Disorders of Hepatobiliary Function and Exocrine Pancreas Function; Disorders of Bladder and Urinary

Accessory Organs of the GI tract

liver, gallbladder, pancreas

Liver Function

• 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

Gallbladder Function

• Stores bile

Pancreas Function

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

Drug-induced Liver Disease

• Frequent cause of acute liver injury (> 50%)

• *Liver: major drug-metabolizing and detoxifying organ ↑ risk for damage

Drug-Induced Liver Disease Risk Factors

Risk factors for ↑ susceptibility:

• Genetic predisposition

• Age

• Underlying liver disease

• Alcohol consumption

• Drug use

Drug-Induced Liver Diseases

- Direct hepatotoxic Injury

-Idiosyncratic reactions

-Cholestatic reactions

-Chronic hepatitis

Direct hepatotoxic injury

- often age and dose dependent.

- Usually the result of drug metabolism that turn into toxic metabolites

eg. acetaminophen, antimicrobials, NSAIDs, psychotropic agents and lipid-lowering drugs

Direct hepatotoxic injury manifestations

Manifestations: ↑ bilirubin levels and jaundice if hepatic necrosis

Idiosyncratic reactions

Damaging metabolites in individuals with specific genetic predispositions

• Manifest as an allergic reaction

Idiosyncratic reactions manifestations

• Manifest as an allergic reaction

Cholestatic reactions

• "Chole" - Greek origin: bile or gall

• Cause ↓ secretion of bile or bile obstruction

• Ex. estradiol

Cholestatic reactions Manifestations

Early onset jaundice and pruritis

Chronic Hepatitis

Diagnosed when cirrhosis develops

Chronic Hepatitis Causes

Multiple drugs or drugs + excess EtOH (alcohol) intake

Viral hepatitis

Acute or chronic inflammation of liver caused by hepatotropic virus

• A, B, C, D, E, and EBV, CMV, herpesvirus, enterovirus

Viral Hepatitis; Mechanism of injury

• Direct cellular injury

• Induction of immune response against viral antigens

Viral Hepatitis; Clinical Course

• 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

Acute: HAV (hepatitis A virus); A for Acute!

Hepatitis A; Transmission

Fecal-oral, sexual, parenteral

Hepatitis A; Prevention+ Manifestations

Prevention: vaccine, hygiene

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

Hepatitis A; Serologic markers

• IgM - acute infection

• IgG - previous infection

Hepatitis B

Hepatitis B virus (HBV); B for inBtween!

• Acute or chronic

Hepatitis B; Transmission

parenteral, sexual, placental, blood exposure

Hepatitis B; Prevention + Manifestations

Prevention: vaccine, precautions

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

Hepatitis B; Serologic Markers

anti-HBs, anti-HBc, anti-HBe antibodies (Throwing Bs)

Hepatitis C

Hepatitis C virus (HCV)

• Chronic (C for Chronic)

Hepatitis C; Transmission

Parenteral, sexual, placental, blood exposure

Hepatitis C; Prevention + Manifestations

Prevention: Precautions

• Often asymptomatic

• Most individuals develop chronic hepatitis -> cirrhosis, liver failure, cancer

Hepatitis C; Serological Markers

HCV RNA

• Antibodies not protective, but serve as markers of disease

Hepatitis D

Requires HBV coinfection

-Acute or chronic

Hepatitis D; Prevention

Prevention: HBV vaccine

Hepatitis E

Acute

• Chronic in immunocompromised persons

Hepatitis E; Transmission

Fecal-oral

Hepatitis E; Prevention + Manifestations

Prevention: hygiene, clean water

• Manifestations: similar to hepatitis A

More severe in pregnant persons

Alcohol-Induced Liver Disease: Alcohol Metabolism

Alcohol (EtOH) absorbed by stomach and intestines --> blood and tissues

Most EtOH metabolized by liver by 2 pathways:

• Alcohol dehydrogenase (ADH)

• Cytoplasm

• Microsomal ethanol-oxidizing system (MEOS)

• Endoplasmic reticulum

• Uses CYP enzymes that also metabolizes drugs, such as Tylenol, which can increase risk of hepatotoxic effects of these drugs with EtOH use

Alcoholic-Induced Liver Diseases

• Fatty liver disease - accumulation of fat in hepatocytes (steatosis)

• Occurs quickly

• Ex. Binge drinking

• Reversible if alcohol intake discontinued

• Alcoholic hepatitis

• Alcoholic cirrhosis

Fatty Liver Diseases

accumulation of fat in hepatocytes (steatosis)

• Occurs quickly

• Ex. Binge drinking

• Reversible if alcohol intake discontinued

Alcoholic Hepatitis

inflammation and necrosis of liver cells due to

excessive alcohol intake

• Cardinal sign: rapid onset of jaundice

Alcoholic cirrhosis

end result of EtOH-related hepatocyte injury

Nonalcoholic Fatty Liver Disease

Fatty liver disease due to causes other than alcohol (metabolic

dysfunction)

• Lipid accumulation in the cytoplasm and formation of free radicals

Nonalcoholic Fatty Liver Disease Comorbitites

obesity, type 2 diabetes, metabolic
syndrome, hyperlipidemia

NASH

nonalcoholic fatty liver steatohepatitis- serious lipid build up

What happens in NASH?

Cirrhosis

Cirrhosis of the Liver

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

Cirrhosis of the liver Causes:

• Excessive alcohol and drug intake

• Hepatitis (chronic)

• Nonalcoholic fatty liver disease

• Biliary obstruction

Cirrhosis: Pathophysiology

Diffuse fibrosis → nodules

• Balance between liver regeneration and scarring

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

• Alcoholic cirrhosis – cumulative toxic effects of alcohol metabolism on liver, inflammation, oxidative stress from lipid peroxidation, and malnutrition

Alcohol is transformed to…

acetaldehyde

• ↑ acetaldehyde alters hepatocyte function → fibrosis

Cirrhosis Manifestations

• Advanced disease

• Weight loss, cachexia, weakness, anorexia

• Late symptoms - related to liver cell failure and portal

hypertension:

• Splenomegaly

• Ascites

• Varices: esophageal, gastric

• Bleeding

Liver Failure

Most severe clinical consequence of liver disease; 80% – 90% of liver function is lost

5 Major Consequences of Liver Dysfunction

1. Portal hypertension

2. Ascites

3. Jaundice

4. Hepatic encephalopathy

5. Hepatorenal syndrome

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