Limjoco - Introduction to Liver Flashcards
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
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
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
Where does exchange of nutrients and oxygen occur?
Sinusoids
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)
What are Kuffper cells?
The histiocytes, or macrophages of the liver
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.
What do Stellate cells store?
*Stellate cells are very important in the fibrotic reaction of the liver
Fat and Vitamin A
What can cause pathology in the liver?
- Infections (mainly hepatitis viruses)
- Alcohol, Drugs
- Metabolic derangements
- Autoimmune diseases
- Congenital diseases
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
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
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
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
What marker?
- Protein produced by liver
- Maintains normal oncotic pressure
- Decreased in liver disease (but level does not correlate with severity of disease)
Albumin
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
What is the brown pigment called? Is it normal?
Lipofuscin - “wear and tear” pigment
- Normally found in liver with aging
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
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
What are the necrotic areas between portal and central venous areas?
- e.g. portal to portal, or venous to venous areas
Bridging necrosis
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
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
Outcomes of what disease?
- Resolve spontaneously with supportive therapy
- Proceed to Acute Liver Failure
- Develop into Chronic Hepatitis
Acute hepatitis
True or False: liver has a large regenerative capacity?
True
- __________ divide even in presence of confluent necrosis or chronic injury.
- Can regenerate from 25% of normal tissue - but need intact normal framework
- Mature hepatocytes
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
