UNIT 7 DISEASES OF THE LIVER CLS 241

what is the liver and biliary tract anatomy? (learning objective; ch.21)

located in the right upper quadrant and contains four lobes and has a dual blood supply… contains kupffer cells (hepatic macrophages) in hepatic sinusoids to remove bacteria and debris from portal blood

what is the dual blood supply of the liver and biliary tract? (learning objective; ch.21)

hepatic artery (25%)

• supplies oxygenated blood to the liver

hepatic portal vein (75%)

• supplies nutrient-rich blood from the GI tract

• delivers nutrients and toxins to liver for detoxification

hepatic veins

• drains into inferior vena cava

hepatic duct

• joins with cystic duct from gallbladder

what are the various functions of the liver? (learning objective; ch.21)

• metabolism of carbohydrates, proteins, and lipids

• production of bile

• chemical detoxification

• porphyrin catabolism

• bilirubin metabolism

• protein synthesis

• excretion of metabolic waste

• storage

• synthesis of:

  • albumin

  • clotting factors

  • lipoproteins

what is the role of the liver in carbohydrate metabolism? (learning objective; ch.21)

maintains blood glucose regulation through glycogenesis, glycogenolysis, gluconeogenesis, and glycolysis

what happens in hypoglycemia in severe liver disease and inhibited gluconeogenesis from alcohol?

• impaired glycogen storage

• reduced glycogenolysis

• decreased gluconeogenesis

• increased glucose consumption during severe illness

what is the role of insulin in liver metabolism? (learning objective; ch.21)

• promotes glycogenesis

• inhibits gluconeogenesis & lipolysis

what is the role of glucagon in liver metabolism? (learning objective; ch.21)

• stimulates glycogenolysis & gluconeogenesis

• promotes lipolysis

what is the role of the liver in the metabolism of proteins? (learning objective; ch.21)

• production of plasma proteins

  • amino acid pool is a mixture of amino acids available in the cell

• deamination of amino acids

  • required before amino acid is converted to carbs or fat

• conversion of amino acids

• formation of waste products

  • removal of ammonia (build up causes mental issues) to convert to urea

• production of nonessential amino acids

what is the clinical significance of decreased albumin and increased ammonia regarding the liver?

decreased albumin

• chronic liver disease

increased ammonia

• hepatic encephalopathy

what is hepatic encephalopathy (HE)? (learning objective; ch.21)

a reversible, potentially life-threatening brain dysfunction caused by severe liver disease, such as cirrhosis, which fails to filter toxins like ammonia from the blood. It causes confusion, personality changes, slurred speech, and tremors

what is the liver’s role in clotting factor metabolism and its clinical significance? (learning objective; ch.21)

primary site of synthesis and is where fibrinolytic systems of proteins are produced → synthesizes vitamin k-dependent factors (2, 7, 9, 10)

hemostasis abnormalities commonly happen in patients with liver disease so PT increases first in liver disease

what is the role of the liver in the metabolism of lipids? (learning objective; ch.21)

• synthesizes most lipoproteins which allows for transport of hydrophobic (insoluble) lipids

• metabolism of lipids to produce ATP

• lipogenesis (conversion of carbs to fat)

• conversion of cholesterol to bile which is needed for fat digestion

what is the function of the biliary system?

• drains bile and waste products from the liver into the duodenum

• stores and concentrates bile in the gallbladder

• releases bile to aid in digestion and absorption of fats

what happens to cholesterol in certain liver diseases?

• in severe hepatocellular disease… cholesterol synthesis is decreased

• in cholestatic liver disease… increased cholesterol

what are the four stages in bilirubin metabolism? (learning objective; ch.21)

1. heme degradation

2. transport

3. liver conjugation

4. intestinal metabolism

what is heme degradation in bilirubin metabolism? (learning objective; ch.21)

macrophages will convert hemoglobin → heme → biliverdin → unconjugated bilirubin (aka indirect bilirubin)

unconjugated bilirubin is toxic and water insoluble

what is transport in bilirubin metabolism? (learning objective; ch.21)

unconjugated bilirubin travels in plasma bound to albumin and cannot appear in urine

what is liver conjugation in bilirubin metabolism? (learning objective; ch.21)

hepatocytes conjugate bilirubin with glucuronic acid using UDP-glucuronyl transferase and produces conjugated (water-soluble) bilirubin (direct bilirubin)

what is intestinal metabolism in bilirubin metabolism? (learning objective; ch.21)

bacteria converts conjugated bilirubin into urobilinogen → most becomes stercobilin (feces) and a small amount becomes urobilin (urine)

what does bile contain and where is it stored?

contains bile acids/salts and cholesterol & is concentrated and stored in the gallbladder

yellow-green fluid that is produced continuously by the liver 500-1000 mL/day

why are bile acids essential?

essential for fat digestion and absorption of fat-soluble vitamins (A, D, E, K)

biliary obstruction → fat malabsorption → decreased vitamin K → prolonged PT

whats the role of bilirubin regarding bile?

it is the primary pigment responsible for the yellow-green color of bile

liver secretes bilirubin into bile which then travels to the small intestine

what is the enterohepatic circulation?

recycling pathway of bile acids between the liver and intestine → 95% of bile acids are recycled via enterohepatic circulation

what are primary bile acids?

synthesized from cholesterol in the liver and conjugated with glycine or taurine (amino acids)… aids in fat digestion and absorption

secreted in bile → stored in gallbladder

what are secondary bile acids?

formed by intestinal bacteria and reabsorbed in the ileum… returned to the liver via the portal vein, reconjugated, and secreted again in bile

what is the bilirubin pattern in hemolysis (prehepatic)?

increased indirect (unconjugated)

what is the bilirubin pattern in hepatic disease?

mixed (increased direct and indirect)

what is the bilirubin pattern in biliary obstruction (posthepatic)?

increased direct (conjugated)

what are phase 1 reactions for detoxification in the liver?

performed mainly by cytochrome p450 enzymes and converts toxins into more reactive intermediates… reactive metabolites (ROS, free radicals) may be generated in phase 1 reactions

what are phase 2 reactions for detoxification in the liver?

produces water-soluble compounds and is excreted through bile or urine… conjugated reactions add chemical groups (e.g. glucuronide, sulfate, glycine) and antioxidants help neutralize reactive metabolites

what diseases would be in unconjugated hyperbilirubinemia?

• gilbert

• crigler-najjar

• hemolysis

what diseases would be in conjugated hyperbilirubinemia?

• dubin-johnson

• rotor syndrome

• obstruction

what is gilbert syndrome? (learning objective; ch.21)

a genetic liver disease that causes a reduced activity of glucuronyl transferase (responsible for conjugated of bilirubin)… common hereditary cause is mild unconjugated hyperbilirubinemia

• most patients are asymptomatic but may show jaundice… will have mildly to moderately elevated Tbil & indirect bilirubin and normal liver enzymes (only increased in direct liver damage)

• triggered by → fasting, illness, stress

what is type 1 crigler-najjar syndrome? (learning objective; ch.21)

rare autosomal recessive which causes a complete absence of glucuronyl transferase which leads to severe unconjugated bilirubinemia and kernicterus… fatal without treatment and phototherapy (put pt into room with light to break down bilirubin)

what is type 2 crigler-najjar syndrome? (learning objective; ch.21)

rare autosomal dominant which causes decreased levels of glucuronyl transferase which leads to chronic bilirubinemia

• responds to phenobarbital → induces glucuronyl transferase; liver enzymes are normal, low albumin, high Tbil (20-50 mg/dL)

what is dubin-johnson syndrome? (learning objective; ch.21)

an autosomal recessive genetic defect that causes a defect in bilirubin transport… transport of conjugated bilirubin from the hepatocytes into bile is impaired which causes black pigmentation of the liver and unusual porphyrin (heme component) excretion

• jaundice happens during adolescence

• diagnosed though liver biopsy, elevated bilirubin, and elevated coproporphyrin 1 excretion

what would hyperbilirubinemia cause in adults?

excess production of bilirubin causing liver damage

what happens in neonatal hyperbilirubinemia? (learning objective; ch.21)

bilirubin production may exceed the liver’s ability to remove it which causes unconjugated bilirubin to cross the blood-brain barrier which causes kernicterus (excess bilirubin depositing itself into fatty tissues like the brain)

what is jaundice? (learning objective; ch.21)

yellow discoloration of the skin and eyes which is caused by elevated bilirubin levels (≥2-3 mg/dL)… scleral icterus is usually the first visible sign of jaundice and would be kernicterus in infants

need to distinguish between hepatic and hemolytic jaundice

what happens in pre-hepatic jaundice? (learning objective; ch.21)

excess bilirubin is being delivered to the liver → unconjugated, insoluble, and bound to albumin → unable to be filtered by the kidney

often seen in hemolytic anemia

what is hepatic jaundice? (learning objective; ch.21)

a defective conjugation - enzyme defect that causes an impaired cellular uptake and abnormal secretion of both unconjugated and conjugated bilirubin

what is post-hepatic jaundice? (learning objective; ch.21)

impaired excretion of bilirubin due to obstruction of bile flow into intestines due to gallstones or tumor → elevated conjugated bilirubin is seen, loss of stool color, and conjugated bili in urine

how is total bilirubin measured in the diagnosis of hyperbilirubinemia?

jendrassik-grof

• caffeine and sodium are added to accelerate the reaction between the diazo reagent and unconjugated bilirubin → azobilirubin complex is formed and is proportional to the amount of total bilirubin

enzymatic

what is hepatitis?

inflammation of the liver that can be caused by viruses, bacteria, chemicals, drugs or alcohol and can be acute or chronic

acute hepatitis, ALT > AST

what is hepatitis A? (learning objective; ch.21)

small, single-stranded RNA virus that is usually transmitted by contaminated food or water (fecal or oral transmission)& may be asymptomatic but there is a vaccine available → diagnosed through serological methods of hep A antibodies

• anti-HAV IgM → acute infection

• anti HAV IgG → past infection or immunity

what is hepatitis B? (learning objective; ch.21)

DNA virus with a central core and outer envelope that can be transmitted either parenterally, perinatally, sexually, or in contact with body fluids of an infected hep B patient

vaccine is available

what is the clinical course of hepatitis B? (learning objective; ch.21)

2/3 may be asymptomatic or have mild flu-like symptoms while the 1/3 experience malaise, irregular fevers with right upper quadrant tenderness, jaundice, and dark uurine

• 90% of patients recover within 6 months

• ~10% will develop chronic hepatitis → ~1% will develop the syndrome of fulminant (sudden) hepatitis which has a high mortality

• chronic HBV results in cirrhosis and hepatocellular carcinoma

what is HBsAg? (learning objective; ch.21)

hepatitis B surface antigen that is routinely tested on all donated units of blood as it is the first serologic marker to appear → identifies infected patients before the onset of clinical illness (current HBV infection whether acute or chronic)

what is hepatitis anti-HBs? (learning objective; ch.21)

found in patients who recover from Hep B or found in those who have received the HepB vaccine → gives immunity to future reinfection

what is HBcAg-core antigen? (learning objective; ch.21)

not detectable in serum but Anti-HBc is → develops earlier than anti-Hbs and indicates exposure to the virus

assay for general use is now available

what is HBeAg? (learning objective; ch.21)

correlates with number of infectious particles and degree of infectivity and its presence is an unfavorable prognosis as it predicts severe course and chronic liver disease

anti-HBe indicates low infectivity of serum

what is the hepB vaccine and what is its purpose? (learning objective; ch.21)

recombinant vaccine containing hepatitis B surface antigen (HBsAg) → stimulates the body to produce anti-HBs antibodies and provides protective immunity against HBV

healthcare workers, infants, and high-risk individuals should be vaccinated

what is the scheduled doses for the HepB vaccine?

0 months → 1 month → 6 months

what is hepatitis C? (learning objective; ch.21)

single-stranded RNA virus that has no vaccine and develops gradually → can have acute HepC (mild, unapparent [60-70%]) or chronic HepC

• transmitted parenterally (contaminated needlestick, hemodialysis, human bite, acupuncture, tattooing, body piercing, sexual intercourse, mother to child) or through blood transfusion or transplant

what is chronic HepC? (learning objective; ch.21)

high rate of progression to chronic form (6-85%) and can cause cirrhosis (10-20%) and carcinoma (1-5%) and is the leading reason for liver transplantation

what is the hepatitis C antibody? (learning objective; ch.21)

anti-HCV → usually not detected in the first few months (present in later stages) and mutates rapidly (stays ahead of the immune system) so it DOES NOT provide immunity

what are the statistics regarding chronic hepatitis?

• 10% of HBV cases progress to chronic form

• HepC high degree of chronicity about 80%

• Hepatitis A is rarely, if ever, associated with chronic disease

  • mildest form of hepatitis

elevated serum transaminase (AST, ALT) levels are present for more than 6 months

how is hepatitis A diagnosed? (learning objective; ch.21)

total antibody assay

• anti-HAV IgM → acute infection

• anti-HAV IgG → immunity/chronic

what is hepatitis D? (learning objective; ch.21)

single-stranded RNA virus that required HBV to replicate by using HBsAg envelope (coinfection)

HBV vaccine prevents HDV

what is hepatitis E? (learning objective; ch.21)

nonenveloped single-stranded RNA virus that is transmitted fecal-oral route and is a severe disease that can occur in pregnant women

how is hepatitis diagnosed in the lab? (learning objective; ch.21)

• total bilirubin → indicates degree of jaundice

• liver enzymes → AST and ALT markedly elevated with ALT > AST

• hepatitis specific assays

what is included in the HepA specific assay? (learning objective; ch.21)

HepA antibody testing includes a total antibody assay and a specific IgM assay to detect a current infection

what would patients with a current HepB infection be positive for? (learning objective; ch.21)

will be positive for HBsAg and/or IgM antibodies to the HBV core

what would patients who are chronic carriers of HepB be positive for? (learning objective; ch.21)

will be positive for HBsAg but not IgM → use HbeAg test and the antibody assay to see if HbeAg is useful for assessing whether the patient is infectious

what would patients who have had HepB be positive for? (learning objective; ch.21)

will be positive for the hepatitis B core antibody but those who have been vaccinated will be positive for the hepatitis B surface antibody

what is included in the HepC specific assay? (learning objective; ch.21)

there is no specific IgM assay to detect an active infection

what is included in the HepD and E specific assay? (learning objective; ch.21)

not performed by routine clinical laboratories → once patient has been diagnosed, there are assays that can quantitate how much virus is present which is useful to provide the appropriate treatment

whats the distribution of iron in the body? (learning objective; ch.21)

• heme proteins and Hb → 65-70%

• myoglobin → 10%

• stored as ferritin → 30%

  • cytochromes → iron containing proteins & are electron carriers in cellular respiration

most abundant trace element in the body

what are the other iron-containing proteins in the body?

• enzymes → catalase, peroxidases

• iron-sulfur proteins (NADH dehydrogenase)

• transport/storage proteins → transferring, lactoferrin, ferritin, hemosiderin

how is iron absorbed? (learning objective; ch.21)

intestinal absorption is the primary regulatory mechanism → if plasma Fe is down, then intestinal absorbance is up

• Fe3+ (ferric [good for transport]) is reduced to Fe2+ (ferrous & more soluble) to bind to a protein to be transported/move

  • reduced by agents like vitamin C (enhances iron absorption) or ferric reductases in intestinal epithelium

• 6-12% of daily intake is absorbed (can increase to 30-40% if necessary)

if a supplement is in a ferrous state, it crosses the barrier right away

where is excess iron (in ferric state) stored? (learning objective; ch.21)

stored in the liver, pancreas, thyroid gland, heart, adrenal glands, kidneys, skin, spleen, stomach, and bone marrow (stored in macrophages too)

• decrease in ferritin = depleted iron stores

• decrease in transferrin and increase in ferritin = iron overload

stored when there are adequate plasma levels

what happens when iron is released? (learning objective; ch.21)

iron is released from ferritin (Fe3+ → Fe2+) and is taken up by transferrin to be transported to the tissues for synthesis → transferrin is a glycoprotein that is synthesized in the liver with 2 binding sites (1/3 of sites are occupied normally)

• transferrin also transports intestinally absorbed iron to the liver or spleen for storage

• transferrin also transports iron from macrophages (to be recycled or to be stored)

what is hereditary hemochromatosis? (learning objective; ch.21)

genetic disease of iron overload → iron accumulates which is toxic to the tissues and produces free radicals that can lead to impaired protein synthesis and cell proliferation… can lead to cell injury and fibrosis

• progresses to cirrhosis and hepatocellular carcinoma (AST and ALT markedly increased)]

• causes diabetes mellitus (pancreatic damage from excess Fe) and skin pigmentation (bronze diabetes)

the most common disease of iron overload

how is hereditary hemochromatosis diagnosed? (learning objective; ch.21)

through an iron panel → will show elevated serum Fe lvls with elevated ferritin levels and transferrin saturation

• definitive diagnosis is made through a genetic blood test which can detect mutations associated with the disease

where is secondary hemochromatosis found? (learning objective; ch.21)

found in disease of increased administration of iron through external factors (transfusions, dietary intake of iron) → common cause is beta thalassemia which requires regular transfusions

how is copper absorbed, transported, and excreted? (learning objective; ch.21)

absorbed in the intestine (40-60% ingested Cu) → complexed to protein (needs to be bound to albumin to move) → transported to liver for storage → transported to tissue via ceruloplasmin (90-95% Cu bound to ceruloplasmin) → excreted through biliary tract and GI tracts

third most abundant trace element (after Fe and Zn)

what are the foods high in copper?

• shellfish

• nuts

• liver

• kidney

• egg yolk

• mushrooms

copper from copper pipes don’t have a significant effect on copper levels

what are the functions of copper? (learning objective; ch.21)

• enzyme co-factor

  • assists enzymes to work more efficiently

• cytochrome component

• SOD (superoxide dismutase) component - antioxidant

  • neutralizes highly reactive O2’s

• formation of collagen crosslinks

what is wilson’s disease? (learning objective; ch.21)

genetic disorder of copper metabolism where the ATP7B gene is abnormal → liver can’t link copper to ceruloplasmin and excrete it into bile which causes excess copper to accumulate in tissues and damages liver, brain, eyes, and kidneys

• liver damage → hepatitis, cirrhosis, liver failure

• neurologic damage → motor disturbances (ataxia, tremors, speech difficulties) and psychiatric deficiencies (personality changes, depression, cognitive decline)

• eye damage → kayser-flesicher rings (copper ring around eye)

serum copper appears low because copper is trapped in tissues instead of circulating

what symptoms would be in fulminant wilson disease?

• neuropsychiatric illness

• musculoskeletal symptoms

• renal symptoms

• liver disease

could also have kidney stones and hematuria

how is wilson’s disease diagnosed? (learning objective; ch.21)

• serum ceruloplasmin <20 mg/dL

• urinary copper excretion is elevated

• presence of kayser-fleisher rings

• copper in liver tissue

• genetic testing for ATP7B gene

• liver function tests

  • AST, ALT, GGT, ALP elevated at first then will decrease as fibrosis increases

  • Tbil and Dbil elevated

  • albumin low

• 24-hour urine copper elevated

what diseases would have end-stage liver disease?

• chronic HepB or C

• alcohol abuse

• hemochromatosis

• wilson disease

• alpha1-antitrypsin deficiency

• autoimmune hepatitis

what are some important findings in cirrhosis and liver failure? (learning objective; ch.21)

• liver biopsy is done to confirm → tests for other liver diseases

• imaging → ascites which is fluid build up in abdominal cavity

• albumin is low and PT is elevated (liver makes coag proteins)

• liver fibrosis → accumulation of tough, fibrous scar tissue in the liver

  • hallmark of cirrhosis is fibrosis and regenerative nodules

what are the risk factors in hepatocellular carcinoma/liver cancer? (learning objective; ch.21)

• chronic infection with HCV, HBV, or both

• cirrhosis caused by alcohol abuse, hemochromatosis, AAT, HBV or HCV

• tobacco use, arsenic exposure

fifth most common form of cancer in the world and 1/3rd of patients may have cirrhosis

how are those with hepatocellular carcinoma/liver cancer diagnosed? (learning objective; ch.21)

medical history, physical examination

• no clinical laboratory test able to diagnose liver cancer

• α-fetoprotein measurement can be used to assess treatment

what is alpha1-antitrypsin? (learning objective; ch.21)

serine protease inhibitor that is made in the liver which inhibits trypsin, neutrophil-derived elastase

what is alpha1-antitrypsin deficiency? (learning objective; ch.21)

genetic condition on chromosome 14 which causes emphysema at an early age without a history of smoking

• 20% of infants develop hepatitis

• 25% die within one year

• 1/3 to ½ of adults will develop cirrhosis

  • hereditary hemochromatosis is also present in 1/3 of pts with AAT deficiency

• can lead to hepatocellular carcinoma

how is alpha1-antitrypsin deficiency diagnosed? (learning objective; ch.21)

serum AAT level to screen

• <80 mg/dL([reference range = 100-300)

serum phenotype and genotype is necessary for diagnosis