. *HFE* gene mutations

11.1.1.1.1. C282Y gene

11.1.2. :arrow_down: hepcidin synthesis

11.1.2.1. Dysregulated iron homeostasis

11.1.3. Clinical Manifestations

11.1.3.1. 5th or 6th decades

11.1.3.2. Symptoms manifest 2° to

11.1.3.2.1. cirrhosis

11.1.3.2.2. cardiomyopathy / Heart Failure

11.1.3.2.3. Bronze diabetes

11.1.3.2.4. Arthritis

11.1.3.3. Lab Findings

11.1.3.3.1. Transferrin Saturation ≥ 45%

11.1.3.3.2. Ferritin: > 200 (men); > 150 (women)

11.1.4. Pathogenesis of Iron Accumulation

11.1.4.1. Periportal hepatocytes

11.1.4.2. oxidative damage to hepatocytes from excess iron

11.1.4.3. Cirrhosis, fibrosis

11.1.5. Treatment

11.1.5.1. Weekly Phlebotomy

11.1.5.1.1. 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

11.2.1.1. *ATP7B* gene

11.2.1.1.1. Transmembrane copper transporting ATPase in hepatocytes

11.2.2. Clinical Manifestations

11.2.2.1. Mean age at Dx: 11-16yo

11.2.2.2. Neuropsychiatric alteration - 40-70%

11.2.2.2.1. behavioral changes

11.2.2.2.2. psychosis

11.2.2.2.3. Parkinsonism

11.2.2.3. Liver disease

11.2.2.3.1. acute, chronic, or rarely acute fulminant hepatitis

11.2.2.3.2. In isolation or in tandem

11.2.3. Lab Findings

11.2.3.1. Liver biopsy

11.2.3.1.1. Copper quantification

11.2.3.2. Screening

11.2.3.2.1. 24-hour urinary copper excretion

11.2.3.3. Serum Ceruloplasmin?

11.2.3.3.1. Acute Phase Reactant

11.2.3.3.2. Can be low in Wilson's but not reliable

11.2.3.4. Slit-Lamp Evaluation

11.2.3.4.1. Kayser-Fleischer rings

11.2.4. Histological Findings

11.2.4.1. Macrovesicular steatosis

11.2.4.2. Vacuolization of nuclei

11.2.4.3. Foci of hepatocyte necrosis

11.2.4.4. Lobular and portal inflammation

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

11.3.1. Clinical Manifestations

11.3.1.1. 4th to 5th decade

11.3.1.2. Liver disease

11.3.1.2.1. 80-90% of PiZZ individuals develop chronic liver disease

11.3.1.3. Childhood Presentation

11.3.1.3.1. cholestatic form of hepatitis in infancy

11.3.2. Autosomal Recessive

11.3.2.1. *SERPINA1* gene

11.3.2.1.1. Transmembrane copper transporting ATPase in hepatocytes

11.3.2.1.2. PiM

11.3.2.1.3. PiZ

11.3.2.1.4. PiZZ

11.3.2.2. 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

12.1.1.1. < 500

12.1.2. Marked Elevations of AST and ALT

12.1.2.1. > 750

12.1.3. AST/ALT Ratio

12.2. 2. Cholestatic Pattern