Gastrointestinal Pathology

what occurs when CCK is released

gallbladder contraction and Sphincter of Oddi relaxation → bile flow back through the cystic duct → CBD → Duodenum

Bile dumped into small intestine to…

emulsifies fats to free fatty acids & monoglycerides for absorption

Gallstones mostly composed of …

cholesterol with or without calcium deposits

Can see bilirubin stones – especially in patients with chronic hemolytic disease

Stones also occur when there is excessive … in the gallbladder

stasis

2 main components of stone formation

Pigment from bile breakdown

Cholesterol (when cholesterol concentration > its percentage solubility)

estrogen in role of cholelithiasis

• increasing cholesterol saturation in bile

• decrease gallbladder motility

• lead to stasis, sludge formation, and stone formation

sx of Cholelithiasis

often asymptomatic or can develop biliary colic

risk for developing cholelithiasis

Female

Obesity & history of high dietary fat intake

History of prior pregnancies (estrogen)

Age (40s)

migration of cholelithiasis can cause

• Biliary colic

  • intermittent cystic duct obstruction; crampy, intermittent RUQ pain, usually after meals

• Cholecystitis

• Choledocholithiasis

  • Stone passes into CBD and causes obstruction

• Pancreatitis

• Gallstone ileus

cholecystitis

inflam of gallbladder

Major clinical presentation of gallstones

cholecystitis

cholecystitis sx present with …

RUQ pain

N/V

Fever → infection E Coli

PE finding of cholecystitis

+ Murphy’s Sign

Leukocytosis +/- bands

complications of cholecystitis

infected or undergo infarction and necrosis leading to sepsis

blood supply of liver

Venous flow from portal vein

Arterial flow from hepatic artery

• Vessels converge within the liver and the combined blood flow exits via the central veins → Drain into hepatic vein to inferior vena cava

portal blood flow normally … P

low hydrostatic P

< 5-10 mmHg

portal vein carries venous blood from … to …

small intestine to liver

Brings absorbed nutrients, medications and toxins

functional unit of liverr

lobules

Each lobule contains …

organized around individual central veins to form hexagons

• Each have portal triads at their corners

  • Branch of Hepatic Artery

  • Branch of Portal Vein

  • 1-2 small Bile Ducts

Sinusoids

Porous blood vessels that carry blood to center of lobule

Kupffer cells

within sinusoid - defense mechanism

function of hepatocytes

detox, lipid, BG level, storage vit/minerals, protein syn

why is bile synthesis is important

digestion and absorption of fats & fat-soluble vitamins in the small intestine

function of hepatocytes

convert cholesterol into bile salts

Bile Salts + Water + Bilirubin = Bile

bile synthesis

• Bile is secreted into bile canaliculi to bile ductules then to bile ducts (of portal triad)

• Bile ducts then unite to form right & left hepatic ducts then merge to common hepatic duct and lead to the cystic duct which take bile to gallbladder

  • Stored here until CCK stimulates release

Four broad categories of normal liver function:

1. Energy Metabolism and Substrate Interconversion

2. Synthesis and Secretion of Plasma Proteins

3. Solubilization, Transport, and Storage Functions

4. Protective and Clearance Functions

what is the energy generation and substrate interconversion of liver

carbohydrate, protein and lipid synthesized, metabolized and interconverted

Products are removed from or released into the bloodstream in response to body’s needs

When blood glucose is high (i.e. after a meal) …

When blood glucose is low –

Hepatocytes convert glucose into a storage molecule (glycogen) through the process of glycogenesis

Hepatocytes break down the glycogen back into glucose through the process of glycogenolysis

… help maintain normal blood glucose levels

Hepatocytes

what convert glucose into a storage molecule (glycogen) through the process of glycogenesis

hepatocytes

Liver is important to protein metabolism (3)

• deamination: remove amine group from amino acids → ATP

• Synthesize Albumin and coagulation factors

• Urea cycle convert nitrogen to less toxic urea for excretion

center of lipid metabolism

Liver

Makes nearly 80% of the cholesterol synthesized in the body from acetyl-CoA via a pathway that connects the metabolism of carbohydrates with that of lipids

Very Low-Density Lipoprotein (VLDL)

Secreted by the liver and help transport triglycerides, fatty acids & cholesterol to cells that use them for energy OR to adipocytes that store them

High Density Lipoprotein (HDL)

Synthesized and secreted by the liver

scavenge & transport excess cholesterol & triglycerides from the peripheral tissues and cells back to the liver where they are broken down to generate energy

lipid metabolism in the liver

synthesize, store, and export triglycerides

Site of keto acid production via pathway of fatty acid oxidation

Controls the body’s cholesterol and triglyceride levels → assembles, secretes and takes up various lipoprotein particles

what is the function of the plasma proteins synthesized in liver?

• plasma oncotic pressure (serum albumin)

• coagulation (clotting factor synthesis and modification)

• blood pressure (angiotensinogen)

• growth (insulin-like growth factor-1)

• metabolism (steroid and thyroid hormone–binding proteins)

where does drug and harmful substance detoxification occur

liver

what binding proteins does the liver synthesize and secret

Transferrin, steroid hormone-binding globulin, thyroid hormone-binding globulin, etc.

what vit does the liver store

Vit A, D, folate and B₁₂

minerals: Iron and Copper

how does the liver metabolize and excrete drugs

Smooth endoplasmic reticulum of hepatocytes contain many enzymes that catalyze metabolic processes needed to detoxify and excrete drugs and other substances

how is the liver protective against excess cholesterol

excretion of excess cholesterol by conversion to and solubilization in bile

protective functions of liver (3)

• Kupffer Cells

• Ammonia Metabolism (AA→ urea)

• Synthesis of Glutathione (prevent oxidative damage to cellular proteins)

type of liver dysfunction (5)

1. Failure of energy metabolism and substrate interconversion

2. failure to make Proteins

3. inability to transport and store

4. decreased protective and clearance functions

5. portal HTN

Portal Hypertension

• Altered hepatic blood flow (primarily from cirrhosis)

• When a pathologic process (fibrosis) results in elevation of normally low intrahepatic venous pressure → blood backs up & finds alternative route back to systemic circulation (this bypasses the liver)

• blood from GI tract is filtered less efficiently before entering systemic circulation

Consequences of portal-to-systemic shunting: (3)

Loss of protective & clearance functions

Functional abnormalities in renal salt & water hemostasis

Greatly increased risk of GI hemorrhage from development of engorged blood vessels carrying venous blood bypassing the liver (varices)

portal HTN can produce or contribute to

encephalopathy, GI bleed & malabsorption of fats and fat-soluble vitamins

Liver Dysfunction effect on BG

Decrease in gluconeogenesis

Severe = fasting hypoglycemia

Liver Dysfunction effect on lipids

fat accumulation that cannot be exported in the form of VLDL

Liver dysfunction effect on protein metabolism

syndrome of altered mental status and confusion = hepatic encephalopathy

Liver dysfunction effect on impaired drug detox

result in sub-therapeutic blood levels of drugs and/or conversion of relatively benign compounds into more reactive (more toxic) ones causing injury to the liver

what are the consequences of liver dysfunction and storage failure

High risk for folic acid and vitamin B12 deficiency

macrocytic anemia

acute disease of disordered bile secretion

• necrosis minimized but can see elevated AST/ALT in the presence of marked jaundice and high bilirubin

• In a neonate – elevated bilirubin can be toxic to the nervous system producing kernicterus

  • Build up of unconjugated bilirubin in basal ganglia = brain damage or death

chronic cholestatic diseases can lead to

fibrosis and cirrhosis and deposition of bile acids in skin → intense pruritus

Liver Dysfunction effects on decreased synthesis & and secretion of plasma proteins

• hypoalbuminemia = edema formation

• decreased clotting Factors = increased risk of bleeding → Elevated/prolonged PT

• decrease of hormone-binding proteins

when liver is dysfunction, there is a loss of protective functions such as

• loss of capacity of Kupffer cells → infections spread rapidly → sepsis

• Impairment of the liver’s ability to detoxify ammonia to urea → hepatic encephalopathy

• Altered Hormone Clearance → Male patients with liver disease display both gonadal and pituitary suppression as well as feminization

Assessing Liver Function AST and ALT

involved in metabolic reactions; liver cells release these into circulation

Better to assess liver injury rather than liver function

Assessing Liver Function Alk phos

mainly present in the cells of bile duct→ think obstruction

MCC of acute hepaitis MCC

infection with one of several types of virus (or drug or poisons)

patho of acute hepatitis

Virus targets cells in liver and infects them → development of abnormal proteins → Immune cells then attempt to infiltrate → CD8+ T cells recognize abnormal proteins and hepatocytes are then destroyed via cytotoxic death

clinical presentation of acute hepatitis

May only see laboratory abnormalities

Anorexia, fatigue, weight loss, nausea, vomiting, RUQ abdominal pain, jaundice, fever, splenomegaly, and ascites may be present

common causes of acute viral hepatits

Hepatitis A -E

hallmark of labs of viral hepaitis

both ALT and AST elevated but ALT sig more elevated

Hep A (HAV)

RNA Virus; spread via fecal-oral route; most cases are mild

Hep B (HBV)

DNA virus; transmitted through sexual contact or contact with infected blood/fluids

Hep C (HCV)

RNA virus; transmitted through blood or bodily fluids

Hep D (HDV)

Known as ‘delta agent’; defective RNA virus that requires HBV helper function to cause infection

Hep E (HEV)

Unclassified RNA virus; spread primarily via fecal-oral route

modes of transmission of hep B

Worldwide: perinatal and early childhood

US: sexual transmission

sx of Hep B

Most cases are asymptomatic or only present with mild disease

An excessive immune response can result in acute liver injury and even liver failure

Hep C acute vs chronic

• Acute infection is characterized by mild to moderate illness

  • usually asymptomatic

• Chronic HCV can lead to life-threatening complications, including:

  • cirrhosis

  • hepatocellular carcinoma (HCC) - usually after decades of infection

pathogen of viral hepatitis

Viral agents first infect the hepatocyte → incubation period intense viral replication in liver cells

leads to appearance of viral components (antigens then antibodies) in urine, stool and body fluids → Liver cell death and associated inflammatory response then occur → changes in liver function tests and appearance of symptoms/signs → liver damage and extrahepatic manifestations

Pre-icteric Phase (prodromal) of Acute Viral Hepatitis

Typically lasts 3-4 days

1. Non-specific constitutional: malaise, fatigue, mild fever

2. GI: anorexia, nausea, vomiting, altered sense of olfaction & taste, RUQ discomfort

3. Extrahepatic: HA, photophobia, cough, coryza, myalgias, urticarial skin rash, arthralgias or arthritis

   *Rarely may see hematuria or proteinuria

Icteric Phase of Acute Viral Hepatitis (6)

• RUQ Pain – from enlarged/tender liver

• Jaundice – sclera, skin or mucus membranes

  • Typically not seen on PE until bilirubin >2.5 mg/dL

• Changes in stool color (lightening) and urine color (darkening)

  • Typically precede jaundice

• Ecchymoses – suggest coagulopathy

  • Due to loss of vitamin K+ absorptive capacity from the intestine – caused by cholestasis; or decreased coagulation factor synthesis

• Mental status changes – seen with fulminant hepatic failure

  • Encephalopathy – partly due to failure to detoxify ammonia (a neurotoxin); also related to inability of GABA not being metabolized

• Renal Dysfunction – may complicate fulminant hepatic failure

  • Serum Cr is more accurate measure than BUN for renal impairment in these pts

Convalescent Phase of Acute Viral Hepatitis (6)

Characterized by complete disappearance of constitutional symptoms

Will have persistent abnormalities in liver function tests

Signs and symptoms gradually improve

Resolution of Acute Viral Hepatitis

Acute hepatitis usually resolved in 3-6 months

If hepatic injury continues for >6 months = chronic hepatitis

toxic hepatitis

• Drug-induced liver injury

  • Most present as acute hepatitis

• Occurs at any time during or shortly after exposure and resolves with discontinuation of the offending agent

• Acetaminophen is most common cause of acute liver failure in US and UK

… most common cause of acute liver failure in US and UK

Acetaminophen

Alcoholic Hepatitis associated with

Female Sex

Prolonged, heavy ETOH consumption

Binge Drinking

labs in alc hepatitis

AST is often disproportionately elevated relative to ALT (AST:ALT ratio >2.0)

Ethanol has direct and indirect toxic effects on the liver

• Direct effects may result from increasing the fluidity of biologic membranes and thereby disrupting cellular functions

• Indirect effects on the liver are in part a consequence of its metabolism

chronic hepatitis characterized

varying severity persisting for >6 months

etiology of chronic hep

Viral Infection (HBV +/- HDV and HCV)

Drugs and Toxins (ethanol, INH, acetaminophen)

Genetic & Metabolic (Wilson Disease, alpha-1 antitrypsin deficiency)

Autoimmune factors

Unknown causes

pathogenesis of chronic hep

Many cases from immune-mediated attack on the liver occurring as a result of the persistence of certain hepatitis viruses or after prolonged exposure to certain drugs or noxious substances

in chronic hep, liver bx will reveal

lymphocyte infiltration (inflammation)

clinical presentation of chronic hep

Fatigue, malaise, low-grade fever, anorexia, weight loss, mild intermittent jaundice and mild hepatosplenomegaly

late course of chronic hep complication of cirrhosis

Variceal bleeding

Coagulopathy

Encephalopathy

Jaundice

Ascites

lab finding in chronic hep

Mild to moderate increases in serum aminotransferase and bilirubin

Serum albumin and PT are usually normal until late progression of liver disease

Persistent infection causing chronic viral hep

Approximately 5% of adult cases of HBV

60-85% of HCV

Individual becomes chronic carrier

• intermittently producing the virus and remaining infectious to others

• severity depends largely on the activity of viral replication and the response of

Chronic viral hep and risk CA

Chronic Hepatitis B infection predisposed to development of hepatocellular carcinoma (HCC)

• Most cases occur in the presence of cirrhosis

Chronic Hepatitis C infection

• HCC develops exclusively in patients with cirrhosis

Alcoholic Chronic Hepatitis

Frequency of alcohol-associated cirrhosis is estimated to be 10–15% among persons who consume over 50 g of alcohol daily for over 10 years

patho of alc chronic hep

Repeated episodes of acute injury → necrosis, fibrosis, & regenerations leading to cirrhosis

s&sx of alc chronic hep

vitamins and calories probably contribute to the development of alcohol-associated hepatitis and its progression to cirrhosis

NAFLD

presence of hepatic steatosis with or without inflammation & fibrosis

NAFL to NASH (nonalcoholic steatohepatitis)

Significant increase in NAFLD along with increasing… in US

obesity

NAFLD associated with

obesity, dyslipidemia, insulin resistance, DMT2

patho of NAFLD

Lipid accumulation in hepatocytes results from an increased influx of lipids to the liver or decreased lipid disposal → Leads to toxicity

Management of NAFLD is centered on …

modifying risk factors and treating metabolic comorbidities

dif between simple steatosis and NASH

Patients with simple steatosis are at low risk of histologic progression, but patients with NASH can progress to cirrhosis and end-stage liver disease and are at risk for HCC

Autoimmune Hepatitis

chronic inflammatory liver disease characterized by a mainly T cell–mediated immune response to as yet unidentified auto-antigen(s)

Autoimmune Hepatitis most improve with …

systemic corticosteroids