Disorders of Hepatobiliary and Exocrine Pancreas Function

Happy Studying, Good Luck on your exams!

Functions of Liver

• Produces bile

• Uptake, storage, and distribution of nutrients and vitamins

• Synthesizes most plasma proteins (albumin, clotting factors)

• Degrades and eliminates drugs and toxins

• Maintains blood glucose levels (glycogenesis, glycogenolysis, and gluconeogenesis)

• Changes ammonia to urea

• Converts fatty acids to ketones

Function of Gallbladder

Stores bile

What is bile?

fluid that is made and released by the liver and stored in the gallbladder. Bile helps with digestion. It breaks down fats into fatty acids, which can be taken into the body by the digestive tract.

Function of the Pancreas

Secretes enzymes involved in digestion of carbohydrates, lipids, and proteins

Characteristics of Liver

• Largest visceral organ in body – weighs ~ 3.3 pounds

• Receives blood via hepatic artery and portal vein

• Hepatic artery: 300 mL/min

• Portal vein: 1050 mL/min

Hepatic blood flow involves these organs..

• Stomach

• Spleen

• Pancreas

• Intestines

• Esophagus

The portal vein….

Drains blood from the stomach, spleen, and pancreas, supplying ~ 75% of total hepatic blood flow

The Hepatic sinusoids are…

Hepatic capillaries that mix 02 rich blood with nutrient rich blood

Hepatic veins function

Drains hepatic blood into the inferior vena cava

Hepatic artery function

Drains blood from the abdominal aorta, supplying ~ 25% of total hepatic blood flow

Inferior vena cava function in hepatic blood flow

Receives blood from the hepatic veins

Metabolic Functions of the Liver involve….

• Carbohydrate metabolism

• Glycogen storage, gluconeogenesis, stores glucose as triglycerides

• Lipid metabolism

• Protein synthesis

• Ammonia → urea

Lipid metabolism in the liver

Involved with…

Synthesis of cholesterol, phospholipids, lipoproteins

Fatty acid oxidation → Ketoacids

Carbohydrates + proteins → triglycerides

Protein synthesis is involved with…

• Clotting factors, fibrinogen

• Plasma proteins (albumin)

  • Colloidal osmotic pressure

  • Plasma proteins serve as carriers

Conversion of ammonia → urea

• Process occurs during metabolism of proteins

• Transamination – transfer of amino group to α- ketoglutarate → α-ketoglutarate + an amino group = glutamate.

• Deamination – removal of amino group from

  glutamate → ammonia + α-ketoglutarate

• Ammonia toxic to tissues (neurons)

• Ammonia + CO2 → urea (1st step of urea cycle)

• Urea excreted by kidneys

Bile formation

Necessary for digestion and absorption of dietary fats and fat-soluble vitamins

• Liver produces 600-1200 mL of bile/day

• Bile is made up of water, bile salts, bilirubin, cholesterol, and more

Bilirubin comes from…

aging RBCs

Unconjugated Bilirubin is…

free bilirubin attached to albumin

Conjugated Bilirubin is….

a water soluble form, component of bile

Jaundice is…

yellowish coloring of skin from abnormally high blood levels of bilirubin

Jaundice is the result of these bodily processes

• ↑ destruction of RBCs

• Impaired uptake by liver

• ↓ conjugation of bilirubin

• Obstruction of bile flow through liver

• ↑ production of bilirubin

Liver function tests: Complete metabolic panel (CMP)

what does this find / what do certain results mean?

• Liver enzymes: (earliest indication of liver disease)

  • ALT – alanine aminotransferase

  • AST – aspartate aminotransferase

• Serum bilirubin (jaundice)

  • ↑ liver disease, RBC hemolysis, gallbladder disease

Liver Function Tests (LFTs): γ-Glutamyltransferase (GGT)

what does this find / what do certain results mean?

Finds endoplasmic reticulum and bile duct epithelial cells

• Most sensitive test for detecting bile duct problems

• ↑ levels suggest hepatobiliary disease

Hepatic Metabolism of Drugs: Phase 1 involves….

chemical modification through oxidation and other chemical reactions

Hepatic Metabolism of Drugs: Phase 2 involves….

conversion of lipid-soluble derivatives to water-soluble substances called conjugates

Hepatic Metabolism of Drugs: Phase 3 involves….

a substance, its metabolites, or conjugates are secreted as bile

Drug-induced Liver Disease is considered…

Frequent cause of acute liver injury (> 50%)

Effects of the liver being a major drug-metabolizing and detoxifying organ include…

increased risk for damage

Risk factors for increased susceptibility for Drug-Induced Liver Disease

• Genetic predisposition

• Age

• Underlying liver disease

• Alcohol consumption

• Drug use

Drug-induced Liver Disease: Direct hepatotoxic injury cause + pathophysiology

• Age and dose dependent

• Metabolism of drug → toxic metabolites

examples of drugs that can cause direct hepatotoxic injury

acetaminophen, antimicrobials, psychotropic agents, lipid-lowering drugs, NSAIDs

Manifestations of direct hepatotoxic injury

↑ bilirubin levels and jaundice if hepatic necrosis

Idiosyncratic reactions pathophysiology and manifestations

• Damaging metabolites in individuals with specific genetic predispositions

• Manifest as an allergic reaction

Cholestatic reactions are caused by…

decreased secretion of bile or bile obstruction

ie estradiol

Manifestations of Cholestatic reactions

Early onset jaundice and pruritis

Chronic hepatitis is.. + cause

• Diagnosed when cirrhosis develops

• Cause: Multiple drugs or drugs + excess EtOH intake

Viral Hepatitis is…

Acute or chronic inflammation of liver caused by hepatotropic virus

Mechanism of injury: Viral Hepatitis

• Direct cellular injury

• Induction of immune response against viral antigens

Clinical Course of Viral Hepatitis

• Varies widely

• Asymptomatic infection

• Acute hepatitis

• Carrier state without clinically apparent disease

• Chronic hepatitis with and without progression to cirrhosis

• Fulminating disease with rapid onset liver failure

Hepatitis A (HAV) transmission methods…

fecal-oral, sexual, parenteral

Hepatitis A (HAV) prevention methods…

vaccine, hygiene

Hepatitis A (HAV) manifestations…

Abrupt onset fever, malaise, nausea, abdominal discomfort, dark urine, jaundice

an acute virus

Hepatitis B virus (HBV) is an ___ or ___ virus

acute or chronic virus

Hepatitis B virus (HBV) transmission methods…

parenteral, sexual, placental, blood exposure

How can HBV be prevented?

Vaccines and taking precautions

Manifestations of HBV

symptoms related to acute or chronic hepatitis. May lead to cirrhosis, liver failure, or carrier state

Hepatitis C virus (HCV) transmission methods…

Parenteral, sexual, placenta, blood exposure

chronic disease

precautions must be taken (only preventative)

Hepatitis C patients are often..

asymptomatic

Most individuals develop chronic hepatitis → cirrhosis, liver failure, cancer

Hepatitis D requires one to have…

Hepatitis B

also acute or chronic

only way to prevent is HBV vaccine

Hepatitis E is..

acute, but can be chronic in immunocompromised persons

transmitted by fecal-oral means

prevented by practicing hygiene and drinking clean water

manifestations similar to hepatitis A, more severe in pregnant persons.

EtOH refers to..

alcohol usage

Most EtOH metabolized by liver by these 2 pathways…

Alcohol dehydrogenase (ADH)

Microsomal ethanol-oxidizing system (MEOS)

Alcohol dehydrogenase (ADH) involves….

the cytoplasm

Microsomal ethanol-oxidizing system (MEOS) involves…

The endoplasmic reticulum and CYP enzymes that also metabolizes drugs, such as Tylenol, which can increase risk of hepatotoxic effects of these drugs with EtOH use

Fatty liver disease results in…

accumulation of fat in hepatocytes (steatosis)

Characteristics of fatty liver disease

• Occurs quickly

• occurs through activities such as Binge drinking

• Reversible if alcohol intake discontinued

Alcoholic hepatitis involves…

inflammation and necrosis of liver cells due to excessive alcohol intake

Alcoholic Hepatitis tends to occur in….

binge drinkers.

alcoholic hepatitis cardinal sign is….

the rapid onset of jaundice

Alcoholic cirrhosis is….

the end result of EtOH-related hepatocyte injury

Nonalcoholic Fatty Liver Disease involves…

Fatty liver disease due to causes other than alcohol (metabolic dysfunction)

Nonalcoholic Fatty Liver Disease characteristics

Lipid accumulation in the cytoplasm and formation of free radicals

Common comorbidities with Nonalcoholic Fatty Liver Disease

obesity, type 2 diabetes, metabolic syndrome, hyperlipidemia

NASH refers to…

nonalcoholic fatty liver steatohepatitis

NASH can lead to…

cirrhosis (over time)

Cirrhosis of the Liver involves…

• Irreversible inflammatory, fibrotic liver disease – end stage chronic liver disease

• Functional liver tissue replaced with fibrous tissue

• Liver develops nodules of hepatocytes encircled by fibrosis

Causes of cirrhosis of the Liver

• Excessive alcohol and drug intake

• Hepatitis (chronic)

• Nonalcoholic fatty liver disease

• Biliary obstruction

Pathophysiology of cirrhosis

• Diffuse fibrosis → nodules

  • Balance between liver regeneration and scarring

• Fibrotic tissue loses normal function and disrupts vascular and biliary flow

Alcoholic cirrhosis involves…

cumulative toxic effects of alcohol metabolism on liver, inflammation, oxidative stress from lipid peroxidation, and malnutrition
• In liver, alcohol is transformed to acetaldehyde

Acetaldehyde in alcoholic cirrhosis

↑ acetaldehyde alters hepatocyte function → fibrosis

Manifestations of cirrhosis include…

• Weight loss, cachexia, weakness, anorexia

• Splenomegaly

• Ascites

• Varices: esophageal, gastric

• Bleeding

• Thrombocytopenia

• Hepatic encephalopathy

• Gynecomastia

• Spider angiomas

What are the five major consequences of liver dysfunction

1. Portal hypertension

2. Ascites

3. Jaundice

4. Hepatic encephalopathy

5. Hepatorenal syndrome

Normal pathway for blood in hepatic portal system

Venous blood returning to heart from abdominal organs collects in portal vein and travels through liver (for filtering) before entering vena cava

Pathophysiology of Portal Hypertension

↑ resistance to hepatic blood flow → ↑ hydrostatic pressure in portal vein

Causes of Portal Hypertension can include…

Pre-hepatic, Intra-hepatic, or Post-hepatic processes

Just tells location in relation to liver.

Clinical consequences of Portal Hypertension

Ascites, Congestive splenomegaly, Varices, Hemorrhoids

Ascites in Portal Hypertensions is due to…

↑ pressure in peritoneal capillaries

Congestive splenomegaly in portal hypertension

anemia, leukopenia, thrombocytopenia → ↑ risk of infection and bleeding

Portal Hypertension and Varices refers to

distended, tortuous veins

Esophageal Varices in Portal Hypertension

• Distended, tortuous veins

• Lower esophagus, stomach

• Thin walled, easily ruptured

• Rupture can be fatal due to hemorrhage

• Lack of coagulation factors and thrombocytopenia due to liver failure → ↑ bleeding

Ascites is characterized as…

• Accumulation of fluid in peritoneal cavity (> 500 mL)

• ↓ fluid available for normal physiologic functions

• Late-stage manifestation of cirrhosis and portal hypertension

Ascites mechanisms

• ↓ colloidal osmotic pressure due to impaired synthesis of albumin by liver

• ↑ portal hydrostatic pressure

• ↑ RAAS → salt and water retention by kidney

CM of Ascites

abdominal distention, ↑ abdominal girth, weight gain

• ↑ volumes (10-20 L) displace diaphragm → dyspnea

Treatments of Ascites

Paracentesis, IV albumin

Hepatic encephalopathy refers to..

CNS manifestations of liver failure

Manifestations of Hepatic encephalopathy

• Neural disturbances range from lack of mental alertness → confusion, coma, convulsions

• Asterixis – flapping hand tremor

• Memory loss and personality changes

• Speech and motor function impairment

Hepatic encephalopathy pathophysiology

• Accumulation of neurotoxins due to loss of detoxifying capacity of liver

• Ammonia accumulation

Jaundice results in + why..

Yellowish discoloration of sclera, skin, and deep tissues resulting from ↑ levels of bilirubin in blood (> 2.5 mg/dL)

Jaundice: Prehepatic cause refers to…

excessive hemolysis of RBCs

Jaundice: Intrahepatic causes refer to…

liver disease

Jaundice: posthepatic causes refer to..

obstructive/cholestatic jaundice, gallstones

Manifestations of Jaundice

Dark Urine

Yellowing of sclera (early in condition) and later, the skin

Hepatorenal syndrome is..

A Functional renal failure that occurs during terminal stages of liver failure with ascites

Manifestations of Hepatorenal syndrome

oliguria, water retention, ↑ serum creatinine, azotemia (↑ nitrogen waste compounds - urea, ammonia)

Hepatobiliary System components

• Gallbladder – stores and concentrates bile. Necessary for digestion and absorption of dietary fats and fat-soluble vitamins

• Bile: water, bile salts, bilirubin, cholesterol, and more

Mechanisms of Hepatobiliary system

• Gallbladder contracts, bile duct sphincter relaxes when food enters intestine

• Stimulated by CCK (cholecystokinin)

components / characteristics of Cholelithiasis

Gallstones

• 80% cholesterol stones

• 20% black or brown stones with calcium salts and bilirubin

• Hemolytic disease, cirrhosis

• ~10% of adults have gallstones, prevalence ↑ with age

Cholelithiasis: Factors that contribute to formation of gallstones include…

• Abnormalities in bile composition

• Bile stasis

• Inflammation of gallbladder

Cholelithiasis: Abnormalities in bile composition

• ↑ excretion of cholesterol into bile

• Obesity, oral contraceptives, multiple pregnancies

Cholelithiasis: stasis of bile is due to…

Obstruction of bile duct