Diagnosis by zhangyun

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									           GALLSTONES
      Adam Slivka, M.D., Ph.D.

OBJECTIVES:
 1. Analyze the function for the gallbladder
    and the sphincter of Oddi.
 2. Describe the pathogenesis of gallstones
    &factors affecting gallstone formation.
                     Gallstones
Over 20 million people in the United States have gallstones,
resulting in 1 million cholecystectomies and 6,000 deaths
each year. The estimated cost of gallstone disease,
including treatment and lost productivity, is in excess of 8
billion dollars. In order to best care for patients with
gallstone disease, one must have a working knowledge of
the physiology of gallstone formation. There are three
types of gallstones: cholesterol stones, black pigment
stones, and brown pigment stones. These stones form in
the gallbladder and bile ducts when lipids and salts are
precipitated in the bile. This precipitation occurs because
of a variety of factors affecting “normal” physiology.
             Types of Gallstones
              Cholesterol      Black       Brown

Site of      Gallbladder Gallbladder Bile ducts
Origin
Pathogenesis Physical-      Physical-   Infectious
             chemical       chemical
Composition cholesterol     Calcium &   Mixed
                            bilirubin
                   Figure 1.
                    Chylomicron    Acetate     HMG-CoA                          Bile Salt
                                               Reductase
                    LDL                                               7-
                                                                  hydroxylase
                    Lipoprotein
                                                      Free
                                                   Cholesterol
                   PLASMA                                                                   BILE
                                                           ACAT

                                                    Cholesterol
                                     Free              Ester
                                  Fatty Acid                             Lecithin
                      VLDL
                      HDL



Cholesterol is carried in the plasma as chylomicrons, which are taken up by hepatocytes
by the apolipoprotein B/E receptor and by endocytosis. Once in the hepatocyte,
cholesterol can be stored as an ester, hydrolyzed to form bile salts, secreted directly into
the bile, or exported as plasma lipoprotein. Synthesis of cholesterol by HMG-Co-A
reductase adds to the pool of free cholesterol.
                  Components of Bile
   Water                                          82%
   Bile Salts                                     12%
   Phospholipid                                    4%
   (Lecithin)
   Cholesterol                                      1%
   Miscellaneous                                    1%
Free Cholesterol is insoluble in water, but is solubilized in bile
by lecithin and bile salts as mixed micelles or vesicles. The
solubility of cholesterol in bile is dependent on the relative
molar proportions of bile salts, lecithin and cholesterol.
Human Bile Components


                  Phospholipids
                  Cholesterol
                  Bilirubin
                  Protein
                  Electrolytes
                  Secondary bile salts
                  Primary Bile salts
                   100        0




Cholesterol (%)                    Lecithin (%)




                  INSOLUBLE

      0                                    100
                  SOLUBLE

    100            BILE SALT (%)             0
       Risk Factors Associated with
      Cholesterol Gallstone Formation
Risk Factors    Proposed Metabolic Abnormality
Age               Cholesterol secretion into bile bile acid synthesis
Female gender     Cholesterol secretion into bile intestinal transit
                  time
Obesity           Cholesterol hypersecretion into bile cholesterol
                  synthesis via HMG-CoA reductase activity
Weight loss       Cholesterol hypersecretion into bile bile acid
                  synthesis and gallbladder hypomotility
TPN               Gallbladder hypomotility
Pregnancy         Cholesterol secretion and gallbladder
                   hypomotility
        Risk Factors Associated with Cholesterol
                  Gallstone Formation
Risk Factors:        Proposed Metabolic Abnormality
Drugs
Clofibrate              bile acid concentration as a result of suppression of 7-α-
                     hydroxylase activity and acyl-CoA:Cholesterol
                     acyltransferase (ACAT) activity, resulting in free cholesterol
                     secretion into bile
Oral                   Cholesterol secretion
Contraceptives
Estrogen tx in         Cholesterol hypersecretion into bile and bile acid synthesis
women
Estrogen tx in men     Cholesterol hypersecretion into bile
Progestogens           Diminished ACAT activity cholesterol secretion and
                       gallbladder hypomotility
Ceftriaxone            Precipitation of an insoluble calcium-ceftriaxone salt
Octreotide              gallbladder motility
    Risk Factors Associated with Cholesterol
              Gallstone Formation

Risk Factors:               Proposed Metabolic Abnormality

Genetic Predisposition:
Native Americans              cholesterol synthesis and conversion of
                            cholesterol into bile salts
Scandinavians                 cholesterol secretion into bile

Apolipoprotein E4/E4          Unknown
alleles
Diseases of the terminal ileum:

 HDL                          activity of HMG-CoA reductase
 Triglycerides                activity of HMG-CoA reductase
               Prevalence of Gallstones
                       Age/Sex
30




20
                                          Men
                                          Women
10




 0
     30   40    50    60
                  AGE
     Cholesterol Content of Gallstones
40


30


20


10


 0
     0   10   20   30   40   50   60   70   80   90   100

                    % of Cholesterol in Gallstones
      Ethnic Variation in Gallstone Prevalence

      100
       90
       80
       70
       60
       50
       40
       30
       20
       10
        0
Pima Indians   Chile   US Mexican Sweden Italy Denmark S. Africa India Japan
                       Americans                      (Black)
 Gallstone Formation During Rapid
            Weight Loss
100

 80

 60
                                 % Patients with new
 40                              gallstone formation


 20

  0
       4                    19

           Dieting, weeks
            Gallstone prevention by
              Ursodiol and ASA
100

80

60
                                      Gallstones
40                                    Sludge


20

  0
      Placebo    Aspirin   Ursodiol
              Pregnancy: Gallstone Formation a
                         High Risk
              100

              80
%, Patients




              60
                                                                        Gallstones
              40                                                        Sludge

              20

                0
                    Controls   1st Trimester 2nd Trimester Postpartum
       Obesity with Gallstones
30

25

20

15                                          Men
                                            Women
10

 5

 0
     <20     20 to 25     25 to 30    >30


           Index Units of Body Mass
Gallstone and Sludge Development
           During TPN
100

80

60
                                        Gallstones
40                                      Sludge

20

  0
      3       4 to 6               >6

          Duration of TPN, weeks
              Sludge Formation Prevented by CCK
                      Administered Daily
               100

                80
%, Patients




                60

                40

                20

                 0
                      Placebo      CCK-OP
Cholesterol Gallstone Formation can
 be Initiated by Gallbladder Stasis
Patient Population             Relative Risk
Spinal cord injury                  ++
Somatostinomas or octreotide therapy ++
After vagotomy                       ++
With Diabetes                        +
     Estrogen Increases the Risk of
         Cholesterol Gallstones
Oral Contraceptives:
  Age <20                                3.5
  Age>30                                 1.3
Early menarche, late menopause           1.7
Oral estrogens, postmenopausal           4.5
Transdermal estrogens, postmenopausal    1.0
Hormonal therapy for prostate cancer    >10
   Relative Risk of Gallstones with
     Alterations in Serum Lipids
                               Relative Risk
Hypertriglyceridemia                 1.6
Hypercholesterolemia               ≤1.0
Fibric Acids:
  Clofibrate
  Gemmfibrozil                     1.5-2.5
Nicotinic Acid                      1.2
HMG CoA Reductase Inhibitors
  Lovastin
  Prevastatin                      <<1
Figure 3.
 Bacterial Skeleton
 At Nidus of Brown Stones



                                              Lecithin
                             Phospholipase
                 Bacteria    A2
                                             Free Fatty Acids

                                             Conjugated bilirubin
                                             (soluble)
                            B-glu-
                            curonidase
             Deconjugase                     Unconjugated bilirubin
    Bile
    Salts                                    (insoluble)




Bile Acids   Ca 2+ Salts
Chronic Liver Disease Predisposes
     Black Pigment Stones
 50
                                                      USA
 40

 30             Taiwan

 20

 10

  0
      Control   CAH     Mild     Severe    Severe
                      Cirrhosis Cirrhosis Cirrhosis
Prevalence of Gallstones in Patients
     with Sickle Cell Anemia
100


 80


 60

 40


 20


  0
      2-4   5-9   10-15    16-20   21-25   26-30   30+
                          AGE

								
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