Limjoco - Introduction to Liver Flashcards by Ellen Petryna

What organ?

Largest organ, 1400-1600 gm
Crossroads between gastrointestinal tract and rest of body
Dual blood supply:
- 2/3 via _______ (from GI tract)
- 1/3 via _______ (from rest of body)
Blood drainage via hepatic veins –> IVC

The Liver

Portal vein

Hepatic artery

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In the liver, blood from both the _______ and the ________ flows into the low-pressure sinusoids. (Sinusoids have Kupffer cells.)

Deoxygenated portal venous blood is rich in nutrients.
Arterial blood provides oxygen to the surrounding liver cells.

Blood then flows from the sinusoids into the central vein, then hepatic veins to return to the heart.

Portal vein, hepatic artery

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Where is Bile produced?

Bonus: How does the flow of bile compare to vascular flow?

Bile is produced in hepatocytes

Flows from canaliculi into portal tract - opposite direction of flow from circulation

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Where does exchange of nutrients and oxygen occur?

Sinusoids

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Facts: Cells to know

Hepatocytes (liver parenchymal cells)
Bile duct cells
Endothelial cells (line sinusoids)
Kupffer cells (histiocytes, macrophages)
Ito stellate cells (line sinusoids, store fat and vitamin A)

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What are Kuffper cells?

The histiocytes, or macrophages of the liver

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What does this histo image show?

Sinusoids are lined by endothelial cells and Kupffer cells
Stellate (Ito) cells are present in the space of Disse.
Clear glycogenated nuclei and lipofuscin pigment are also present.
Hepatocytes show steatosis, with accumulation of small and large droplets of fat.

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What do Stellate cells store?

*Stellate cells are very important in the fibrotic reaction of the liver

Fat and Vitamin A

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What can cause pathology in the liver?

Infections (mainly hepatitis viruses)
Alcohol, Drugs
Metabolic derangements
Autoimmune diseases
Congenital diseases

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What are the functions of the liver?

Metabolism (carbohydrates, lipids, amino acids)
Synthesis (albumin, clotting factors I, II, V, VII - XIII, lipoproteins VLDL, LDL, HDL, cholesterol, glycogen)
Catabolism (removes ammonia ->urea, hormones, detoxifies foreign compounds/drugs/chemicals)
Storage (glycogen, triglycerides, Fe++, Cu++, fat-soluble vitamins)
Excretion (bile, endogenous waste products)
Blood reservoir (can hold and release 10-15% of total blood volume)
Endocrine (modifies hormone action vit D to 25(OH)D, removes circulating hormones glucagon, etc.)

** mnemonic: My Skinny Cat Sees Every Bird Enter

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What are the substances that the lab looks for in liver disease?

Serum transaminases
- AST (SGOT) - aspartate aminotransferase
- ALT (SGPT) - alanine aminotransferase
ALP - Alkaline phosphatase
GGT - Gamma glutamyl transpeptidase
Albumin

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What enzyme that is elevated in liver dysfunction?

Removes PO4 groups
In liver, bone, intestine as different isoenzymes
In cell membrane bordering bile canaliculi cells, but also found in placenta and bone
Elevated in cholestatic disorders

Alkaline phosphatase

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What enzyme?

Enzyme found in bile canaliculus
Involved in glutathione metabolism, drug detoxification
Most sensitive indicator of liver disease BUT not very specific
Therefore, if elevated together with ALP –> hepatobiliary disease

*** Also important in alcoholic liver disease

GGT - Gamma glutamyl transpeptidase

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What marker?

Protein produced by liver
Maintains normal oncotic pressure
Decreased in liver disease (but level does not correlate with severity of disease)

Albumin

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Etiologies of what disease?

Etiologies - myriad

VIRUSES (72%)
Excessive alcohol consumption
Acetaminophen overdose
Idiosyncratic response to medications
Autoimmune diseases (Autoimmune hepatitis)
Metabolic disorders (Reye syndrome, Acute fatty liver of pregnancy)
Circulatory disorders (Budd-Chiari syndrome, right-sided heart failure)

Acute Hepatitis

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What is the brown pigment called? Is it normal?

Lipofuscin - “wear and tear” pigment

Normally found in liver with aging

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What can been seen in this histology slide of a liver with hepatitis?

Spotty/lytic necrosis
Clusters of inflammatory cells (neutrophils/lymphocytes)
Ballooning edematous liver cells - loss of polygonal shape

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What is interface hepatitis?

Inflammatory cells spill over past the limiting plate between the edge of the portal tract and hepatic parenchyma into the lobule

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What are the necrotic areas between portal and central venous areas?

e.g. portal to portal, or venous to venous areas

Bridging necrosis

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What are apoptotic cells called in the liver?

DNA fragmentation, cell shrinkage, degraded to apoptotic bodies that are phagocytosed by ______

Alternate pathway of death in hepatitis
Histology: individual cells with densely eosinophilic cytoplasm + fragmented nuclear remnants

Acidophil bodies

Kupffer cells

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These are the clinical manifestations of what disorder - severe cases?

Acute encephalopathy
Coagulopathy
Acute renal failure
Gastrointestinal bleeding
Infection, sepsis
Respiratory failure
Cardiovascular collapse

Acute hepatitis

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Outcomes of what disease?

Resolve spontaneously with supportive therapy
Proceed to Acute Liver Failure
Develop into Chronic Hepatitis

Acute hepatitis

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True or False: liver has a large regenerative capacity?

True

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__________ divide even in presence of confluent necrosis or chronic injury.
- Can regenerate from 25% of normal tissue - but need intact normal framework

Mature hepatocytes

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What is the clinical syndrome that results from **80-90% reduction** of liver’s functional capacity – either due to diminished cell number or impaired function? ACUTE DECOMPENSATED - from compensated chronic disease with sudden flare of activity (acute-on-chronic liver failure) = as patient with underlying cirrhosis

Acute hepatic failure

What disease state? * Coagulopathy (INR \>1.5 --\> prolonged clotting), hepatic encephalopathy, developing within **26 weeks of first insult**, in a patient without preexisting disease or cirrhosis * In patients with chronic liver disease/cirrhosis, may also develop acute liver failure if disease recognized **\<26 weeks**, with sudden flare of activity precipitatedd by insult (bleeding, infection, drug)

Acute Hepatic Failure

Pathology of what disease? * Acute massive hepatic necrosis (**80-90%** of liver function lost) * Non-necrotic liver failure (acute fatty liver of pregnancy/tetracycline toxicity/Reye syndrome) * Chronic liver disease/cirrhosis - most common route to hepatic failure (e.g., undiagnosed Wilson’s disease, autoimmune or B viral hepatitis, severe alcoholic hepatitis)

Acute Hepatic Failure

Clinical manifestations of what disease? * Jaundice * Due to retention of bilirubin – not excreted from body, accumulates in fatty tissues * Yellow skin, sclerae, mucous membranes * Nausea, vomiting - toxins

Acute hepatic failure

What manifestiation of acute hepatic failure? * Neuropsychiatric abnormalities * Potentially reversible * Altered metabolic milieu due to: shunting of blood from portal to systemic circulation, bypassing liver * **Hyperammonemia** main cause * Rigidity, hyperreflexia (asterixis),EEG changes * Behavioral abnormalities, personality changes

Hepatic encephalopathy

What manifestation of acute hepatic failure? * Bleeding diathesis (decreased production of clotting factors) * Increased prothrombin time (decreased Factor VII) * Thrombocytopenia (hypersplenism, marrow suppression) * Disseminated intravascular coagulation (liver fails to clear activated factors from circulation)

Coagulopathy

What does this histology slide of acute hepatic failure show?

* Microvesicular steatosis/fatty change * Swollen hepatocytes with foamy-looking cytoplasm * small lipid vesicles (less than 1 μm in diameter) may or may not be visible. * Typically centrally located nucleus

Laboratory Findings of what disease? * Markedly elevated serum AST, ALT * Hypoalbuminemia * Hyperammonemia

Acute Hepatic Failure

Mnemonic - Causes of Acute Hepatic Failure: A B C D E F

* A Acetaminophen, Hep A, autoimmune hepatitis * B Hep B * C Hep C, cryptogenic * D Drugs, toxins, Hep D * E Hep E, esoteric causes (Wilson's dis, Budd-Chiari) * F Fatty change of microvesicular type (fatty liver of pregnancy, valproate, tetracycline, Reye syndrome)

What can be associated with acute hepatic failure? * Kidney failure * Due to decreased renal perfusion in cirrhotic patients * Portal HTN --\> systemic vasodilatation --\> compensatory renal vasoconstriction * Decreased vasodilators, increased vasoconstrictors on renal circulation * Pulmonary failure * Due to pulmonary vasodilatation causing ventilation-perfusion mismatch --\> hypoxia, shortness of breath \*Function normalizes with renal transplant

* Hepatorenal syndrome * Hepatopulmonary syndrome

What disease? (Associated with acute hepatic failure) * 1/16,000 - rare, potentially fatal cx in 3rd trimester or early post-partum * Microvesicular steatosis (liver biopsy rarely needed) * Due to abnormal fatty acid metabolism – accumulation of toxic products from placenta and fetus in mother

Acute Fatty Liver of Pregnancy

Manifestations and treatment of what disease? **Clinical Manifestations** * Malaise, N/V, RUQ pain, jaundice, fever, pruritus * Resemble preeclampsia, HELLP (Hemolysis, Elevated Liver tests, Low Platelets) syndrome – but with higher liver enzyme levels, more severe hypoglycemia **Treatment** * Supportive care, fluids, mx of complications, delivery of baby

Acute Fatty Liver of Pregnancy

What disorder? (Associated with acute hepatic failure) * First described in 1963; last reported cases in 1997 * Acute metabolic encephalopathy in babies and children following **acute respiratory viral illness** + associated with **salicylate** (esp. aspirin) intake. * Due to _abnormal fatty acid and carnitine metabolism_ * Affects primarily the liver and brain, and presents with certain biochemical and anatomic features

Reye syndrome

What disorder? **Clinical Manifestations** * Acute encephalopathy, pernicious vomiting, evidence of liver dysfunction especially in \<2 yr old **Liver Biopsy** * Microvesicular steatosis * Need to test for Inborn Errors of Metabolism ( ___ syndrome-like conditions) **Treatment** * Supportive measures, especially maintaining normal blood glucose levels

Reye Syndrome

What disease? * Various liver diseases + abnormal tests lasting **longer than 6 months/26 weeks** associated with _progressive fibrosis_ * Ultimately leads to **CIRRHOSIS**

Chronic Liver Disease

Etiologies of what disease? * NAFLD (Non-Alcoholic Fatty Liver Disease) * Hepatitis B, C * Alcoholic Liver Disease * **Hereditary Hemochromatosis** (abnormal retention of iron in liver, iron toxic to cells - treat with phlebotomy) * Alpha-1 Antitrypsin Deficiency * Wilson's Disease * PBC, PSC * Autoimmune hepatitis

Chronic Liver Disease

FACT:

Pathology of what disorder? * **Fibrosis** c/o _delicate bands_ or _broad scars_ surrounding multiple adjacent regenerative lobules * Entire liver architecturally disrupted by interconnecting fibrous scar = bridging portal-portal, portal-central, central-central fibrosis

Liver Cirrhosis

Pathology of liver cirrhosis - form --\> * \_\_\_\_\_\_\_\_\_\_\_\_\_\_\_: **Micro (\<3mm)** and **macro (\> 3 mm)** nodules from regeneration of liver cells in **canals of Hering** (progenitors of parenchymal and bile duct cells)

Regenerative Nodules

Pathogenesis of Liver Cirrhosis: Stimulation of _____________ by **reactive oxygen species**, **growth factors**, **tumor necrosis factors**, **IL-1** produced by damaged hepatocyte * Becomes \_\_\_\_\_\_\_\_\_\_: produces smooth muscle **actin, GFAP** * Collagen deposited \>\>\> fibrosis \>\>\> cirrhosis

Perisinusoidal Stellate Cells (Ito Cells) myofibroblast-like

What stain picks up the **reticulin framework** (fibers that support the framework of the liver)?

Silver stain

What is the most important change in liver cirrhosis?

Alterations in microvasculature architecture!

Pathology of what disorder? * ALTERATIONS IN MICROVASCULATURE ARCHITECTURE – very important consequence! * Loss of sinusoidal cell fenestrations * Shunt development - bypasses the liver **microcirculation** * High-pressure, fast-flowing vessels WITHOUT solute exchange --\> Loss of functional integrity!

Liver cirrhosis

Manifestations of what disorder? * Can be silent * Can have nonspecific symptoms - Weakness, anorexia, weight loss * Can lead to advanced disease: Progressive liver failure * Can lead to portal HTN - Ascites, portosystemic venous shunts, congestive splenomegaly, hepatic encephalopathy

Liver cirrhosis

**ADVANCED** Liver cirrhosis leads to what manifestations? * * * *

* Encephalopathy * Hyperreflexia, asterixis (flapping tremor), confusion, clonus, drowsiness, poor memory and alertness * Impaired metabolism of estrogenic compounds * Gynecomastia, spider angiomas

Symmary of portal HTN from cirrhosis picture

When cirrhosis is inactive for years, histology may show well-defined septal margins and incomplete septa. _______ may occur, but abnormal microvasculature and dysfunction remain.

Regression of cirrhosis

Bile is: * A complex fluid of ______ and \_\_\_\_\_\_\_, produced by liver * Flows through biliary tract into the small intestine, where bile acids are reabsorbed and returned to the liver and re-secreted * 500 – 600 mls produced daily!

* BIle acids and bilirubin

What are some functions of bile acids?

* Emulsification and micelle formation for absorption of **dietary fat** in the gut * Provides **bicarbonate** for neutralizing gastric acid * Helps eliminate _cholesterol_, highly protein-bound _organic molecules, heavy metals, lipophilic drug metabolites_ that the kidney cannot filter * **Protects gut from infection – excretes IgA, cytokines**

Structure of bile?

* Hydrophobic and hydrophilic side, forms mycelles and facilitates absorption of fat from diet

Bile salts are __________ (catabolic products of \_\_\_\_\_\_\_\_) that are conjugated with **taurine or glycine** * Are detergents - solubilize water-insoluble lipids * **Cholic acid, chenodeoxycholic acid** are two main bile acids * 95% bile acids/salts reabsorbed from intestine and returned to liver

* Bile acids * Cholesterol

What are 2 main bile acids?

Cholic acid, chenodeoxycholic acid

What is the other component of bile (Besides bile salts)? * Comprises only **2%** of bile * Breakdown product of **heme** (from senescent red blood cells) formed in SPLEEN; no real function * Accounts for _yellow color in bruises, jaundice_ * **UNCONJUGATED** form - water insoluble, toxic to cells – so is bound to albumin, travels in blood * **CONJUGATED** form - water soluble, occurs in liver, is nontoxic, secreted in bile ducts

Bilirubin

What is urobilinogen? - how is it excreted?

In the GUT, bacteria convert bilirubin into **UROBILINOGEN** * excreted as **stercobilinogen** (stool) * reabsorbed in gut, recirculated, metabolized in liver or excreted via kidneys in urine

* The tiny bile canaliculi between hepatocytes become \_\_\_\_\_\_\_\_\_, then \_\_\_\_\_\_\_, then larger \_\_\_\_\_\_\_\_\_. * Beyond the **porta hepatis**, the main hepatic duct merges with the \_\_\_\_\_\_\_\_to become the \_\_\_\_\_\_\_, which goes to the duodenum.

* ductules, interlobular bile ducts, larger hepatic ducts. * gallbladder's cystic duct, common bile duct

What is the name for decreased bile flow accompanied by accumulation of substances normally excreted in bile (bilirubin, bile acids, cholesterol)? Bonus: will present with what physical finding?

Cholestasis * Jaundice (occurs when 2-3x excess of normal levels of bilirubin) * **Prehepatic:** * Hemolysis * **Hepatic**: * Hepatitis (viral, drug-induced, autoimmune) * Cirrhosis (decompensated) * Malignancy * Defect in bilirubin metabolism * **Posthepatic:** * Gallstones * Tumors, strictures * Compression by tumor (pancreatic head cancer)

What step? * senescent RBCs, hemoproteins Pathology: * Prehepatic * Unconjugated hyperbilirubinemia * hemolytic anemia, hematoma/internal hm’ge, ineffective erythropoiesis (PA, thalassemia)

Bilirubin Production

What step? * Bilirubin-albumin complex transported across cell membrane, taken up by protein carrier Pathology: * Intrahepatic * Unconjugated hyperbilirubinemia * Impaired uptake/binding * hepatocellular injury * drugs (interfere with membrane carrier system) * physiologic jaundice of NB – immature system * Gilbert's syndrome

Uptake/binding

What step? * Conjugated bilirubin diffuses through cell to bile canaliculus, excreted into bile Pathology: * Intrahepatic or posthepatic * Predominantly conjugated * Dubin-Johnson, Rotor (deficiency of canalicular membrane transporter) * Autoimmune (IgG4) cholangiopathy * Duct obstruction

Excretion

Summary: * Bile excreted into \_\_\_\_\_\_\_\_ * Bilirubin hydrolyzed to free bilirubin by gut bacteria (by their \_\_\_\_\_\_\_\_\_) * Degraded to mix of **pyrroles + urobilinogen** * Urobilinogen mostly excreted in **feces** * 20% reabsorbed in ______ and goes back to liver (enterohepatic circulation), then re-excreted in bile or in urine

* Small bowel * beta-glucuronidases * Ileum

Micrograph of what?

Cholestasis in the liver * Feathery degeneration, clear cytoplasm, wispy cytoplasmic threads due to retained bile acids

Clinical manisestations of what disorders? * Increased serum bilirubin: \_\_\_\_\_ * Serum bile acids: \_\_\_\_\_\_ * Malabsorption of fats: \_\_\_\_\_\_\_ * Malabsorption of vitamins A D K: \_\_\_\_\_\_\_\_\_\_\_\_ * Increased serum cholesterol: \_\_\_\_\_\_\_\_\_\_\_\_\_

* Jaundice * Pruritis * Steatorrhea * Hemorrhagic, clotting disorders * Xanthomas