Chapter 12

Disorders of the Liver and Biliary Tract

Lecture 12

The Nature of DiseasePathology for the Health Professions

Thomas H. McConnell

Overview of Today’s Lecture

– Review of Liver and Biliary Tract

– Liver response to injury

– Viral Hepatitis

– Non-viral inflammatory liver disease

– Toxic Liver Injury

– Metabolic Liver Disease

– Diseases of the intrahepatic bile ducts

– Circulatory disorders

– Tumors of the liver

– Disorders of the Gallbladder and extrahepatic bile ducts

Liver, Portal venous system, and Bile ducts

Figure from: McConnell, The Nature of Disease, 2nd ed., LWW, 2014

The Enterohepatic Circulation

Figure from: McConnell, The Nature of Disease, 2nd ed., LWW, 2014

Liver Metabolic Tasks/Actions

Table from: McConnell, The Nature of Disease, 2nd ed., LWW, 2014

The Liver Response to Injury• Most important liver diseases:

– Viral hepatitis

– Alcoholic liver disease

– Non-alcoholic liver disease

– Malignancy

• Four common endpoints (clinical syndromes) of liver disease1. Jaundice and cholestasis (usually occur together)

• Jaundice – Abnormal increase is bilirubin, e.g., in skin, sclera

• Cholestasis – reduced production/flow of bile

2. Cirrhosis – Widespread, irreversible, scarring (fibrosis) of liver

3. Portal hypertension – increased pressure in portal venous system

4. Hepatic failure – Severe enough to cause hepatic encephalopathy

Metabolism of Bilirubin

Figure from: Huether & McCance, Understanding

Pathology, 5th ed., Elsevier, 2012

What if there is an imbalance between the production and excretion of bilirubin?

Etiology of Jaundice

• What are the three conditions leading to imbalance of bilirubin?

1. Overproduction of bilirubin– Prehepatic jaundice

– Unconjugated hyperbilirubinemia

2. Defective liver functioning – Hepatic jaundice

– Both conjungated and unconjugated hyperbilirubinemia

3. Biliary obstruction– Posthepatic jaundice

– Conjugated hyperbilirubinemia

Figure from: Huether & McCance, Understanding Pathology, 5th ed., Elsevier, 2012

(Also see 12.4 in McConnell)

Pathophysiology of Jaundice

• Unconjugated hyperbilirubinemias– Hemolytic Disease of the Newborn

• Liver is typically immature at birth

• Unconjugated bilirubin deposits in brain (Kernicterus)

– Gilbert Syndrome & Crigler-Najjar Syndrome• Autosomal recessive; lack of glucuronyl transferase

• Conjugated hyperbilirubinemias– Dubin-Johnson Syndrome & Rotor Syndrome

• Autsomal recessive

• Neither typically needs treatment

Cholestasis

• Impaired bile formation and bile flow– Accumulation of bile pigments in liver

– Usually accompanied by jaundice, possibly pruritis

– Several causes• Liver disease

• Biliary obstruction

• Drug interference with bile secretion

• Pregnancy

– Problems resulting from lack of bile acids• High blood cholesterol (xanthomas)

• Fat malabsorption

Cirrhosis• Widespread scarring of liver

• Irreversible and Incurable

• Common endpoint for many liver diseases

• 65% from alcoholism and chronic hepatitis

• 25% - cryptogenic cirrhosis

• Intrahepatic pressure rises– Hepatocyte damage

– Portal flow obstructed -> PH

– Portal blood flow is diverted

• Two anatomic types– Portal cirrhosis (normal liver anatomy

disrupted)

– Biliary cirrhosis (normal liver anatomy maintained)

Figures from: McConnell, The Nature of Disease, 2nd ed., LWW, 2014

Portal Hypertension (PH)• Increased pressure in portal venous system

– Due to increased resistance in portal flow

– May occur at three points• Before blood reaches liver (prehepatic)

– Thrombosis, narrowing, external pressure on portal vein

• As blood flows through liver (hepatic) – cirrhosis

• After blood exits liver (posthepatic)– Severe right sided HF

– Restrictive pericarditis

– Thrombotic (or other) obstruction of hepatic vein

– S & S• Ascites – intraperitoneal accumulation of watery (serous) fluid

• Portosystemic shunts – alternate pathways of blood into veins– Rectal veins (hemorrhoids), esophageal veins (varices), falicform lig (caput medusa)

• Spleomegaly from chronic passive congestion; hypersplenism

Hepatic Failure• Loss of hepatic metabolic function severe enough to cause

hepatic encephalopathy

• Usually 80-90% nonfunctional liver

• Acute (uncommon)– Acetaminophen

– Other drugs, industrial chem., autoimmune and viral hepatitis

• Chronic (most common) – mainly from cirrhosis

• S&S– Bilirubin excretion failure leading to what?

– Decreased albumin production leading to what?

– Factor hepaticus (musty odor of body/breath)

– Hormonal imbalance

– Hepatic encephalopathy (from ammonia, other toxic products) – asterixis

– Hepatorenal and Hepatopulmonary Syndromes (causes unk)

Viral Hepatitis• Viral Hepatitis (Hepatotropic viruses: A, B, C, D, and E; H#V)

– Inflammation of the liver caused by viral infection

– Viral types differ in • mode of transmission and incubation period

• mechanism, degree, and chronicity of liver damage

• ability to evolve to a carrier state

• ability to cause hepatocellular carcinoma

– General phases of acute hepatitis infection• Incubation & Prodromal; about 2 weeks

• Icterus (onset of jandice, dark urine, clay-colored stools); 4-8 weeks post exposure

• Convalescence (Recovery) about 8 weeks after onset

– Diagnosis based on detection of ag (HBsAg) or antibodies, e.g., anti-HAV, anti-HBc

– Pathophysiology• Major route of transmission: fecal-oral, contact with infected blood/body fluids

• Can lead to acute (fecal-oral) or chronic disease (contact with body fluids/blood)

• HBV can exist in asymptomatic carrier state

• Effects vary from death of a few hepatocytes to massive liver necrosis/cirrhosis and HCC

• Can be explosively acute and progress to fulminant liver failure very quickly = catastrophic liver failure (usually HAV or HBV)

Viral Hepatitis

• Viral Hepatitis (Hepatotropic viruses: A, B, C, D, and E)

– Hepatitis viruses designated as HAV, HBV, etc.

– Some other viruses can infect the liver as well, e.g., EBV, CMV, HSV

– Viral infection typically causees inflammation of the liver

– Hepatitis viral types differ in • Mode of transmission

• Length of incubation period

• Mechanism, degree, and chronicity of liver damage

• Ability to evolve to a carrier state

• Ability to cause fulminant hepatitis (sudden, catastrophic liver failure)

• Ability to cause hepatocellular carcinoma

Viral Hepatitis – Clinicopathological Syndromes

Viral Hepatitis - HAV• HAV

– Fecal-oral route

– Anti-HAV IgM ab – marker of acute infection

– Only Acute (think of ‘A’ as acute); no carrier

– Vaccine available

Figure from: McConnell, The Nature of Disease, 2nd ed., LWW, 2014

Viral Hepatitis - HBV• HBV

– IV/Sex

– HBsAg and anti-HBc ab – markers of acute infection

– Can be: chronic, carrier, carcinoma

– 1/3 of world’s population shows evidence of being infected

– Vaccine available

Figures from: McConnell, The Nature of Disease, 2nd ed., LWW, 2014

Viral Hepatitis - HCV

• HCV– IV/Sex; Healthcare

employment (no vaccine available)

– HCV-RNA as acute marker

– Can be: chronic, carrier, carcinoma

– Major cause of chronic liver disease; most common indication for txplant

Figures from: McConnell, The Nature of Disease, 2nd ed., LWW, 2014

Non-viral Inflammatory Liver Disease• Most bacterial/fungal infections result in liver abscess

– Ascending cholangitis

– Hematogenous

– Penetrating trauma

• E. histolytica– Poor sanitation (fecal contamination of unwashed food )

– Burrow into intestine, travel up portal vein to liver

– Liver abscesses

• Schistosomiasis– Parasite; one variety causes chronic immune rexn

– Infiltrates portal system -> PH, cirrhosis

• Autoimmune hepatitis– T- cell mediated

– Over 50% have some other autoimmune disease, e.g., UC, Sjogren, SLE

– 80% cases female

Toxic Liver Injury• Two Types

– Dose-related – predictable, proportional to dose• Usually from chemotherapy, accidental/intentional drug overdose

• 50% of cases from acetaminophen (Tylenol)

– Non-dose related (idiosyncratic reactions)• Some causes include sufonamides, isoniazid, halothane, chlorpromazine

• Drug-induced hepatitis same pathology as viral hepatitis• Reye syndrome

– Children

– Fatty liver, acute brain dysfunction

– Following administration of aspirin after acute viral illness

– Sever vomiting, lethargy, irritability, hepatomegaly

– 25% progress to coma

Alterations in Liver Function

From: Pathophysiology: A Clinical Approach, Braun & Anderson, Lippincott, 2011

Alcohol abuse – A Leading Cause of Liver Disease

- More than 10 million chronic alcoholics in US (estimated)

- Contributes to over 100,000 deaths annually (50% drunk driving)- Blood concentration (BAL) of 80 mg/dl (0.08%) = intoxicated in US

- Three drinks is sufficient (1 drink = 12 oz beer, 5 oz wine, 1.5 oz hard)

- Effects vary by age, gender, and percent body fat, genetics

- Fatty foods and milk slow absorption

- Rate of metabolism (mostly hepatic cyt P450) affects BAL

- Absorbed directly from stomach and small intestine

- Effects involve the CNS (and other organs as well)- Depressant

- Affects subcortical structures first, then brainstem

What is the nutritional caloric content of alcohol?

Alcohol Abuse

- Liver and nutritional disorders most common side effects of chronic alcohol abuse

- Liver- Fatty liver and fatty degeneration of hepatocytes (steatosis)

- Alcoholic hepatitis – more severe than fatty liver (steatohepatitis)

- Alcoholic cirrhosis - irreversible; may cause portal hypertension

- Increased risk of hepatocellular carcinoma

- Nutritional- Deficiencies of Mg2+, vit B6, thiamine, P

- Folic acid deficiency (especially serious for pregnant women; may cause Fetal Alcohol Syndrome)

- Vitamin B12 – due to impaired absorption

- Additional effects- Acute gastritis

- Cardiomyopathy

- Possible systemic hypertension

- Regressive changes in skeletal muscle

Is Alcohol Good for Anything Besides a Buzz?

- Association between light to moderate (≤ 25g/day) alcohol consumption and cardiovascular disease

Figure from: http://pubs.niaaa.nih.gov/publications/arh27-1/39-51.htm

Beneficial effects on CVS (coronary heart disease, CHD) believed to be due to:

-Increased levels of HDL-C

- Prevention of clot formation

- Reduction in platelet aggregation

- Increased fibrinolysis

Metabolism/Hepatic Effects of Ethanol

Three enzyme systems in liver that convert EtOH to acetaldehyde:

1.Alcohol dehydrogenase (ADH)

2.Microsomal ethanol oxidizing system (MEOS; activated with high EtOH levels)

3.Catalase

*Hepatic effects of acetaldehyde:- Inflammation- Fat deposition- Hepatomegaly- Microtubular txport defects- Increased cellular H2O- Decreased FA oxidation in mt- Increased membrane rigidity- Necrosis

Metabolic Liver Disease• Non-alcoholic Fatty Liver Disease

– Group of related conditions manifesting with fatty liver

– Closely associated with the metabolic syndrome

• Obesity, hyperlipemia/hyperlipidemia, pre-diabetic insulin resistance

• Pathology: steatosis to steatohepatitis (NASH)

• Hemochromatosis– Autosomal recessive iron storage disorder

– Accumulation of iron in liver, pancreas, heart

– Abnormally high iron absorption from intestine

– Usually men

Figure from: McConnell, The Nature of Disease, 2nd ed., LWW, 2014

Metabolic Liver Disease• Wilson’s Disease

– Autosomal recessive (rare)

– Toxic copper accumulation in liver and brain

– In eye -> Kayser-Fleischer ring

Figure from: http://www.eurowilson.org/en/living/guide/pathway/index.phtml

From: https://lostinzhoushan.wordpress.com/

Metabolic Liver Disease

• Alpha-1 Antitrypsin (AAT)– Recall its role in emphysema

– Genetic form results in low levels of AAT

– Accumulation of excess non-functional AAT in liver causes damage (mechanism unk)

– Death caused by emphysema and cirrhosis

Biliary Cirrhosis

• Prolonged obstruction in extrahepatic biliary tree can damage the intrahepatic bile ducts liver

• Two forms– Primary biliary cirrhosis

• Autoimmune nflammatory destruction of intrahepatic bile ducts

• Most patients have another autoimmune disease, e.g, SLE, Sjogren

• Most are middle-aged women

• Cholestasis: xanthelasma, fat malabsorption

• Death from cirrhois, PH, and hepatic failure

– Secondary biliary cirrhosis• Gallstones, cancer in head of pancreas, surgical scars

• Cholestasis -> inflammation -> scarring -> biliary cirrhosis

• May cause ascending cholangitis

Biliary Cirrhosis

• Primary sclerosing cholangitis– Inflammation of both intra- and extrahepatic bile ducts

– >60% have UC; some with other IBD

– Usually men under age of 40

– Scarring of bile ducts inside and outside liver

– “Onionskin” fibrosis

– Results in chronic cholestatic liver disease

Figure from: www.medscape.com

Circulatory Disorders of the Liver

• Areas of obstruction of blood flow in/out of the liver– Blood flow into liver (prehepatic)

• Arterial obstruction (uncommon; atherosclerosis or thromboembolism)

• Portal obstruction– Thrombosis associated with intra-abdominal disease

– Results in portal hypertension

– Blood flow within liver (intrahepatic)• Cirrhosis

• Right HF -> chronic passive congestion of liver (cardiac cirrhosis)

– Blood flow out of liver (posthepatic)• Obstruction of one or more branches of the hepatic vein

• Occlusion of main hepatic vein: Budd-Chiari syndrome (PV)

• Pregnancy, oral contraception

• Coagulation disorders

Tumors of the Liver

• *Most common neoplasm IN the liver is metastatic carcinoma (usually from abdominal organs)

• Benign tumors– Cavernous hemangioma

• Non-neoplastic vascular mass

• Usually beneath fibrous capsule of liver

– Hepatic adenoma• Hepatocytic tumor

• Most often associated with contraceptive use in young women

• Usually regresses after contraceptive use stops

Figure from: McConnell, The Nature of Disease, 2nd ed., LWW, 2014

Notice multiple tumor masses

Tumors of the Liver

• Malignant tumors– Hepatoblastoma

• Hepatocytic tumor

• In children

– Hepatocellular carcinoma (HCC)• Hepatocytic tumor

• Related to chronic HBV and HCV infections

• Tendency to invade hepatic veins; then metastasize

• Very poor prognosis

– Cholangiocarcinoma• Bile duct epithelium

• Intra- or extrahepatic bile ducts, or gallbladder

• Risk factors: sclerosing cholangitis, HCV, chronic Schistosomiasis

Notice single primary tumor mass

Figure from: McConnell, The Nature of Disease, 2nd ed., LWW, 2014

Disorders of the Gallbladder and Extrahepatic Ducts

• Gallstones – most important problem of gallbladder– In gallbladder or biliary tree – cholelithiasis

– In bile ducts – choledocholithiasis

– Most are cholesterol; minor proportion are pigment stones

– Cholesterol oversaturates bile and stones form

– Small/medium size stones worst

– Some risk factors• Age/sex

• Weight

• Ethnic, hereditary, and geographic

• Drugs

• Acquired conditions

• (Fair, fat, fertile, female, forty)

Figure from: McConnell, The Nature of Disease, 2nd ed., LWW, 2014

Cholecystitis• Inflammation of the gallbladder

– Acute• Most common complication of gallstones

• Most associated with obstruction at neck of gallbladder

• Bacterial infection; pus formation (empyema)

• Can occur without gallstones (pregnancy, burns, sepsis, surgery)

• Gallbladder is enlarged, tense, and inflamed

– Chronic• May occur after repeated acute attacks, or

without history of acute attacks (most often)

• Almost always associated with gallstones

• Complications are the main problem: ascending cholangitis, gallbladder perforation, septicemia

Figures from: McConnell, The Nature of Disease, 2nd ed., LWW, 2014

Obstruction in Extrahepatic Ducts

Figure from: McConnell, The Nature of Disease, 2nd ed., LWW, 2014