Hepatic Disorders Flashcards
Liver
Gross Anatomy
-
Location:
- From right 5th intercostal space in midclavicular line to just below right costal margin
-
Size/Weight:
- 10-12cm span
- 1,400-1,600gm (adult weight)
-
Lobes:
-
Visually divides as:
- Right ⇒ includes right lobe, caudate and quadrate lobes
- Left
-
Physiologic division:
- Divide into 2 equal parts w/ line extending from IVC to gallbladder
-
Visually divides as:
Liver
Connections
- Glisson’s capsule: CT covering liver
-
Falciform ligament: connects liver → diaphragm & anterior abdominal wall
- Fetal life: carries umbilical vein
-
Later life: carries paraumbilical vein
- May serve as collateral vessels in portal HTN
Liver
Vascular Supply
-
Inflow:
-
Hepatic artery: usually from celiac artery
- Supplies 30-40% of blood flow
-
Portal vein: formed from convergence of superior mesenteric and splenic veins (i.e. most of venous drainage of abdomen)
- Supplies 60-70% of blood flow
- True infarcts rare d/t dual supply of blood
-
Hepatic artery: usually from celiac artery
-
Venous drainage:
- Extrahepatic veins drain into inferior vena cava
Liver
Biliary System
Intrahepatic ducts (lobular and septal) → right and left hepatic ducts (extrahepatic) ⇒ unite to form common hepatic duct
Cystic duct from gallbladder enters ⇒ forms common bile duct (CBD)
Ampulla of Vater: slightly dilated portion of CBD as it empties into second portion of duodenum
Pancreatic duct drains into ampulla in two-thirds of population
Liver
Functional Unit Models
Zonation of the parenchyma
- Gradient of activity displayed by many hepatic enzymes
- Zonal distribution of certain types of hepatic injury
- Acinar model ⇒ describes physiologic relationship b/t hepatocytes & vascular supply
- Classic lobular model ⇒ describes histopathology of the liver
Liver
Lobular Model
- Hexagon shaped
- Center ⇒ terminal hepatic veins (“central vein, efferent vein”)
- Hepatocytes near terminal hepatic vein ⇒ “centrilobular”
- Periphery ⇒ portal tracts
- Hepatocytes near portal tract ⇒ “periportal”
- Center ⇒ terminal hepatic veins (“central vein, efferent vein”)
- Pros: easy to define
- Cons: not physiologic
Liver
Acinar Model
- Triangle shaped
- Apex ⇒ central vein
- Distal apices ⇒ terminal hepatic veins (“central vein, efferent vein”)
- Base ⇒ formed by septal venules from portal vein that extend out from portal tracts
- Based on blood flow
-
Parenchyma is divided into three zones
Zones numbered higher as blood flows toward central vein-
Zone 1: adjacent to portal vein
- Freshest blood flow
- Zone 2: between 1 & 3
-
Zone 3: closest to central v.
- Furthest from afferent blood supply
-
Most susceptible to blood supply problems
- Ischemia d/t poor portal flow
- Congestion/ischemia d/t problems w/ blood exiting liver
-
Most susceptible to drug/toxin insults
- Hepatocytes tend to have active drug metabolizing enzyme systems
- Susceptible to buildup of toxic metabolite byproducts and injury from toxins in general
-
Zone 1: adjacent to portal vein
- Pros: physiologic
- Cons: harder to visualize
Liver
Portal Tract
-
Contains 3 structures
- Hepatic artery branch
- Portal vein branch
- Bile duct branch
- Connective tissue matrix
- Others
- Lymphatic branch
- Scant inflammation
-
Limiting plate
- Hepatocytes that abut portal tract
Hepatocytes
- Polygonal eosinophilic cell
- Central nucleus, prominent nucleolus
- Arranged as 1 cell thick cord after 5 y/o w/ occasional interanastomosis
-
Surfaces:
- 2 sinusoidal surfaces w/ numerous microvilli facing into Space of Disse
- 1 canalicular surface
Hepatocyte and Sinusoids
Arrangement
Liver
Bile Flow
Bile flow: canaliculus → bile duct
- Bile canaliculus: formed by apposition of two adjacent hepatocytes
- Held together by tight junctional complexes
- Bile actively transported into canaliculus
- Canaliculus → canals of Hering @ border of portal tract → portal bile duct branch
Liver
Sinusoid
- Formed by fenestrated endothelium w/ no basement membrane
-
Space of Disse:
- Space between hepatocyte and endothelial cell
- Usually not seen on routine histology
- Contains fibronectin and type I collagen
- Scaffold of liver architecture
-
Kupffer cell:
- Resident macrophage sits either on top or between endothelial cells
-
Ito cells:
- Stellate cells in space of Disse
- Can function as facultative fibroblasts and secrete extracellular matrix components and growth factors
- When activated, see liver fibrosis and can go on to cirrhosis
- Can store fat
Liver Functions
- Metabolic
- Synthetic
- Storage
- Catabolic
- Excretory
Liver Disease
Overview
- Mechanisms of injury: metabolic, toxic, microbial, circulatory, and neoplastic
- Main primary diseases of the liver: viral hepatitis, alcoholic liver disease, nonalcoholic fatty liver disease (NAFLD), and hepatocellular carcinoma (HCC)
- Liver can also be damaged by: cardiac decompensation, disseminated cancer, and extrahepatic infections
-
High functional reserve ⇒ masks impact of mild liver damage
- Insidious process (other than fulminant hepatic failure)
- Takes place over weeks, months, years
- Hepatic decompensation ⇒ symptoms
- Insidious process (other than fulminant hepatic failure)
- Injury is detectable w/ lab tests
- Chronic liver disease causes 27k deaths/yr in the US
Liver
Response to Injury
- Hepatocyte degeneration and intracellular accumulations
- Hepatocyte necrosis and apoptosis
- Inflammation
- Regeneration
- Fibrosis
Liver Function Tests (LFTs)
Overview
- Serologic tests used in the evaluation of liver disease
- Commonly include: ALT, AST, Alkaline Phosphatase, GGTP, Total & Direct Bilirubin, Albumin & Total Protein
- Many reflect the health of the liver and are not direct measures of its function
- Commonly used LFTs may be abnormal even in pts w/ a healthy liver
-
Liver injury tests (enzymes):
- Serum alanine aminotransferase (ALT)
- Serum aspartate aminotransferase (AST)
- Serum alkaline phosphatase (ALP)
- Serum gamma glutamyl-transferase (GGTP)
-
Tests of hepatic synthetic function:
- Albumin
- Prothrombin time
-
Marker of hepatic transport:
- Serum bilirubin
Patterns of LFT Abnormalities
Clinically observed patterns of biochemical tests:
-
Hepatocellular Injury Pattern
- AST/ALT elevated > 5x upper limit of normal
- Normal for females: < 19 IUs
- Normal for males: < 30 IUs
- ALP levels elevated ≤ 2-3x upper limit of normal
- Normal = 38-126
- AST/ALT elevated > 5x upper limit of normal
-
Cholestatic Pattern
- ALP levels elevated 3-5x upper limit of normal
- AST/ALT elevation minor
- ALP levels elevated 3-5x upper limit of normal
- Mixed pattern
Serum Aminotransferases
Most accurate markers of hepatocellular necrosis
Part of gluconeogenic pathway
Normal levels: < 40 IU/ml
-
AST: Aspartate Aminotransferase
- Oxaloacetate → Malate
- Found in the mitochondria and cytosol
- Not specific for liver disease
- Found in the liver, heart, skeletal muscles, kidney, brain, pancreas, lungs, leukocytes and erythrocytes
-
ALT: Alanine Aminotransferase
- Pyruvate → Lactate
- Primarily found in the liver cytosol
- More specific indicator of liver injury than AST
Elevated AST/ALT
Interpretation
-
Mild ⇒ < 3x ULN
- NAFLD; NASH
- Chronic Viral Hepatitis B & C
-
Moderate ⇒ 3-20x ULN
- Alcoholic Hepatitis (2-3:1 ratio AST:ALT)
- Acute Viral Hepatitis (1:1 ratio)
- Autoimmune hepatitis
-
High ⇒ > 20x ULN
- Drug toxicity (acetaminophen)
- Acute Viral Hepatitis
- Ischemia
- Autoimmune Hepatitis
- Wilson’s Disease
-
Ratio AST > ALT
- Alcoholic liver disease
- Cirrhosis of any etiology
Serum Alkaline Phosphatase (ALP)
- Family of isoenzymes which catalyze hydrolysis of phosphate esters @ alkaline pH
- Reaction requires zinc
- Function in the liver unknown
-
Four different genes:
- 1 = liver, bone, 1st trimester placenta and kidney
- 2 = 3rd trimester placenta and intestine
- 3 = intestine
- 4 = fetal intestine
-
↑ ALP in liver diseases that involve:
- Inflammation
- Destruction or blockage of large and small intra- and extrahepatic bile ducts
-
If ALP ↑ ⇒ must ID source
- Gel electrophoresis to separate the various types of ALP
- Measure 5’ nucleotidase or GGTP ⇒ elevated along w/ ALP when 2/2 liver disorder
- ↑ ALP + nl GGTP ⇒ more likely 2/2 bone disorder
Elevated Serum Alkaline Phosphatase
Hepatic Etiologies
- Chronic cholestatic or infiltrative diseases
- Partial bile duct obstruction
- Primary biliary cholangitis (PBC) (previously called primary biliary cirrhosis)
- Primary sclerosing cholangitis (PSC)
- Idiopathic adulthood ductopenia
- Drugs ⇒ androgenic steroids; phenytoin
- Infiltrative diseases ⇒ sarcoidosis; other granulomatous diseases; metastases
Serum Gamma Glutamyltransferase (GGT)
- Found in hepatocytes and biliary epithelial cells
- Very sensitive indicator of hepatobiliary disease
- Usefulness limited by lack of specificity
- Elevated levels also seen in a wide variety of other clinical conditions: pancreatic disease, MI, CKD, COPD, DM, Alcoholism, Phenytoin and Barbiturates
- Occult alcohol use ⇒ sensitivity ranges from 52-94%
-
Clinical uses:
- Evaluate a cause for ↑ ALP
- Support a suspicion of alcohol abuse w/ AST:ALT ratio > 2:1
Hepatic Synthetic Function
Tests
Tests measure how well the liver is working:
-
Serum Albumin
- Most important protein in plasma synthesized by the liver
- Total pool = 500 grams, 12-15 gm synthesized daily
-
T ½ = 20 days
- Not helpful in acute liver disease
- Influenced by nutritional status, hormone balance and osmotic pressure
-
Prothrombin Time
- Liver synthesizes most coagulation factors
- Factors II, VII, IX, X, (vitamin K)
- < 50% of normal levels are needed to prolong PT
- Liver synthesizes most coagulation factors
Bile Physiology
- Secreted by hepatocytes
-
Functions:
- Emulsify dietary fats in the duodenum
- Facilitates transport of fat-soluble vitamins (A, D, E, K)
- Rids body of bilirubin
- Enables excretion of cholesterol, lipophilic wates (drugs, toxins)
-
Contains:
- Water
- Bile salts
- Bilirubin (pigmented)
- Electrolytes (isotonic to plasma)
- Phospholipids and cholesterol
Bilirubin
Synthesis & Transport
-
Heme derived end product
- 85% from senescent RBCs
- 15% from other sources
- Breakdown of other hepatic hemoproteins
- Cytochrome P-450 enzymes
- Premature RBC breakdown in bone marrow
- Breakdown of other hepatic hemoproteins
-
RBC phagocytosed by MΦ in reticuloendothelial system (RES)
- Heme porphyrin ring → biliverdin by microsomal heme oxygenase
- Biliverdin → bilirubin by biliverdin reductase
-
Unconjugated BRN is released into the plasma
-
Majority bound to albumin
- Insoluble in water ⇒ cannot be excreted in urine or bile
- Transported to the liver
- BRN released by albumin and taken up by hepatocytes
-
Unbound (free) bilirubin
- Toxic to brain of newborns ⇒ kernicterus
- Drugs competing w/ bilirubin for albumin binding sites ↑ free bili
-
Majority bound to albumin
Bilirubin
Metabolism & Excretion
-
Hepatic BRN metabolism__:
-
Uptake:
- Bilirubin dissociates from albumin in the space of Disse
- Carrier mediated transport of unconjugated BRN across hepatocyte membrane
- Glutathione-S-Transferase (ligandin) binds bilirubin in the cell
-
Conjugation:
- BRN conjugated w/ glucuronic acid by UDP glucoronyltransferase (UGT) in the ER
- Forms BRN mono- and diglucuronide ⇒ both water soluble
-
Excretion into the bile:
-
Conjugated BRN excreted into bile canaliculus via active transport by MRP2 transport protein
- Rate limiting step for transhepatic transport of bilirubin
-
Conjugated BRN excreted into bile canaliculus via active transport by MRP2 transport protein
-
Uptake:
-
Transport of conjugated BRN__:
- Bile → biliary system → ampulla of Vater → 2nd portion of the duodenum → large intestine (colon)
- Bacteria convert conjugated BRN → colorless urobilinogens → excreted in the feces
- Urobilinogens → colored urobilins ⇒ gives stool its color
- 20% of urobilinogens deconjugated by colonic bacteria and reabsorbed by enterohepatic circulation
- 1% is excreted in the urine
Bilirubin
Measurement
- Total bilirubin = 0.1-1.5 mg/dL
-
Unconjugated or “indirect” = 0.1-1.0 mg/dL
- Not soluble in water
- Not measured directly in serum
- Indirect BRN = Total – Direct BRN
-
Conjugated or “direct” = 0-0.3 mg/dL
- Water soluble
- Small amount leaks out from liver
- Directly measured in the serum
Excess Bilirubin
- Hyperbilirubinemia: ↑ bilirubin concentration in blood (> 1.0 mg/dL)
- Jaundice (icterus): yellow skin and sclerae (> 2-2.5 mg/dL)
- Cholestasis: visible bile plugs and bile by microscopic examination of liver
- Cholestatic jaundice: Cholestasis and hyperbilirubinemia
Jaundice
“Icterus”
- Yellow discoloration of skin, sclera and mucous membranes
-
Excess serum bilirubin ⇒ deposited in tissues
- Tissues w/ high [elastin] ⇒ ↑ affinity for serum bilirubin
- E.g., sclera of the eye
- Tissues w/ high [elastin] ⇒ ↑ affinity for serum bilirubin
- Normal serum bilirubin 0.3-1.5 mg/dL
- ↑ BRN becomes clinically evident when > 2-4 mg/dL
-
Other conditions can cause yellow discoloration of the skin but not scleral icterus
- Carotenemia (excess serum carotene from carrots)
- Tanning products
- Side effects of medication (e.g., quinacrine or busulfan)
Unconjugated Hyperbilirubinemia
Disorders are not usually ass. w/ significant hepatic disease
-
Displacement of BRN from albumin by drugs
- Rifampin
- Overproduction__:
- *Overproduction of BRN** ⇒ exceeds hepatic conjugative capability
- BRN rarely > 5mg/dL
- Jaundice usually mild
-
Hemolytic disorders
- Sickle cell anemia, thalassemia, G6PD deficiency, paroxysmal nocturnal hemoglobinuria
-
Ineffective erythropoiesis
- Fe deficiency, vitamin B12 deficiency, sideroblastic anemia, lead toxicity
- Resorption of large hematomas
-
Impaired uptake__:
- 1°: Gilbert’s syndrome
- 2°: Certain drugs, e.g., rifampin, may compete w/ BRN uptake
-
Impaired conjugation__:
- 1°: Crigler-Najjar syndrome
- 2°: Acquired defects in conjugation
- Drugs (e.g. chloramphenicol)
Gilbert’s Syndrome
- AD disorder, 3-8% of population
-
Mutation of bilirubin UDP-GT
- ↓ Uptake of unconjugated BRN by hepatocytes
- Partial defect in BRN conjugation (50% of normal)
-
Mild unconjugated hyperbilirubinemia
- BRN levels ≤ 6mg/dL
- No other biochemical/histological abnormalities
- Pts asymptomatic at baseline
- Occasionally exhibit jaundice w/ illness, stress, fatigue, premenstrual state and alcohol abuse
- Liver biopsy is not indicated, no specific therapy
Crigler-Najjar Syndrome
Unconjugated Hyperbilirubinemia
Impaired conjugation of BRN caused by ∆ UDP glucoronyltransferase activity.
-
Type 1
- AR disorder
- No UDPGT activity
-
Fatal for neonates
- Severe unconjugated hyperbilirubinemia (> 20 mg/dL)
- Often die by 18 m/o w/ kernicterus
- Tx: phototherapy, plasmapheresis, liver transplantation
-
Type 2
- AD disorder
- ↓ UDPGT activity (10% of normal)
- BRN levels 10-16 mg/dL
- No kernicterus
- Tx: Phenobarbital to induce UDPGT activity
Neonatal Jaundice
- Seen in 70% of full-term newborns
- Physiologic in first 5 days of life
- D/t incompletely developed hepatic BRN metabolism
- ↓ Ligandin and ↓ UGT
- Result in unconjugated hyperbilirubinemia
- UGT ↑ by 2 wks of life to adult levels
- Bilirubin crosses placenta and is dealt w/ by mom in utero
-
Other factors:
- RH and ABO blood incompatibilities: hemolytic anemia ⇒ pathologic + physiologic jaundice in newborn
- Hypothyroidism
- Breast milk jaundice resulting from an inhibitor of UDPGT activity in maternal breast milk
Conjugated Hyperbilirubinemia
- Definition: conjugated BRN level > 30% of total BRN
-
Congenital causes:
- Dubin-Johnson syndrome
- Rotor’s syndrome
- Progressive familial intrahepatic cholestasis (PFIC) (“Byler’s disease”)
-
Acquired causes:
- Cholestasis: impaired formation or excretion of all components of bile
Dubin-Johnson Syndrome
Conjugated Hyperbilirubinemia
- AR condition
- Mutated MRP2 transporter
- Impaired storage and excretion of BRN
- Serum BRN levels 2-5mg/dL
- Histological exam reveals a darkly pigmented (black) liver
- No specific therapy
Rotor’s Syndrome
Conjugated Hyperbilirubinemia
- AR condition
- Impaired intracellular storage of BRN
- Bile salt excretion is normal
- BRN levels 2-5mg/dL
- Liver is not pigmented
- Liver function unaffected
- No specific therapy
Progressive Familial Intrahepatic Cholestasis (PFIC)
“Byler’s Disease”
Conjugated Hyperbilirubinemia
- AR condition
- Defective hepatic secretion of bile acids across the canalicular membrane
- Particularly affecting the Amish kindred
- Pts present w/ severe watery diarrhea, cholestatic jaundice, fat-soluble vitamin deficiency and occasionally pancreatitis
Cholestasis
Overview
- Impaired formation or excretion of all components of bile
- ↑ Serum and tissue bilirubin
-
2 major mechanisms:
- Defect in excretion of BRN from hepatocytes into bile ⇒ intrahepatic cholestasis
- Mechanical obstruction to the flow of bile through the bile ducts ⇒ extrahepatic cholestasis
-
Biochemical pattern:
- ↑ Serum BRN (usually conjugated)
- ↑ ALP
- ↑ GGTP
- Mild ↑ AST/ALT (≤ 2x ULN)
Differentiating
Cholestasis
- Considerable overlap in biochemical pattern seen in intrahepatic and extrahepatic causes
- Additional testing to look for an extrahepatic cause
- Abdominal US
- CT
-
MRCP (magnetic resonance cholangiopancreatography)
- MRI of the biliary and pancreatic trees
-
ERCP (endoscopic retrograde cholangiopancreatography)
- Endoscopic contrast study of the biliary tree
- Obstruction in the biliary tree (gallstone, pancreatic tumor or malignant biliary tract CA) ⇒ bile ducts will appear dilated on imaging
Intrahepatic Cholestasis
Etiologies
-
Bile canaliculus
-
Hepatocellular injury
- Viral and alcoholic hepatitis
- Sepsis
- Prolonged total parenteral nutrition
- Congestive hepatopathy (from right heart failure)
- Infiltrative disorders (sarcoidosis, amyloidosis, lymphoma etc.)
- Graft-versus-host disease (after bone marrow transplant)
-
Drugs
- Steroid hormones, chlorpromazine, OCP, NSAIDs etc.
- Benign post-operative cholestasis
- Pregnancy
-
Hepatocellular injury
-
Bile ductule
- ? Drugs
-
Portal tract bile duct
- Primary biliary cholangitis (PBC) (“Primary biliary cirrhosis”)
- Intrahepatic biliary atresia
-
Medium and large interlobular bile ducts
- Sclerosing cholangitis
- Cholangiocarcinoma
- Parasite
- Vanishing bile duct syndrome (idiopathic adulthood ductopenia, chronic rejection)
Intrahepatic Cholestasis
Morphologic Features
Cholestasis & cell necrosis
-
Early cholestasis
- Preferential localization in zone 3
- See bile in hepatocytes
-
Late cholestasis
- Bile plugs in zone 1
-
Feathery degeneration
- Swelling
- Bile pigment
- Reticulation of cytoplasm
- Mallory hyaline
- Fibrosis/Cirrhosis
Extrahepatic Cholestasis
Etiologies
- Choledocholithiasis (gallstones impacted in common bile duct)
-
Sclerosis and strictures of biliary tree
- Sclerosing cholangitis
- Secondary causes
-
Neoplasia
- Cholangiocarcinoma (bile ducts)
- Pancreatic adenocarcinoma
- Ampullary carcinoma
- Duodenal neoplasm
- Metastases to hepatic hilum
- Portal LN involvement by any neoplasm
- HIV cholangiopathy
- Haemobilia (blood clots in biliary tree)
- Infectious cholangiopathy: worms impacted in bile ducts (Clonorchis, Ascaris, Fasciola)
- Chronic pancreatitis
- Benign biliary strictures (post-cholecystectomy, post liver transplant, related to PSC, ischemic)
-
Pediatric pts
- Extrahepatic biliary atresia
- Choledochal cysts
Extrahepatic Cholestasis
Morphologic Features
Cholestasis & Cell Necrosis
Plus
- Portal tract edema
- Bile duct proliferation
- Neutrophils
- Bile infarct
- Extravasated bile
Cholestasis
Clinical Manifestations
- Dark urine ⇒ “tea colored”
- Light stools ⇒ “clay colored”
-
Pruritus
- D/t retention of bile salts and other products
- Tx w/ bile salt binders (cholestyramine)
- Abd pain
- Weight loss
- Fat malabsorption (steatorrhea)
-
Fat soluble vitamin deficiency states:
- Vit A ⇒ night blindness
- Vit D ⇒ osteomalacia
- Vit K ⇒ coagulopathy
- High cholesterol ⇒ xanthomas
- Secondary biliary cirrhosis
Predictable
Hepatotoxins
- Fundamental property of toxin
- Injury in majority of people
- Dose dependent
- Zonal necrosis
- Two mechanisms:
- Direct
- Indirect
Carbon Tetrachloride Toxicity
Unpredictable
Hepatotoxins
- Idiosyncratic reaction
- Host dependent
- Non-dose dependent
- Non-zonal
- Two mechanisms:
- Hypersensitivity
- Metabolic aberration
Acute and Chronic Hepatitis
Common Causes
- Viral
- Drug/Toxin
- Alcohol
- Non-Alcoholic Fatty Liver
- Autoimmune Related Disorders
- Metabolic Disorders
- Ischemic/Congestive
- Extrahepatic biliary obstruction