Lecture 8: Lab Testing, Acute & Chronic Injury Cirrhosis

Liver Blood supply

Dual blood supply via:

Hepatic Artery from Aortic Celiac trunk

Portal Vein from GI tract

Venous drainage via Hepatic Vein into IVC

Portal Triads at periphery carry Portal Vein + Hepatic Artery + Bile Ductule

Arterial & Venous blood mix in the sinusoids & collect at the Central vein of lobule (Central vein region, Zone 3, is the most hypoxic region)

Sinusoids are lined by endothelial cells with gaps between them (Fenestrae)

Hepatic Plates (the hepatocytes between sinusoids) are 1-2 layers thick

Liver Specialized Cells

Kupffer cells are resident liver Macrophages attached to endothelial cell surfaces

Beneath endothelium is space of Disse with Stellate Cells (Ito cells)

Stellate cells store fat & fat-soluble vitamins like Vit A & produce extracellular matrix Type III collagen (Reticulin) for structural support

If activated by inflammation, can differentiate into Myofibroblasts & produce Type I Collagen (Scar tissue)

Acute Liver failure Labs

Increased Ammonia → Hepatic Encephalopathy

Hypoglycemia

Severe bleeding (Lab: ↑ PT/INR)

Chronic Liver Disease

Hypoalbuminemia → ↓ oncotic pressure → Ascites, Edema

Impairs breakdown of Estrogen → Feminization in men

Drug choices & dosages must be adjusted

If impaired excretory functions

In GI tract, ↓ bile acids → fat malabsorption (Steatorrhea) & deficiencies of fat-soluble vitamins (A, D, E, K)

In Blood, ↑ Bile acids → Pruritus; ↑ Cholesterol → Xanthomas

If impaired conjugation or excretion of Bilirubin (Cholestasis) → ↑ Bilirubin → Jaundice, Biliary cirrhosis

Enterohepatic Circulation of Bile Acids

Bile Acids: secreted into the duodenum; most reabsorbed in ileum for reuse

Bilirubin: Small amounts of unconjugated Bilirubin along with urobilinogen are reabsorbed from the colon into the blood

Drugs: Some drugs are reabsorbed & re-excreted in the bile

↑ in severe Hepatocyte injury or death

AST, ALT, LD

↑ in Bile ductal obstruction/bile ductal epithelial injury

Total Bilirubin

Conjugated Bilirubin (Direct)

ALP

GGT

to assess for Liver Failure

Albumin, PT, Ammonia

Aminotransferases

used to detect Hepatocyte injury

Aspartate aminotransferase (AST): Not specific; may be from Liver, Skeletal muscle, heart, kidney, RBCs, pancreas

Alanine aminotransferase (ALT): Clinically specific to liver

Hepatocyte Injury/Death

Cytosolic enzymes released; elevated in serum

AST & ALT + Lactate Dehydrogenase

Hepatocyte necrosis likely if:

AST, ALT > 10x upper limit normal

AST and ALT are >> ALP (Alkaline phosphatase)

AST > 2x ALT in Alcoholic liver disease

AST > ALT in Cirrhosis

Elevations may be due to toxins, drugs, hepatitis, metabolic diseases, poor perfusion

Minor elevations occur in biliary obstructive diseases

Tests for Bile duct obstruction & Bile ductal epithelial injury

Hyperbilirubinemia Bilirubin, particularly the Conjugated form (Direct)

GGT: ↑ in biliary obstruction disproportionately to AST & ALT

GGT is localized to luminal cell membranes of bile canaliculi & bile ductal cells & is the only enzyme specific to liver

Alkaline Phosphatase (ALP):

↑ 3-5 X in extrahepatic & usually < 3 X, for intrahepatic cholestasis

ALP is found in Bile duct canalicular cells, Bone & Placenta

Children have reference range above adults

Hypercholemia (↑ serum Bile Acids) & ↑ Cholesterol (Hyperlipidemia) in bile obstruction

Increased unconjugated bilirubin

Hemolysis

Increased unconjugated and conjugated

Hepatocyte pathology

Indirect (Unconjugated) Hyperbilirubinemia

↑ Hemolysis

↑ LD; AST may be mildly elevated, ALT normal; ALP normal

Resorption of blood from internal bleeding (hematoma)

Hereditary unconjugated Hyperbilirubinemias (Normal ALP, GGT, AST, ALT, LD)

Gilbert common; benign

Crigler-Najjar Type II; benign (but Type I is lethal in newborns)

Unconjugated bilirubin predominates over conjugated (direct) hyperbilirubinemia in advanced liver disease (not enough cells to conjugate!):

Cirrhosis of the liver

Hepatitis, late in disease

Acute liver failure

Direct (Conjugated) Hyperbilirubinemia

Urinary bilirubin also ↑ as it is water-soluble

Hepatitis, acute or early

Intrahepatic cholestasis due to deficiency of bile pump/transporter proteins

Bile duct obstruction

Intrahepatic biliary disease: obstruction due to cancer, abscess, etc.

Extrahepatic obstructions

Hereditary: Dubin Johnson, Rotor syndromes

Physiologic Jaundice of the Newborn (Neonatal Jaundice)

Unconjugated (indirect) hyperbilirubinemia

Transient, usually mild

Noted 2-3 days after birth, peaks in about a week

Due to immature Liver at birth (conjugating enzyme level low)

Exacerbated by breast feeding (milk contains deconjugating enzymes; unconjugated bilirubin in baby's gut gets reabsorbed)

Phototherapy, blue light, that converts unconjugated bilirubin into water soluble Lumibilirubin

Kernicterus (Bilirubin Encephalopathy)

unconjugated bilirubin levels are >20 mg/dL

Unconjugated bilirubin can cross the blood-brain barrier as it is lipid-soluble

permanent neurologic damage or death

Physiologic Jaundice of the Newborn

Crigler-Najjar

Increased in unconjugated bilirubin

Type I: Absent conjugating enzyme activity; Fatal in neonatal period

Type II: Reduced conjugating enzyme; generally mild; occasional Kernicterus; Rx with phenobarbital if Bili > 15-20

Phenobarbital ↑ hepatic glucuronosyl transferase activity

Gilbert Syndrome

Increased in unconjugated bilirubin

Innocuous; ↓ conjugating enzyme activity

↑ Conjugated bilirubin

Dubin-Johnson Syndrome → Innocuous; impaired canalicular secretion of conjugated bilirubin due to mutation in drug efflux channel (Multidrug Resistance Protein 2/MRP2)

Pigmented cytoplasmic globules in cytoplasm → liver black

Rotor Syndrome → innocuous

Alkaline Phosphatase (ALP)

Synthesized & excreted by the biliary tract

Elevated in bile duct obstruction, external & internal (extra- or intra-hepatic)

External obstruction results in the highest elevations of ALP & is accompanied by a parallel rise in direct (conjugated) bilirubin

Moderate elevations ≈2x normal

Space-occupying lesions (primary & metastatic tumors to the Liver or Bone)

Intrahepatic biliary tract disease

Hepatic congestion (heart failure); Hepatic injury (hepatitis)

Non-liver ALP sources: Osteoblasts (bones in growing kids/teens), Placenta (pregnancy), Intestines

Gamma Glutamyl Transpeptidase (GGT)

manufactured by bile ducts; specific to liver

Elevated with Alcohol ingestion even w/o liver disease due to microsomal induction

Obesity

Cholestasis

Decreased bile flow due to impaired secretion by hepatocytes or to obstruction of bile flow through the intrahepatic or extrahepatic bile ducts

increased serum concentrations of:

Conjugated bilirubin, Bile acids/salts, Cholesterol

↑ Direct (Conjugated) bilirubin; Cholesterol; ALP

Jaundice, Pruritus due to retained bile acids, skin Xanthomas

Acute liver failure

Encephalopathy & Coagulopathy that occurs < 6 months (usually < 2 months) after the initial liver injury & in absence of preexisting liver disease

Causes: Acetaminophen overdose, Drugs/toxins, Hep A, Hep B, Autoimmune hepatitis, Hep E

AST, ALT > 10x upper limit normal & are >> ALP

Jaundice & Icterus, N&V

↑ Bilirubin: mostly conjugated, but ↑ unconjugated too

Coagulopathy: prolonged PT/INR & PTT

Easy bruising, intracranial hemorrhage, DIC

Hepatic Encephalopathy: ↑ serum Ammonia

Confusion, stupor, coma, Asterixis "liver flap"

Hepatorenal Syndrome: ↓ urine output, ↑ BUN & Creatinine

Fetor Hepaticus: foul smelling breath due to portosystemic shunt of Thiols (organosulfurs)

Two pathogenetic patterns of Acute Liver Failure

Massive necrosis

Diffuse Microvesicular Steatosis:

AST, ALT not massively elevated (not due to necrosis)

Seen in Fatty Liver of Pregnancy, some Drugs (valproate, tetracycline), Reye syndrome (aspirin to children) or idiosyncratic

Mechanism is acute metabolic failure due to impaired mitochondrial Fatty Acid β-oxidation

Chronic Liver Failure

Encephalopathy & Coagulopathy

background of other complications of inadequate liver function occurring after a long-standing (> 6 months) liver illness

Cirrhosis: Nodules of hepatocytes completely surrounded by fibrous (collagenous) tissue

Portal hypertension

Persistent Cholestasis can result in retention of Bile Acids in blood with Pruritus (Itching)

Impaired breakdown of Estrogen: Palmar Erythema (due to vasodilation), Spider Angiomas of skin, Hypogonadism (menstrual irregularities, testicular atrophy) & Gynecomastia

Causes of Cirrhosis

Chronic Hep B, Hep C, NASH (Non-Alcoholic Steatohepatitis), Alcoholic Liver Disease

Cirrhosis-associated Immune Dysfunction syndrome

immunocompromised & have ↑ susceptibility for spontaneous bacterial infections, hospital-acquired infections, & infections from uncommon pathogens

Portosystemic shunting impairs liver clearance of gut-derived bacteria in the portal circulation

↓ phagocytic activity

Spontaneous Bacterial Peritonitis (SBP) in the Ascitic fluid, Urinary tract infection, Pneumonia, Bacteremia, & soft tissue infection

Cirrhosis

Cirrhosis

Cirrhosis

liver is shrunken with a “hobnail” capsule & micronodular cut surface

Cirrhosis Morphology

Diffuse involvement of entire liver by regenerating hepatocyte nodules surrounded by dense bands of scar

Ductular reaction (proliferation of reactive bile ducts within the fibrotic septa)

Some Regression of fibrosis may occur (eg, treated Hep C, EtOH abstinence) via thinning of fibrous scars

Hyperestrogenemia in advanced Chronic Liver disease

Pathogenesis: inability to break down Estrogen

Palmar erythema (due to vasodilation)

Spider angiomas (may be due to ↑VEGF)

Hypogonadism & Gynecomastia (breast enlargement in men)

Secondary Amenorrhea in women

Portal Hypertension

Increased pressure in Portal Vein → ↑ resistance to Portal blood flow

Cirrhosis (intrahepatic) is the most common cause

In Cirrhosis, resistance to portal flow at the level of sinusoids is due sinusoidal disruption from scarring & Arteriolar vasoconstriction due to ↓ NO production by sinusoidal endothelial cells

Causes include pre-, intra- & post- hepatic

Four major consequences of portal hypertension are:

Formation of Portosystemic venous shunts/varices

Hepatic encephalopathy

Ascites

Congestive splenomegaly

Portosystemic venous shunts

Portal Hypertension is an impedance to return of blood to the IVC & causes development of, & use of, portocaval anastomoses to decompress the portal circulation

Rectum → Hemorrhoids

Esophagogastric Junction (producing Esophageal & Gastric Varices): often rupture, causing massive bleeding, death

Periumbilical/Abdominal wall venous collaterals (producing Caput Medusa)

Hepatic Encephalopathy

Ammonia toxic to CNS accumulate due to impaired liver function + shunting of blood around liver

Severe Hepatocyte loss or impairment reduces liver’s capacity to detoxify Ammonia into Urea

Biggest source of Ammonia is the GI tract from bacterial & enterocyte metabolism of Glutamine

With significant portosystemic shunting, Ammonia bypasses the liver

GI enema with Lactulose traps ammonia

Ascites

Caused by cirrhosis; normally are Transudates; may seep through diaphragm to cause hydrothorax

Spontaneous Bacterial Peritonitis, an ascitic fluid infection without an evident intra-abdominal surgically treatable source, presumably by transmigration of bacteria through the gut wall

Suspect if cirrhotic patient develops fever, abdominal pain/ tenderness to palpation, altered mental status, or hypotension

Rx if Paracentesis fluid PMNs > 250/mm3, or if + Leukocyte Esterase or + Nitrite

Splenomegaly

Hypersplenism sequestration → Thrombocytopenia or Pancytopenia

Schistosomiasis

common cause of Portal Hypertension

Intrahepatic “Pipestem Fibrosis” due to granulomatous inflammation to eggs within intrahepatic branches of the portal vein

Indications for TIPS procedure (Transjugular Intrahepatic Portosystemic Shunt) for Rx of Portal Hypertension

Uncontrolled variceal hemorrhage from esophageal or gastric varices that do not respond to endoscopic or medical management

Refractory Ascites

Hepatic pleural effusion (Hydrothorax)