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DISEASES OF THE LIVER Chapter 21

LIVER FUNCTIONS
Metabolism of carbohydrates, proteins, and lipids
Production of bile
Chemical detoxification
Porphyrin catabolism
Bilirubin metabolism
Protein synthesis
Waste products
Storage

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METABOLISM OF CARBOHYDRATES
Liver aids in blood glucose regulation
Pancreas produces insulin and glucagon
Glycolysis: conversion of glucose into pyruvate or lactate
Glycogenesis: glucose to glycogen
Glycogenolysis: glycogen to glucose
Gluconeogenesis: using noncarb sources to make glucose (amino acids,
glycerol, lactate and pyruvate)

METABOLISM OF PROTEINS
Production of plasma proteins from amino acid pool
Deamination of amino acids and conversion of amino acids
Production of clotting factors
Nitrogen balance:
 dietary intake = urea excretion

Formation of waste products

 In the liver, nitrogen is removed from free amino acids, and ultimately ammonia
and ketoacids are produced.
 The ammonia is converted to urea and excreted in the urine.
 Ketoacids are oxidized through the citric acid cycle and converted to glucose or
fat.

METABOLISM OF LIPIDS
Lipids stored in adipose tissue
Reserve source of energy
Liver synthesizes most lipoproteins
Metabolism of lipids to produce ATP
Conversion of glycerol to glucose
Conversion of carbohydrates and proteins to fats
Conversion of cholesterol to bile
The primary functions of the biliary system are to drain waste
products from the liver into the duodenum and to help in the digestion
of fat with the controlled release of bile.

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BILIRUBIN METABOLISM
Bilirubin is a useless and toxic breakdown product of hemoglobin and is
generated in large quantities.
 Dead and damaged red blood cells are delivered by phagocytic cells to
the liver.
 The iron is recycled and stored in liver.
 The globin chains are made of protein, catabolized, and the components
are reused.
 Heme is not recyclable and must be eliminated.
 High amounts of unconjugated bilirubin lead to cell damage
Liver synthesizes proteins necessary for iron transport
Fat-soluble vitamins stored in liver
Within macrophages, heme is first converted into free bilirubin and
released into plasma. It binds to albumin and is carried to the liver.
Bilirubin is stripped of albumin by hepatocytes and is conjugated to
glucuronic acid (water soluble). This conjugated bilirubin is converted to
urobilinogen by bacteria and is mainly excreted in the feces.

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DETOXIFICATION IN THE LIVER

Primary organ of detoxification
Two pathways
Phase 1 is cytochrome P-450
 Toxic to less toxic form
 occurs through oxidation, reduction, and hydrolysis reactions.
 Antioxidants are substances that can reduce the damage caused by free
radicals.

Phase 2 is conjugation
 Addition of chemical group such as cysteine, glycine, or sulfur to create less
harmful form that is water soluble so it can be excreted

GILBERT SYNDROME
Genetic liver disease
Reduced activity of glucuronyl transferase
 Responsible for conjugation of bilirubin

Most common hereditary cause of hyperbilirubinemia

 5 to 10% of population

Most patients asymptomatic, slight jaundice

Total bilirubin levels are 1-5 mg/dL

CRIGLER-NAJJAR SYNDROME
Type I
 Complete absence of glucuronyl transferase
 Potentially life-threatening but rare
 Severe unconjugated bilirubinemia, kernicterus
 Total bilirubin is 20 to 50 mg/dL

Type II
 Decreased levels of glucuronyl transferase
 Chronic bilirubinemia
 Total bilirubin is 7 to 20 mg/dL

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DUBIN-JOHNSON SYNDROME
Genetic defect
Defect of bilirubin transport across the membrane that separates the
hepatocyte from the bile canaliculi
Dark pigmentation of liver
Unusual porphyrin excretion

HYPERBILIRUBINEMIA,
JAUNDICE, AND KERNICTERUS
Hyperbilirubinemia in adults
 Excess production: rapid increases in the breakdown and destruction of red
blood cells; called prehepatic jaundice (hemolytic anemias or transfusion
reactions)
 Liver damage: can prevent bilirubin from flowing through the liver

Jaundice: yellow color of skin and eyes

 Prehepatic, hepatic, post-hepatic

Neonatal hyperbilirubinemia
 Production may overcome removal (hemolytic disease of the newborn)
 Immature liver

Kernicterus: brain damage from hyperbilirubinemia

DIAGNOSIS OF HYPERBILIRUBINEMIA
Liver disease increases total and direct bilirubin levels
Total bilirubin methodology
 The initial colorimetric tests for bilirubin involved adding diazotized sulfanilic
acid to serum, which immediately turned red. This detected direct bilirubin
(conjugated).
 In order to measure unconjugated bilirubin, an accelerator (alcohol, later
caffeine) was added to the reagent.
 Currently, manufacturers use a modified Jendrassik-Grof, which uses caffeine
and sodium benzoate to accelerate the reaction between the diazo reagent and
unconjugated bilirubin. An azobilirubin complex is formed and is proportional to
the amount of total bilirubin.
 Conjugated (direct) bilirubin is measured using a diazo reaction without
accelerators present.
 Conjugated bilirubin is water soluble, which is why it is found in urine.

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JOSE’S CASE
Jose is a 54yr old Hispanic man with fatigue, diarrhea, and a fever.
He suspected the flu but his symptoms continued for more than a week.
He visits his physician and also reports lighter than usual stools. His
physician noted that his sclera appeared yellow. His liver function and
bilirubin test show the following:
 Total bilirubin: 5 mg/dL
 AST: 350 IU/L
 ALT: 450 IU/L

What is the probable condition?

What tests should be ordered next? Why?

HEPATITIS
Inflammation of the liver
Causes
 Viruses
 Bacteria
 Chemicals, drugs, or alcohol

Acute (6mo or less) or chronic (more than 6mo)

Acute viral hepatitis profile
 Anti-HAV IgM
 HBsAg
 Anti-HBc IgM
 Anti-HCV

HEPATITIS A
Small, single-stranded RNA virus
Oral-fecal route of exposure
Risk of spreading:
 The virus replicates in the liver. It is excreted via the biliary system into the feces.
 Person-person contact
 Contaminated food
 Poor hygiene or sanitation
 Risk of spreading is greater in the 2-week incubation phase

Vaccine is available

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HEPATITIS B
DNA virus with a central core and envelope
 Hepatitis B surface antigen (HBsAg) is located in the outer capsule.
 The inner core contains the hepatitis B core antigen (HBcAg) and the hepatitis B
e-antigen (HBeAg).

Transmission modes
 remain infectious on environmental surfaces for up to 1 month.
 The route of exposure is by parenteral or mucosal exposure to HBsAg-positive
body fluids from persons who are either carriers or those with acute infection.

Chronic hepatitis B in 15 to 25% of those infected

Vaccine available

ACUTE HEP B markers

CHRONIC HEP B markers

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HEPATITIS C
Single-stranded RNA virus
Transmission routes:
 Blood transfusions were the leading route of transmission before routine
screening of blood products began in 1991.
 The most efficient route of transmission is direct contact through contaminated
needles.

Gradual onset
HCV and cirrhosis: 60 to 85% develop cirrhosis
No vaccine

HEPATITIS D AND E
Hepatitis D:
 Single-stranded RNA virus
 HBV must be present
 Coinfection
 HBV vaccine prevents HDV

Hepatitis E:
 Nonenveloped single-stranded RNA virus
 Fecal-oral route of transmission

LABORATORY DIAGNOSIS OF HEPATITIS

Total bilirubin
 Indicates level of jaundice

Liver enzymes:
 In hepatitis, AST and ALT levels are markedly elevated

Hepatitis-specific assays
 HAV IgG anf IgM
 HBsAg, anti-HBs IgM & IgG, anti-HBc IgG & IgM, HBeAg, anti-Hbe IgG & IgM
 Anti-HCV
 Anti-HDV
 Anti-HEV IgG

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HEREDITARY HEMOCHROMATOSIS
Genetic disease of iron overload
Iron accumulation
 Excess iron is hazardous. It produces free radicals that lead to impaired protein
synthesis and cell proliferation. This can lead to cell injury and fibrosis.

Progresses to cirrhosis and hepatocellular carcinoma

Causes diabetes mellitus
Diagnosis: iron and ferritin levels + genetic test
Secondary hemochromatosis
 Transfusions or excess iron intake

WILSON DISEASE
Genetic disorder of copper metabolism
Excess copper damages liver, brain, and eyes
Fulminant Wilson disease: neuropsychiatric illness
Liver cannot link copper to ceruloplasmin and excrete it into bile
Diagnosis
 Both ceruloplasmin levels and copper levels are low in Wilson disease.
 Serum copper levels are decreased due to the accumulation of copper in the
tissues and the inability of copper to be transported through the serum.
 Kayser-Fleisher rings

CIRRHOSIS AND LIVER FAILURE

End-stage liver disease
Final phase of many chronic liver diseases
Hallmark of cirrhosis is fibrosis
Loss of hepatic function
Accumulation of toxic metabolites
Diagnosis
 Serum albumin levels will decrease, as will concentrations of blood clotting
factors. This can lead to bleeding episodes.
 Ammonia levels may increase because the liver will be unable to rid the body of
this toxin.
 Although a liver biopsy is the ultimate diagnostic tool, it is not possible to
perform in some patients.

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LIVER CANCER
Hepatocellular carcinoma
One third of patients may have cirrhosis
Risk factors:
 Alcohol abuse
 hemochromatosis
 AAT
 HBV or HCV

Diagnosis
 There is no clinical laboratory test able to diagnose liver cancer.
 An α-fetoprotein measurement can be used to assess treatment.

Α1-ANTITRYPSIN DEFICIENCY
Genetic condition
Patients are predisposed to obstructive pulmonary disease and liver
disease.
The genetic defect prevents the AAT molecule from being released
from hepatocytes. The accumulation can destroy these cells, and the
decreased amount of AAT in the alveoli lead to damage there.
Emphysema at an early age
Hepatitis and cirrhosis are also seen
Diagnosis
 decreased levels of AAT
 serum phenotype and genotype is necessary for diagnosis.

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