Case 1:

CLINICAL VIGNETTES AND QUESTIONS - HEMATOLOGY

A 57-year-old female complains of fatigue, tingling and numbness of her fingers and toes. The
symptoms have become progressively worse over the last 6 months. She reports that she had
changed her dietary habit to strict vegetarian diet two years ago. Physical examination shows
pallor, jaundice and decrease in position and vibration sense in her toes. A complete blood count
(CBC) shows: White blood cells: 4000/mm3 (normal: 5000 to 11,000/mm3)
Hemoglobin concentration: 9 g/dL (normal:12-16g/dL) Hematocrit (Hct): 27 percent (normal:
36-46%) Mean corpuscular volume (MCV): 110 femtoliter (normal: 79-97 fL) Platelet count:
160,000/mm3 (normal: 150,000 to 450,000/mm3) She is diagnosed as having megaloblastic
anemia and advised supplementation of vitamin B12.
Questions:

1. Describe the risk factors, etiology, pathogenic mechanism, altered morphology & physiology,
signs and symptoms, basis for signs and symptoms, differential diagnosis, screening and
confirmatory investigations, prognosis and complications of macrocytic anemias.

Macrocytic anemia’s are subdivided into megaloblastic (eg. Folate or vitamin B12 deficiency)
and nonmegaloblastic anemia.

Vitamin B12 Deficiency Folate deficiency

Etiology (risk Malnutrition, pure vegan diet, Decreased intake (chronic alcoholics),
factors): malabsorption (eg. Crohn’s disease, malabsorption (Celiac disease),
pernicious anemia), increased impaired metabolism (eg. Drug
utilization (pregnancy), induced – methotrexate, trimethoprim),
Diphyllobathrium latum (fish increased utilization (eg, pregnancy,
tapeworm) hemolytic anemia)
Pathogenic Vitamin B-12 and folate coenzymes are required for thymidylate and purine
mechanism of synthesis; thus, their deficiency results in retarded DNA synthesis. Impaired
macrocytic DNA synthesis causes delayed nuclear maturation and results in a block in
anemia in folate cell division leading to large, nucleated hematopoietic cells. The cellular
and vitamin B12 RNA and protein synthesis continue unabated and the cytoplasmic volume
deficiency continues to expand. The enlarged calls are called megaloblasts. It affects all
rapidly dividing cells: RBCs, leukocytes, platelets, and intestinal epithelium.
As a result there is ineffective erythropoiesis. Megaloblastic precursors
outside the bone marrow sinusoids are phagocytosed by macrophages and
magaloblastic precursors undergo apoptosis causing pancytopenia (anemia,
neutropenia, and thrombocytopenia)
Altered Vitamin B12 is in meat, eggs, and Folate is present in green vegetables
morphology & dairy products. Parietal cells and animal proteins in the form of
physiology synthesize intrinsic factor and polyglutamates. It is converted to
hydrochloric acid. The gastric acid monoglutamates by intestinal
then converts pepsinogen to pepsin, conjugase (inhibited by phenytoin).
and pepsin frees vitamin B12 from Monoglutamates are reabsorbed in the
ingested proteins. Free vitamin jejunum and converted to
B12 is bound to R-binders methyltetrahydrofolate, the circulating
synthesized in the salivary glands. form of folate. Reabsorption is
Pancreatic enzymes in the blocked by alcohol and oral
duodenum cleave off the R-binders contraceptives. Only a 3-4 month
 and vitamin B12 binds to IF to supply of folate in the liver.
form a complex. The vitamin B12-
IF complex is reabsorbed in the
terminal ileum. Vitamin B12 binds
to transcobalamin II and is secreted
into plasma, where it is delivered to
metabolically active cells or stored
in the liver(6-9 years).

Signs and Symptoms usually do not arise Similar to Vitamin B12 deficiency with
Symptoms until anemia is severe: pallor, the exception of neurologic disease.
dyspnea, palpitations, angina. Increased risk of open neural tube
Symptoms related to underlying defects in the fetus.
disease. Smooth sore tongue with
atrophy of papillae (glossitis),
Neurologic disease: peripheral
neuropathy, dementia, and subacute
combined degeneration of the
spinal cord (affects posterior
columns, lateral corticospinal tract,
dorsal spinocerebellar tract) due to
involvement of B12 in fatty acid
pathways
Differential Microcytic anemia (eg. Iron deficiency, thalessemia), Normocytic anemia
diagnosis (eg. Aplastic anemia, chronic renal failure)
Screening and Lab findings: decrease serum Lab findings: decreased serum folate
confirmatory Vitamin B12, increased serum and RBC folate (best screening test),
investigations homocysteine and methylmalonic increased homocysteine, and normal
(MCV > 100 acid (most sensitive test for mehtylmalonic acid
um3) Vitamin B12 deficiency Peripheral blood and bone marrow
Peripheral blood findings: findings are similar to Vitamin B12
pancytopnenia, oval macrocytes, deficiency
hypersegmented neutrophils (five
or more lobes) which is the maker
for folate and vitamin B12
deficiency
Bone Marrow Findings:
megaloblastic nucleated cells with
primitive open (lacy) chromatin
pattern
Prognosis Treatment: IM injection of vitamin Treatment: oral administration of
B12 monoglutamic folic acid
Takes about six weeks for Prognosis is good, tissues replenished
hematologic abnormalities to be even in malabsorption situations.
corrected but neurologic symptoms
may take much longer.
Complications Important to distinguish folate from vitamin B12 deficiency. Pharmacologic
doses of folate will correct the hematologic findings of both folate and
vitamin B12 deficiency; however, neurologic disease is not corrected and
 may even worsen symptoms

Schilling test: used to localize some of the causes of B12 deficiency though not routinely
performed anymore. Achieved by combining orally administered radioactive vitamin B12 with
IF, or with pancreatic extract, or alone after pretreatment with antibiotics followed by a 24 hr
urine collection to measure radioactive vitamin B12. Low levels are seen in defective GI
absorption. If low, repeat with oral intrinsic factor with B12 to assess change, this will increase
urinary excretion of oral dose if problem is due to lack of IF production. If this is low give oral
antibiotic with B12 to assess change, this will increase urinary excretion if problem is parasitic.
And if antibiotics do not help, the problem is likely one of absorption in the small bowel.
Nonmegaloblastic macrocytosis
Occurs in various clinical states, but all of which is fully understood. It is suspected in patients
with macrocytic anemias in whom testing excludes vitamin B12 and folate deficiencies. There is
incorporation of excess cholesterol and phospholipid into membrane, transferred form plasma
lipoproteins. The RBC then attempts to maintain most energy efficient shape: target cells, spur
cells.
Differences from megaloblastic macrocytic anemia’s: macrocytes are round rather than oval,
hypersegmented neutrophils are not presents, leukocytes and platelets are quantitatively normal,
absence of glossitis and neuropathy, anemia may not be present, alcohol excess is the most
common cause.
1. Liver disease
2. Alcoholism: macrocytosis and bone marrow suppression can occur in the absence of
folate/B12 deficiency
3. Reticulocytosis: reticulocytes are bigger than mature RBCs increased MCV
4. Metabolic disorder: congenital deficiencies of purine or pyrimidine synthesis
5. Drugs: hydroxyurea, AZT

2. Describe the normal anatomy and histology of the bone marrow.

Anatomy:
Bone marrow is found in the medullary canals of long bones and in the cavities of cancellous
bones (vertebral bodies, ribs, found inside the epiphysis or head of long bones). Cancellous bone
has large, open spaces (marrow spaces), surrounded by anastomosing plates of bone.

Two types of bone marrow have been described based on their appearance on gross examination:
red (hematogenous) bone marrow (color is produced by blood and blood forming cells) and
yellow bone marrow (color is produced by great number of adipose cells). In newborns, all bone
marrow is red and is active in production of blood cells. As the child grows, most of the bone
marrow gradually changes into yellow marrow. In adults, red marrow remains mainly in the
short and flat bones. Under certain conditions (severe bleeding, or hypoxia) yellow bone marrow
is replaced by red bone marrow.
Normal bone marrow biopsy will show 30-50% cellular components and approx 50% fat.

Histo:
Bone:
On a transverse section of a decalcified rib, we will find:
-haversian canals (house blood vessels that connect osteocytes)
-Volkmann’s canals (connect haversian canals)
-osteocytes in their lacunae
-endosteum (part of the bone that does not participate in the ossification process and remains a
soft tissue component).
Bone marrow:
-stroma: 3-D meshwork of reticular fibers containing hematopoietic cells and macrophages,
made of collagen Type I and III, fibronectin, laminin, and proteoglycans
-adventitial reticular cells (cells responsible for storing fat in the marrow)
-sinusoids (discontinuous layer of endothelial cells)
-blood vessels
-Pluripotent hematopoietic stem cell
-numerous cells undergoing hematopoiesis
-Megakaryocytes

3. Explain the normal development of the formed elements of blood from bone marrow stem
cells (hematopoiesis).

http://upload.wikimedia.org/wikipedia/commons/6/69/Hematopoiesis_%28human
%29_diagram.png
GRANULOCYTE MATURATION

Overall trend is from larger to smaller size; round, fine nucleus to dark, segmented nucleus;
increasing cytoplasm; no granules to primary (azurophilic) granules to specific (secondary)
granules.

1. Promyelocyte (10-20 µm): round nucleus, reddish-blue and fine to slightly condensed
chromatin, 1-2 nucleoli, increased basophilic cytoplasm, and primary (azurophilic) granules.

2. Myelocyte (10-18 µm): oval (to round) slightly indented nucleus; reddish-blue and slightly
granular chromatin; nucleoli may or may not be present; moderate bluish pink cytoplasm;
primary and specific granules (fine and pale). This is the first appearance of specific granules
(neutrophilic, eosinophilic and basophilic). The eosinophilic myelocyte is the most easily
determined with its coarse eosinophilic granules.

3. Metamyelocyte [ neutrophilic and eosinophilic ] (10-18 µm): indented nucleus (kidney bean);
light blue-purple and granular chromatin; no nucleoli are present; moderate clear pink cytoplasm;
specific granules are obvious.

4. Band Neutrophil (10-16 µm): elongated, horseshoe nucleus; blue-purple and clumped
granular chromatin; no nucleoli are present; abundant pink cytoplasm; specific granules. This
cell stage is not distinguished for the eosinophil and basophil maturation.

5. Granulocytes: Mature granulocytes are divided into

 Basophils- bilobate nucleus, densely basophilic granules, found in blood
 Eosinophils- bilobate nucleus, eosinophilic granules of uniform size
 Neutrophils- multilobed nucleus, large spherical azurophilic granules

ERYTHROCYTE MATURATION

The overall trend in RBC maturation is large, pale nucleus to darker, smaller nucleus to loss of
nucleus; increase in cytoplasm; gradual decrease in size; cytoplasm from intensely blue (full of
RNA) to grayish (mixture of RNA and hemoglobin) to reddish (full of hemoglobin, no RNA).

1. Proerythroblast (14-19 µm): Nucleus is large with fine chromatin and nucleoli; cytoplasm is
scant and basophilic.

2. Basophilic erythroblast (12-17 µm): Slightly smaller nucleus with slight chromatin
condensation; increased cytoplasm and intensely blue (RNA abundance); no granules and no
nucleoli present.

3. Polychromatophilic erythroblast (12-15 µm): Moderately condensed chromatin; lighter,

grayish cytoplasm. The nucleus is condensed and intensely basophilic with coarse
heterochromatin granules giving a characteristic checkerboard appearance.
4. Orthochromatophilic erythroblast (8-12 µm): Dark, opaque nucleus; gray-red cytoplasm
(trace blue). The nucleus has become pyknotic and there is abundant acidophilic hemoglobin.

5. Reticulocyte (7-10 µm) Nucleus has been extruded; cytoplasm is reddish-pale blue. RNA is
still present.

6. Erythrocyte (7-8 µm): No nucleus; orange-red cytoplasm; RNA is lost.

OTHER CELLS

1. Megakaryocytes (50-150 µm): Stages of maturation go from Megakaryoblast to

Megakaryocyte to Platelets (small cytoplasmic fragments).

2. Monocytes (9 - 12 µm): Stages of maturation go from monoblast to promonocyte to monocyte

to macrophage (in tissues). The nucleus is oval, horseshoe or kidney shaped and is usually
eccentric. The chromatin is less dense than in lymphocytes. The cytoplasm is basophilic.

3. Lymphocytes (6 - 8 µm): Stages of maturation go from lymphoblast to prolymphocyte to

lymphocyte. Small amount of pale cytoplasm.
 T lymphocytes- mature in thymus
 B lymphocytes- mature in bone marrow
-Plasma cells- offcenter nucleus, clock-face chromatin distribution, ubundant RER and
well developed Golgi apparatus

4. Describe the mechanism of folate trap in producing vitamin B12 deficiency.

Methylene-THF is formed from THF by the addition of methylene groups from one of
three carbon donors: formaldehyde, serine, or glycine. Methyl tetrahydrofolate can be made from
methylene-THF by reduction of the methylene group with NADPH. It is important to note that
Vitamin B12 is the only acceptor of methyl-THF. There is also only one acceptor for methyl-B12,
which is homocysteine in a reaction catalyzed by homocysteine methyltransferase. This is
important because a defect in homocysteine methyltransferase or a deficiency of B12 can lead to
a methyl-trap of THF and a subsequent deficiency. Thus, a deficiency in B12 can generate a
large pool of methyl-THF that is unable to undergo reactions and will mimic folate deficiency.
5. Identify the biochemical reaction and enzyme that requires both folic acid and vitamin B12.
Methylcobalamin serves as an intermediate in the transfer of a methyl group from N5-
methyltetrahydrofolate to homocysteine, forming methionine. In the process, N5-
methyltetrahydrofolate is converted to tetrahydrofolate, the precursor of folate cofactors.
This explains is how vitamin B12 (cobalamin) and folic acid metabolism are linked and
explains why megaloblastic anemia of vitamin B12 deficiency can be partially corrected by
ingestion of relatively large amounts of folate.

NOTE: disruption of the methionine synthesis pathway is the cause of neurological

problems and that folic acid in the setting of vitamin B12 deficiency will NOT correct
neurological manifestations.

6. Explain why methylmalonate levels are elevated in a patient with Vitamin B12 deficiency.

B12
Methylmalonyl-CoA  Succinyl-CoA
(associated with myelin)

Vitamin B12 is required for the isomerization of methylmalonyl-CoA to succinyl-CoA by

the enzyme methylmalonyl-CoA mutase. In vitamin B12 deficiency this reaction cannot
take place and methylmalonyl-CoA and methylmalonic acid accumulate.

B12 acts as a cofactor for homocysteine methyltransferase and methylmalonyl-CoA

Case 2:
A 58-year-old male who complains of mild fatigue for the past nine months is being evaluated.
Physical examination reveals mild pallor and an enlarged spleen. Complete blood count reveals:
White cell count: 68,000/mm3 (normal: 5000 to 11,000/mm3) Differential white cell count: 1%
blasts, 3% promyelocytes, 10% myelocytes, 10% metamyelocytes, 15% bands, 50% segmented
neutrophils, 3% monocytes, 3% basophils, 3%, eosinophils, 2% lymphocytes. Peripheral smear
shows a few nucleated RBCs. Platelet count: 400,000/mm3 (normal: 150,000 to 450,000/mm3)
Hemoglobin concentration: 9.4 g/dL (normal:12-16g/dL) Blood smear picture is shown below.

Questions:
1. Describe the risk factors, etiology, pathogenic mechanism, altered morphology & physiology,
signs and symptoms, basis for signs and symptoms, differential diagnosis, screening and
confirmatory investigations, prognosis and complications of chronic leukaemias (both chronic
myelogenous leukemia & chronic lymphocytic leukemia.

Chronic Myelogenous Leukemia Chronic Lymphocytic Leukemia

Risk factors Exposure to ionizing radiation and
benzene
Etiology t9;22 (95%)
-translocation of ABL proto-
oncogene: ABL fuses with break
cluster region (BCR) on
chr.22chr.22 w/translocation is
called Philadelphia chromosome
Pathogenesis Neoplastic clonal expansion of the -neoplasm of virgin B cellscan’t
pluripotential stem cell myeloid differentiate into plasma cells
stem cell proliferation hypogammaglobulinemia (50%)
Altered Peripheral blood smear: ↑ leukocyte Peripheral blood smear: ↑ # of
morphology and count (mainly neutros, lymphos w/dense nuclear chromatin
physiology metamyelocytes, basophils), ↑ and little cytoplasm; lymphos are
platelets, ↓RBCs very fragile and produce “smudge

Bone marrow: hypercellular due to
hyperplasia of granulocytic and
megakaryocytic precursors
Spleen: red pulp enlarged—looks like
BM b/c of hematopoiesis
Signs and sx -30-60y
(and basis) -initial sx are slow and nonspecific:
fatigue, weakness, weight loss
-Splenomegaly (extrameduallary
hematopoiesis)dragging sensation
-generalized painless
lymphadenopathy (metastasis)
Differential Other chronic myeloproliferative
diagnoses diseases: polycythemia vera, essential
thrombocytosis, myelofibrosis
Screening and -presence of Philadelphia chr (in the
confirmatory other chronic myeloprolif diseases we
investigations see JAK2 mutation)
-low leukocyte alkaline phosphatase
(do not see a leukemoid reaction as in
other chronic myeloprolif diseases—
↑WBC count with left shift and ↑
leukocyte alkaline phsphatase)
Prognosis/ -enlarged spleen compromises local
Complications blood supplysplenic infarct
-blast crisis: accelerate and transform
into AML or ALL in ~5 yrs (↑ in
myeloblasts or lymphoblasts—more
immature cells)
LAP: mature neutros have alkaline phosphatase in them—will take up the stain (neoplastic cells
don’t—won’t take up the stain)
2. Identify the source and function of erythropoietin.
Source: Peritubular capillary endothelial cells of the kidney and to a much lesser extent liver.
Function: Acts on stem cells of the bone marrow to stimulate red blood cell production. Also,
initiates the production of hemoglobin.
3. Identify the morphology and functions of the formed elements of blood (red blood cells, white
cells”
Bone marrow: complete replaced by
neoplastic B cells
Involved LN: sheets of small round
lymphocytes
- >60y
-often asx
-generalized, non-tender
lymphadenopathy
-warm antibody autoimmune
hemolytic anemia (IgG)
-neutropenia, noromocytic anemia
(50%), thrombocytopenia (40%)
Other B-cell neoplasms: Hairy cell
leukemia (mature B cell tumor in
elderly), Mantle cell lymphoma
(also expresses CD5)
-mature B cells w/CD19, CD20,
CD23, B cell receptor, CD5
-BM aspirate, peripheral blood
smear
-course and prognosis is variable;
~survival=4-6yr
-death due to infection b/c no Ig
-as time passes, CLL transforms into
aggressive tumor (resemble pro-
lymphocytic leukemia or diffuse
large B-cell lymphoma)then
survival is <1yr
blood cells and platelets).
Formed Elements Morphology
RBC Anucleate, biconcave
Platelets Small cytoplasmic fragments
derived from megakaryocytes
WBC: Defense against infections
Neutrophil Multi-lobed nucleus with
neutrally staining granules
Eosinophil Bilobate nucleus with large
eosinophilic (red) granules of
uniform size
Basophil Bilobate nucleus with densely
basophilic (dark blue) granules
Lymphocyte Round, densely staining
nucleus. Small amount of pale
cytoplasm
Monocyte Large. Kidney-shaped nucleus.
“Frosted-glass” cytoplasm
4. Describe hemoglobin synthesis and degradation. Describe the factors that shift the
oxyhemoglobin dissociation curve.
Function
Transports O2 & CO2 b/w
peripheral tissues and lungs
Promotes blood clotting and
prevents leakage of RBCs from
damaged vessels.
Phagocytic. Important in acute
inflammatory response.
Important in parasitic and
protozoan infections. Involved
asthma and allergic responses.
Plays a role in parasitic and
allergic responses.
B cell = Antibodies
T cell = Cellular immune
response, regulate B cells and
macrophages
Differentiates into
macrophages, which
phagocytose bacteria and
damage cells. Also an APC.
Heme synthesis:
The enzymatic process that produces heme is called porphyrin synthesis.
The pathway is initiated by the synthesis of D-Aminolevulinic acid (dALA or δALA) from the
amino acid glycine and succinyl-CoA from the citric acid cycle.
The rate-limiting enzyme responsible for this reaction, ALA synthase, regulated by intracellular
iron levels and heme concentration.
A low-iron level, e.g., in iron deficiency, leads to decreased porphyrin synthesis, which prevents
accumulation of the toxic intermediates.
The organs mainly involved in heme synthesis are the liver and the bone marrow.

Heme degradation:
Degradation by macrophages in the spleen, after 120 days.
heme is converted to biliverdin by the enzyme heme oxygenase (HOXG).
NADPH is used as the reducing agent, molecular oxygen enters the reaction, carbon monoxide
CO is produced and the iron is released from the molecule as the ferric ion (Fe3+).
HMOX1/2
heme --------------> biliverdin + Fe3+
/ \
H+ + NADPH NADP+

O2 CO
In the second reaction, biliverdin is converted to bilirubin by biliverdin reductase (BVR):
 BVR
biliverdin -----------> bilirubin
/ \
H+ + NADPH NADP+
Bilirubin is transported into the liver bound to serum albumin, where it is conjugated with
glucuronic acid to become more water soluble. The reaction is catalyzed by the enzyme UDP-
glucuronide transferase (UDPGUTF).

UDPGUTF
bilirubin + 2 UDP-glucuronate ------------> bilirubin diglucuronide
\
2 UMP + 2 Pi
bilirubin is excreted from the liver in bile. The intestinal bacteria deconjugate bilirubin
diglucuronide and convert bilirubin to urobilinogens. Some urobilinogen is absorbed by
intestinal cells and transported into the kidneys and excreted with urine. The remainder travels
down the digestive tract and is excreted as stercobilinogen, which is responsible for the color of
feces.
References:
Biochem BRS page 284
Goljan page 199 and 359

Factors Affecting Oxygen-hemoglobin dissociation curve

Reference : first aid

Left shift Right shift

↑in O2 affinity ↓in O2 affinity
↓ metabolic needs ↑metabolic needs
↓pCo2 ↑pCo2
↓T, ↓ H+, ↓ 2,3 DPG ↑T, ↑H+, ↑2,3 DPG
Fetal Hb (increased in beta thalasemia, Goljan Respiratory acidosis
page 198) High Altitude
CO (Carbon monoxide) Exersie
Bohr effect Sickel cell
Methaemoglobin ( ferrous (Fe2+), which is
normally is converted to the ferric (Fe3+) )

"CADET, face Right!" for CO2, Acid, 2,3-

DPG, Exercise and Temperature
5. Compare and contrast the structure of HbA, HbA2, HbF, HbS.

HBA-2α/2β globin chains (97% in adults)

HBA2-2α/2δ globin chain (2% in adults)
HBF-2α/2γ globin chains (1% in adults)
HBS-α2βS2 globin chains (HBS is a predominant hemoglobin in people with sickle cell anemia.
The alpha chain is normal. The disease-producing mutation exists in the beta chain, giving the
molecule the structure, a2bS2 (mutation in both beta chains!). People who have one sickle mutant
gene and one normal beta gene have sickle cell trait which is benign.

Case 3:
An 18-month-old boy presents with a painful left knee. His father reports that the child had large
bruises following immunizations at 12 months. He also states that his wife’s uncle had a similar
history of “easy bruising”. Physical examination reveals warm, tender, and swollen left knee.
Remainder of physical examination is normal.
Laboratory tests show: Platelet count: 330,000/mm3 (normal: 150,000 to 450,000/mm3),
Activated partial thromboplastin time (aPTT): 80 seconds (normal: 27-32 sec) Prothrombin time
(PT): 12 seconds (normal: 11-15 sec). The child’s plasma factor VIII activity is found to be 32%
of a normal pooled- plasma standard, which is designated as having 100% activity or the
equivalent of factor VIII.
Questions:

1. Describe the risk factors, etiology, pathogenic mechanism, altered morphology & physiology,
signs and symptoms, basis for signs and symptoms, differential diagnosis, screening and
confirmatory investigations including genetics, prognosis and complications of hemophilia A
and B.
 Disease Hemophilia A
Hemophilia B
Etiology A: hereditary (X-linked recessive)  30% new mutations
B: hereditary (X-linked disorder)
Pathogenesis A: deficiency of factor VIII  increased PTT (Intrinsic pathway)
B: deficiency of factor IX  increased PTT (intrinsic pathway)
Signs and Easy bruising, massive hemorrhage after trauma or operative procedures
Symptoms Recurrent bleeds into the joints (hemarthroses)
Petechia is characteristically ABSENT
Investigation Normal PT time; Prolonged PTT
Treatment Infusion of recombinant factor VIII; infusion of recombinant factor IX
Complication 15% of most severely affected patients, replacement therapy is complicated
by the development of neutralizing antibodies against factor VIII

2. Describe the mechanism of coagulation of blood by both intrinsic and extrinsic pathways.

The coagulation pathways consists of 3 portions, the extrinsic, the intrinsic which finally
converge into a common pathway.
The extrinsic pathway is activated by factors extrinsic from the vessels in the blood, therefore
when tissue is damaged, coagulation factors from these tissues activate the extrinsic pathway.
The extrinsic pathway is mediated by Factor VII.
The intrinsic pathways is activated by damage to the blood itself or the exposure of blood to
collagen which are in the vessel walls. The intrinsic pathway is mediated by Factors XII, XI, IX
and VII.
The converged common pathway involves X, V, II and I. Of which Factor II (thrombin) is the
most important due to the activation of many other pathways.

Remember PT tests for extrinsic and PTT tests for intrinsic.

Diagram:
3. Explain how the following laboratory tests help in distinguishing the common causes for
bleeding: activated partial thromboplastine time, clotting time, bleeding time, Prothrombin time
and platelet count.

Clotting time is the time required for a sample of blood to clot in vitro under standard
conditions.

Bleeding time is the time it takes for a standardized skin puncture to stop bleeding.

Platelet count is part of the CBC and can give information about disorders involving low or high
platelet levels. Normal platelet levels in adults are 150,000 – 400,000 / mm3

Activated partial throboplastin time (aPPT) measures the intrinsic and common coagulation
pathway and is prolonged when there are reduced levels of factors XII, XI, VIII, IX, X, V, II
and I activity. With a prolonged aPTT, these factors can be present in lower concentrations or
present in normal concentrations being actively inhibited by other molecules. The aPTT is also
sensitive to the presence of heparin bound to antithrombin and used to monitor the effects of
unfractionated heparin.

Prothrombin time (PT) measures the extrinsic and common coagulation cascade and is
prolonged when there are reduced levels of factors VII, X, V, II and I activity. PT is used to
monitor warfarin. Because all vitamin K-dependent factors (II, VII, IX, X, protein C and protein
S) are lowered by warfarin, eventually the aPTT will be prolonged too, but since factor VII has
the shortest half-like the PT is prolonged initially.

Disorder Platelet Bleeding PT aPTT

count time
Thrombocytopenia   - -
Hemophilia A or B - - - 
Von Willebrand’s disease -  - - or 
DIC    
Vitamin K deficiency - -  
Bernard-Soulier disease   - -
Glanzmann’s -  - -
thrombasthenia

4. Determine the assessment of risk of carrier state in a family with sickle cell disease. Solve
problems related to recurrence risk in a family with history of sickle cell anemia (autosomal
recessive).

Just use pedigrees and punnett squares on all possible combinations. Because the disease is
inherited in an autosomal recessive fashion, an individual needs two alleles for the disease to be
present and one allele for the carrier state.

Examples:
Both parents have sickle disease - ss crossed with ss = 100% chance of sickle cell disease.
One parent sickle cell disease, one carrier  - ss crossed with Ss = 50% disease 50% carrier
and so on -   ss x SS = 100% carriers
Ss x Ss = 25% disease 25% unaffected 50% carriers
Ss x SS = 50% unaffected 50% carriers
SS x SS = 100% unaffected

5. Based on pedigree analysis, differentiate between X-linked, autosomal recessive and

autosomal dominant disorders.

Autosomal dominant

Autosomal Recessive

X-linked

6. Describe the role of vitamin K in blood clotting.

Vitamin K is an extremely important aspect of the clotting of blood. Clotting factors II, VII, IX
and X are vitamin K dependent, which means that they need vitamin K as a cofactor for the
gamma-carboxylation of specific glutamic acid residues that make it possible for calcium
binding and allowing the coagulation cascade to occur. Protein C and S are also vitamin K
dependent but are opposite from the clotting factors in that they are anticoagulant proteins that
help balance the bodies clotting and clot degradation functions. Warfarin functions by
antagonizing the action of vitamin K retarding the action of the clotting factors.

Case 4:
A 7-year-old African American girl came with swelling in the lower jaw on the left side for the
past 2 months. Physical examination revealed a solitary, diffuse swelling measuring
approximately 6cm×5cm in size on the left side of the mandible. The surface of the swelling
appeared smooth, stretched, and erythematous. On palpation, it was firm in consistency, tender
and fixed to the underlying structures. The left submandibular lymph nodes were enlarged, firm
and fixed.
The laboratory investigations revealed: Increased total white blood cell count; Negative HIV test
and elevated serum alkaline phosphatase. Histopathological section of the enlarged left
submandibular lymph node showed dysplastic cells arranged in sheets with scanty stroma.
Lymphocytes were large and round with scanty cytoplasm and increased nuclear to cytoplasmic
ratio. Many abnormal and normal forms of mitoses were evident. Numerous macrophages within
the tumor tissue gave a characteristic "starry-sky appearance". Cytogenetic testing revealed
t(8;14) aberration. The child was diagnosed to have Burkitt’s lymphoma.
Questions:

1. Describe the risk factors, etiology, pathogenic mechanism, altered morphology & physiology,
signs and symptoms, basis for signs and symptoms, differential diagnosis, screening and
confirmatory investigations including immunophenotyping and cytogenetics, prognosis, and
complications of: i) Follicular lymphoma and ii) Burkitt’s lymphoma.

Follicular Lymphoma
Ages Affected: 40-60- Male and Female equal

Translocation: 14; 18 – this will turn on the BCL2 gene to block apoptosis pathway

Markers: CD 19, CD20,BCL 6 CD 10, BCL2

Presents with: Painless lymphadenopaty that can progress beyond the nodes to
marrow and spleen or become a diffuse large B cell Lymphoma which has a poor prognosis

INDOLENT and DIFFICULT TO CURE

HISTO: Looks like normal germinal centers with less mitosis. Evidence of contours
and course nuclear chromatin

Survival and prognosis: Median survival is 10 years but can range from anywhere
from 1 yr to 20 yrs with some never needing treatment. 5 yr survival rate is 22%

BURKITT’S LYMPHOMA
Ages : Adolescents and young adults

Translocation: 8;14 – this will move the cmyc gene next to the heavy chain Ig gene

Markers: CD 19,CD20, CD 10, IgM

Presents with: Is tied to an infection with the EBV. -involves a growth along the jaw
line or other facial bone ( endemic form ( seen in Africa)) or iliocecal jxn (sporadic form) both of
which are extremely fast growing and responsive to chemo.

HISTO: Starry Sky appearance with uniform round nuclei and 2-5 nucleoi, with a
high rate of division

Survival and Prognosis: treatment with rituximab has an 8 yr survival rate of 91%.
BL. Responds well to chemo and is cureable

2. Describe the immunology of blood transfusion reactions.

ABO Blood Groups:

According to ABO blood system, there are 4 different types of blood groups:
Blood Group Antigen on RBC Anti-IgM in Comment
plasma*
A A antigen Anti-B-IgM
B B antigen Anti-A-IgM
AB A and B antigen No Anti-IgM Universal recipient
O Neither A nor B Both Anti-A-IgM Universal donor
antigen and Anti-B-IgM

*Note: Common gut bacteria bear antigens that are similar or identical to blood group antigens.
This results in formation of antibodies to these antigens in individuals who do not bear a
corresponding antigen on their RBC. (Simply put: An individual with Group A blood type who
has never been exposed to Type B blood still has Anti-B-IgM due to an antigen identical/similar
to RBC B antigen present on gut bacteria).
This accounts for the immediate agglutination response that occurs when an individual is
presented with incompatible blood transfusion. The outcome is detrimental leading to
hemolysis, renal failure, shock and even death.

Rh Antigen:
Some people also have Rh antigen on the surface of their RBCs
Rh+: → have Rh antigen on RBC surface→no Anti-Rh-IgG antibodies
Rh-:→ no Rh antigen on RBC surface→can produce Anti-Rh-IgG antibodies if exposed to blood
of Rh+ invidiual. Typical example is an Rh- mother giving birth to Rh+ child. This exposure
often occurs during birth itself resulting in mom making anti Rh IgG that can cross placenta
during subsequent pregnancy causing hemolytic disease of the newborn (the next Rh+ child at
risk!)

Note: Anti-AB antibodies (IgM) do not cross placenta

Anti-Rh antibodies (IgG) cross placenta
3. What is meant by “chromosomal translocation”? Illustrate this in chronic myeloid leukemia
(CML), acute myeloid leukemia (AML), Follicular lymphomas and Burkitt’s lymphoma.

Chromosomal translocation is a transfer of chromosome parts between two nonhomologous

chromosomes; translocations can be balanced or unbalanced.

Chronic myeloid leukemia (CML): t(9;22 )translocation of the ABL proto-oncogene. ABL
fuses with the break cluster region (BCR) on chromosome 22 (BCR-ABL fusion gene).
Chromosome 22 with the translocation is called the Philadelphia chromosome.

Acute myeloid leukemia (AML): In acute promyelocitic leukemia (M3) there is a t(15;17)
translocation

Follicular lymphomas: t(14:18)

Burkitt’s lymphoma: A translocation that puts the C-myc oncogene next to a very active
promoter such as an immunoglobulin promoter. t(8;14), t(8;22), t(8;2)

GIT

Case 1
1. Describe etiology, pathogenesis, histopathology, clinical features and complications of peptic
ulcer disease.

Gastric Ulcer (25% of ulcer cases) Duodenal Ulcer (75% of ulcer cases)

Etiology 80% of cases caused by H.pylori 90-95% of cases caused by H.pylori

- NSAIDs

Pathogenesis Defective mucosal barrier due to Defective mucosal barrier due to H.pylori
H.pylori making it more susceptible making it more susceptible to acid;
to acid; muscosal ischemia, bile increased acid production
reflux, delayed gastric emptying

Histopathology Gross: clean, “punched out” margins unlike the raised/irregular margins of
carcinoma
Histo: Four layers in sequence are noted in histologic sections of ulcers

1. necrotic debris
2. inflammation with a predominance of neutrophils
3. granulation tissue (repair tissue)
4. fibrosis
 Clinical Features Epigastric pain exacerbated by Epigastric pain relieved by eating (weight
eating (weight loss) gain)

Complications G.I. bleeding (most common) G.I. bleeding (most common)

Perforation Perforation
Recurrence Recurrence
Patients with H.pylori associated Gastric outlet obstruction, pancreatitis
ulcer have increased risk of gastric Duodenal ulcers are never malignant
malignancy

2.Describe the histology of gastric mucosa.

Innermost layer
– Mucosa
o Epithelium: Secretory & Absorptive = simple columnar with no
goblet cells
o Lamina propria: connective tissue w/ capillaries, gastric glands, GALT
-> IgA
o Muscularis mucosa: thin, smooth muscle layer (facilitates discharge of
secretions from glands)
– Submucosa
o Loose connective tissue with large blood vessels and mucus-secreting
glands
o Meissner’s Plexus (intrinsic gut motility - 1)
- Muscularis Externa
o 2 layers: inner circular and outer longitudinal
o Fxn: controls lumen size and responsible for peristalsis
o Auerbach’s Plexus (second network of neuronal ganglia, intrinsic gut
motility -2, is located between the two layers of muscularis externa)
- Serosa
o Mesothelium and loose connective tissue
o Surrounds each intestinal loop and then doubles to form the mesentery
within which run blood and lymphatic vessels.

Note:
- all GI smooth muscle is connected by gap jxns
- extrinsic autonomic innervation: parasympathetic and sympathetic
- Sensory fibers go with PNS and mediate visceral reflexes, and hunger, rectal
fullness
- Visceral pain fibers go with SNS (excessive contraction/ distention of the
smooth muscle) and is referred to the body dermatome
More histology….

The stomach has three distinct histological areas:

Cardia
Body/Fundus
Pyloric antrum

Gastric pits
- deep invaginations that line the inner surface of the stomach, are closely
spaced
- lined by mucous-producing cells
- penetrate into the thickness of the mucosa and extend to accept the openings
of gastric glands
Gastric glands (5 million glands in stomach, secrete 2 L fluid a day)
- composed of the following cells: Parietal cells, Chief cells, mucous neck cells,
EE cells, and stem cells.
- Glands of the cardiac region have no Chief cells and only a few parietal cells
- Glands of the pyloric region are very deep, coiled, and possess no Chief cells
and only a few parietal cells, contain mainly mucous cells
- Glands of the fundic region possess all five cell types (many Chief cells and
Parietal cells), extend into the muscularis mucosa, glands are very tightly packed
*neither cardiac nor pyloric glands have chief cells
-Surrounded by an extensive capillary network to remove the large amount of
HCO3- produced while H+ is secreted

Mucus-secreting cells
- located on the inner surface of the stomach, in the pit and in the neck, the
transitional region between pits and glands
- surface mucus: neutral glycoproteins
- neck mucus: acidic glycoproteins
- in cardiac and pyloric regions, mucus cells are the major cell type in glands

Parietal cells
- located in the upper regions of gastric glands
- have numerous elongated tubulovesicles (deep invaginations of the apical
surface) that upon activation fuse with the cell membrane and provide the
increased surface area required for additional H+/K+ ATPase for HCl pxn. By
doing this, they increase the number of microville that project into the
intracellular canaliculi.
- Are larger than Chief cells

Chief cells
- located deep in the deep aspect of fundic glands.
- secrete pepsinogen stored in granules, have a granular appearance

Enteroendocrine cells
- diffuse neuroendocrine system (paracrine)
 Region Major Mucosal cell Function of Surface Mucosal
Characteristics types at surface Cells
Body and Rugae: shallow Mucus cells Mucus; form protective layer
Fundus pits; deep glands (surface) against acid; tight junctions
between these cells
contribute to the acid barrier
of the epithelium

Chief cells Pepsinogen and lipase

(base) precursor

Parietal cells HCl and Infrinsic factor

Enteroendocrine Peptide hormones

(EE) cells
Pylorus Deep pits; shallow, Mucous cells Same as above
branched glands Parietal cells Same as above
EE cells High [ ] Gastrin

Mention the functions of different cells of gastric mucosa.

Cell type Secretion Action of secretory Stimulus for Inhibitors of

product secretion secretion
Parietal HCl Kills pathogens Gastrin Low pH inhibits
(oxyntic) Activates Pepsinogen ACh (from X) by inhibiting
cells to Pepsin Histamine gastrin)
*Body/Fundus Prostaglandins
Chyme in
duodenum (via
GIP and secretin)
Intrinsic factor Vit. B12 absorption in
ileum
Chief cells Pepsinogen Converted to pepsin ACh (from X) H+ (via
*Body/Fundus (zymogen) by ↓pH and pepsin Gastrin somatostatin)
(autocatalytic) HCl
Digests up to 20% of
proteins
G cells Gastrin ↑HCl secretion -Small H+ (via
*Antrum/ (Parietal cells) peptides, aa, somatostatin)
Pylorus ↑Pepsinogen Ca2+ in
secretion lumen of
(Chief cells) stomach
↑histamine secretion -X (via GIP)
 by ECL cells -Stomach
distention
Mucous Mucus Forms gel on mucosa ACh (from X)
cells to protect mucosa
*Entire from HCl and pepsin;
stomach traps HCO3- to help
neutralize acid.

3. Describe the cellular mechanism of gastric acid secretion.

Physiology

Gastric acid is produced by parietal cells (also called oxyntic cells) in the stomach. Parietal
cells contain an extensive secretory network (called canaliculi) from which the gastric acid
is secreted into the lumen of the stomach. These cells are part of epithelial fundic glands in
the gastric mucosa. The pH of gastric acid is 2 to 3 in the human stomach lumen, the acidity
being maintained by the proton pump H+/K+ ATPase. The parietal cell releases bicarbonate
into the blood stream in the process, which causes a temporary rise of pH in the blood,
known as alkaline tide.

The resulting highly acidic environment in the stomach lumen causes proteins from food to
lose their characteristic folded structure (or denature). This exposes the protein's peptide
bonds. The chief cells of the stomach secrete enzymes for protein breakdown (inactive
pepsinogen and renin). Gastric acid activates pepsinogen into pepsin–this enzyme then
helps digestion by breaking the bonds linking amino acids, a process known as proteolysis.
In addition, many microorganisms have their growth inhibited by such an acidic
environment which is helpful to prevent infection.

Secretion

Gastric acid secretion happens in several steps. Chloride and hydrogen ions are secreted
separately from the cytoplasm of parietal cells and mixed in the canaliculi. Gastric acid is
then secreted into the lumen of the oxyntic gland and gradually reaches the main stomach
lumen.

Chloride and sodium ions are secreted actively from the cytoplasm of the parietal cell into
the lumen of the canaliculus. This creates a negative potential of -40 mV to -70 mV across
the parietal cell membrane that causes potassium ions and a small number of sodium ions
to diffuse from the cytoplasm into the parietal cell canaliculi.

The enzyme carbonic anhydrase catalyses the reaction between carbon dioxide and water
to form carbonic acid. This acid immediately dissociates into hydrogen and bicarbonate
ions. The hydrogen ions leave the cell through H+/K+ ATPase antiporter pumps.

At the same time sodium ions are actively reabsorbed. This means the majority of secreted
K+ and Na+ ions return to the cytoplasm. In the canaliculus, secreted hydrogen and chloride
ions mix and are secreted into the lumen of the oxyntic gland.
There are three phases in the secretion of gastric acid:

1. The cephalic phase: 30% of the total gastric acid to be produced is stimulated by
anticipation of eating and the smell or taste of food.
2. The gastric phase: 60% of the acid secreted is stimulated by the distention of the
stomach with food. Plus, digestion produces proteins, which causes even more
gastrin production.
3. The intestinal phase: the remaining 10% of acid is secreted when chyme enters the
small intestine, and is stimulated by small intestine distention.

Regulation of secretion

Gastric acid production is regulated by both the autonomic nervous system and several
hormones. The parasympathetic nervous system, via the vagus nerve, and the hormone
gastrin stimulate the parietal cell to produce gastric acid, both directly acting on parietal
cells and indirectly, through the stimulation of the secretion of the hormone histamine
from enterochromaffine-like cells (ECL). Vasoactive intestinal peptide, cholecystokinin, and
secretin all inhibit production.

The production of gastric acid in the stomach is tightly regulated by positive regulators and
negative feedback mechanisms. Four types of cells are involved in this process: parietal
cells, G cells, D cells and enterochromaffine-like cells. Besides this, the endings of the vagus
nerve (CN X) and the intramural nervous plexus in the digestive tract influence the
secretion significantly.

Nerve endings in the stomach secrete two stimulatory neurotransmitters: acetylcholine

and gastrin-releasing peptide. Their action is both direct on parietal cells and mediated
through the secretion of gastrin from G cells and histamine from enterochromaffine-like
cells. Gastrin acts on parietal cells directly and indirectly too, by stimulating the release of
histamine.

The release of histamine is the most important positive regulation mechanism of the
secretion of gastric acid in the stomach. Its release is stimulated by gastrin and
acetylcholine and inhibited by somatostatin.
4. Compare and contrast where stomach contents from a perforation of the posterior, versus
the anterior, stomach wall will initially accumulate.
 Anterior perforation

-peritoneal cavity- patient present with sudden, intense, continuous epigastric pain that spreads
rapidly throughout the abdomen often becoming prominent in the right lower quadrant and at
times referred to one or both shoulders
 Posterior perforation
- Pancreas- pain may be intense, persistent and usually referred to the back
5. Describe the blood supply of stomach. List the blood vessels which may be eroded in
ulceration of the posterior wall, lesser curvature and greater curvature of the stomach.
(Anatomy BRS pg 206, First Aid pg 306)

Arteries Area supplied

1. Left gastric Supplies derivatives of foregut (lower esophagus,

2. Common hepatic stomach, proximal half of the duodenum, liver,
3. Splenic arteries gallbladder, pancreas) and spleen
Branch off the CELIAC TRUNK, which
arises from the front of the ABDOMINAL
AORTA

Splenic via the short gastrics and left gastro- Fundus and the greater curvature of the stomach
omental/gastroepliploic

Common hepatic artery  gastroduodenal Greater curvature of stomach

artery  right gastro-omental/
gastroepliploic

Common hepatic artery  right gastric Runs to the pylorus and the lesser curvature of the
artery stomach and anastomoses with the left gastric artery

Left gastric Lesser curvature of the stomach and the lower

esophagus

FYI

Gastroduodenal from the common hepatic Upper duodenum and pancreas

via the superior pancreaticoduodenal

Splenic via the short gastrics and left gastro- Spleen

omental

Proper hepatic Liver, gallbladder, and biliary tree

 Ulceration Site Arteries Eroded

posterior wall Splenic artery

lesser curvature Left gastric

Right gastric  common hepatic artery

greater curvature of the stomach Left gastro-omental/ gastroepliploic and short gastrics 
splenic

Right gastro-omental/ gastroepliploic  gastroduodenal 

common hepatic

Gastric ulcers may perforate into the lesser sac and erode the pancreas and the splenic artery causing
fatal hemorrhage

Duodenal ulcers may erode the pancreas or the gastroduodenal artery (branch off the common
hepatic artery) causing burning and cramping epigastric pain, and are three times more common than
gastric ulcers

Case 2
1. Compare and contrast the following aspects of ulcerative colitis and Crohn’s
disease: Etiology, pathogenesis, morphology, organs involved, serology, clinical
features and complications.
Crohn’s disease Ulcerative colitis
Etiology -possible: disordered response to -possible: autoimmune
intestinal bacteria (antigenic -No gender preference
trigger; ie. mycobacterium -More common in Caucasian
paraTB) -14-38yrs
-No gender preference -lower incidence in smokers
-Caucasian, Jewish and other nicotine users
-smoking is risk factor
-most cases: 11-35yrs
Pathogenesis Genetic Genetic
-HLA-DR7 and DQ4 (30% of N. -HLA-DRB1
American males) -defective IL-23R; normally
-NOD2 protein: in Paneth cells; produces IL-17
plays a role in host response to Immunologic
bacteriaif defective, chronic -CD4+: 1° damaging agents
infections estbinflamm
 -defective IL-23R; normally
produces IL-17
Immunologic:
-CD4+: 1° damaging agents
-TNF (pathogenic role)
Gross -thick bowel wall (due to
morphology inflamm, submucosal fibrosis)
and narrow lumenobstruction
-aphthous ulcers in bowel (early)
-deep linear ulcers w/
cobblestone pattern
-linear fistulas, fissures
-fat creeping around serosa
Microscopic -noncaseating granulomas (60%)
morphology w/in the inflammatory infiltrate
of the muscle layer in LI
-lymphoid aggregates
-deep, linear ulcers
-dysplasia or cancer less likely
Organs -any portion of the GI tract
involved/ (usually terminal ileum and
Extent colon)
-skip lesions, rectal sparing
Transmural
Serology -anemia
Clinical -recurrent right lower quadrant
features colicky pain (obstruction)
w/diarrhea
-blood diarrhea only w/colon
involvement (fistulas; abscesses)
-apthous ulcers in mouth (open
sore; canker sore)
-outside GI: erythema nodosum,
sacroiliitis (inflamm of sacroiliac
joint—d/t HLA-B27
asscankylosing spondylitis),
gangrene, iritis (inflamm of iris),
migratory polyarthritis
Radiograph: “string” sign in
terminal ileum from luminal
narrowing by inflammation,
fistulas
Complications -strictures, fistualas of intestine
-perianal disease
-diffuse ulceration of mucosal
surface w/islands of inflamed
mucosa (pseudopolyps)
-hemorrhage
-ulcers and crypt abscesses
containing neutros
-no granulomas
-dysplasia or cancer may be
present
-colitis=colon inflammation
-continuous colonic lesions
always w/rectal involvement
(no other part of GI)
Mucosal and submucosal
-anemia
-p-ANCA antibodies in >45%
-recurrent left-sided abdominal
cramping w/bloody diarrhea
and mucus
-fever, tenesmus, weight loss
-outside GI: primary sclerosing
cholangitis (chronic liver
disease d/t
progressive inflamm and
scarring of bile ducts
inflamm impedes the flow
of bile to the gut); erythema
nodosum, gangrene, HLA-B27
positive arthritis
Radiograph: “lead pipe”
appearance in chronic disease
-Malnutrition
-toxic megacolon (hypotonic
 -malabsorption nutritional
depletion macrocytic anemia
due to vitB12 def
-calcium oxalate renal calculi (↑
reabsorption of oxalate through
inflamed mucosa)
and distended bowel)
-colorectal adenocarcinoma
(risk factors: early onset,
duration of disease >10yrs)

2. Determine the lymph nodes that may drain tumors in various parts of the small and large
intestine.

Area of body 1° lymph node drainage site

- Stomach Celiac

- Duodenum, Jejunum Superior mesenteric

- Sigmoid Colon Colic  inferior mesenteric

- Rectum (lower part), Internal iliac

anal canal above pectinate line

- Anal canal below pectinate line Superficial inguinal

From there it goes to the Thoracic Duct then to Left Subclavian Vein
3. Compare and contrast secretory and osmotic diarrheas. Describe the electrolyte and acid-base
imbalances in diarrhea.
Secretory
- increase in the active secretion, or inhibition of absorption
- little to no structural damage.
- diarrhea intestinal fluid secretion is isotonic with plasma
- continues even when there is no oral food intake.
- Ex. cholera
Osmotic
- too much water is drawn into the bowels.
- Diarrhea stops when offending agent (e.g. milk) is stopped.
- Ex. malabsorption (e.g., pancreatic disease or celiac disease), osmotic laxatives, lactose
intolerance
Normal anion gap acidosis: is an acidosis that is not accompanied by an abnormally increased
anion gap. Seen in diarrhea.
Anion gap = ([Na+]+[K+]) − ([Cl−]+[HCO3−])
Electrolyte Profile in blood: ↓ HCO3-, ↑ Cl-, ↓ K+, ↑ Na+
Drop in HCO3− is compensated by an increase in Cl− & the drop in K+ is compensated by a
increase in Na+; therefore, anion gap is normal. It is acidosis because you are losing HCO3-.

4. Explain where free air in the peritoneal cavity can accumulate and
its clinical importance.

Free air is seen in Sub-diaphragmatic space the uppermost area in the peritoneal
cavity

Bowel gas is usually confined to the lumen of the gut, but owing to a variety of
pathological processes, gas may escape into the peritoneal cavity. It is important to
recognise the radiographic signs of pneumoperitoneum because bowel perforation
usually requires surgical intervention.

Caused by :

Perforated peptic ulcer

Bowel obstruction
Ruptured diverticulum
Penetrating trauma
Ruptured inflammatory
bowel disease
(e.g. megacolon)
Necrotising enterocolitis/Pneumatosis coli[2]
Bowel Cancer
Ischemic bowel
Steroids Frontal chest X-ray. The air bubble
After laparotomy below the right hemidiaphragm (on the
After laparoscopy left of the image) is a
Breakdown of a surgical anastomosis pneumoperitoneum.
Bowel injury after endoscopy
Peritoneal dialysis

5. Describe the development of an ileal (Meckel) diverticulum

Directly from Goljan

1. Meckel diverticulum
a. Vitelline (omphalomesenteric) duct remnant
 (1) True diverticulum
 (2) Mnemonic: 2 inches long, 2 feet from ileocecal valve, 2% of
population, 2% symptomatic
b. Contains pancreatic rests and heterotopic gastric mucosa
 Increase the risk for bleeding

Newborn with fecal material in umbilical area: persistence of

vitelline duct

c. Clinical findings
  (1) Newborn finding
 Fecal material in umbilical area due to persistence of vitelline
duct
 (2) Bleeding (most common finding)

Meckel diverticulum: bleeding most common complication

 Common cause of iron deficiency in newborns and young

children
 (3) Diverticulitis
 Clinically impossible to distinguish Meckel diverticulitis from
appendicitis

Meckel diverticulitis: mimics acute appendicitis

d. Diagnosis
 99mTc nuclear scan identifies parietal cells in ectopic gastric
mucosa.
e. Treatment is surgery.

Case 3
1. Describe the digestion and absorption of lipids in the gastrointestinal tract.
DIGESTION
Dietary Lipids: Triglycerides, Cholesterol, Phospholipids
Stomach (≈10% of lipid digestion)

1. Mixing breaks lipids into droplets→↑ surface area for digestion by pancreatic enzymes
 2) Lingual & gastric lipases-initiate lipid digestion by hydrolyzing a very small about of
TAGs into glycerol and FAs.
3) Cholesystokinin (CCK) slows gastric emptying →slows delivery of lipids from stomach
to duodenum allowing adequate time for digestion and absorption in intestine
Small Intestine (MOST of lipid digestion occurs here)

1. Bile salts emulsify lipids in the SI→↑ surface area for digestion
2. Pancreatic Lipases (secreted by pancreas) hydrolyze lipids
o Pancreatic Lipase: TAG→Monoglyceride+2 FAs
o Cholesterol Ester: Cholesterol Ester→Cholesterol+FA
(it also hydrolyzes ester linkages of TAGs yielding glycerol)
- Pholspholipase A2: Pholpholipid→Lysolecithin+FA
3) These hydrophobic end products of lipid digestion (all except for glycerol which is
hydrophilic) must be solubilized in micelles
Micelle:core-hydrophobic products of lipids digestion;exterior- bile salts-amphiphatic
ABSORBTION

1. Micelles come into contact with absorptive surface of epithelial cells→their hydrophobic
content diffuses into the cells.
2. In the intestinal cells, the products of lipid digestion are reesterified to TAGs, cholesterol
esters, phospholids and form chylomicrons
3. Chylomicrons are transported out of intestinal cells by exocytosis. They are transferred to
lymph vessels and enter bloodstream via thoracic duct (do not enter blood stream directly
b/c they are too large to enter capillaries)

2. Explain how lactose is digested and absorbed in the gut. List all brush border
enzymes and their functions.
Lactose is a disaccharide composed of glucose and galactose. The small intestines
cannot absorb dissacharides therefore the -14 glycosidic bond must be broken down
by lactase at the brush border. Deficiency of lactase leads to lactose intolerance. The
undigested lactose is then metabolized by enteric bacteria which produce large
amounts of gases which lead to a range of abdominal symptoms such as cramps,
bloating, flatulence, etc… Furthermore, nonabsorbed lactose and water in the lumen of
the GI tract can cause osmotic diarrhea.
The brush borders of the intestinal lining are the site of terminal carbohydrate
digestions. Only monosaccharides are absorbed.
Enzyme Function

Maltase Maltose  glucose and glucose

Sucrase Sucrose  glucose and fructose

 Lactase Lactose  glucose and galactose

α -dextrinase Breakdown of dextrin to polymers of D-glucose

units linked by α-(1,4) or α-(1,6) glycosidic bonds

Peptidases Proteins  amino acids

Enterokinase Trypsinogen  trypsin (activates other pancreatic

proenzymes)

3) List the enzymes present in pancreatic juice and their role in digestion of lipid,
carbohydrate and proteins. Explain the role of cholecystokinin and secretin in
altering composition of pancreatic juice.

Carbohydrates:
Pancreatic alpha amylase acts on oligosaccharides and forms disaccharides.
Nucleic acids:
Pancreatic ribonucleases and pancreatic deoxyribonucleases form oligonucelotides and then
nucleosides and finally conversion into free bases, ribose and deoxyribose.
Protein:
Zymogens consists of trypsin, chymotrypsin, elastase and carboxypeptidases. These are the
active degradation enzymes, the inactive forms are secreted by the pancreas, trypsinogen,
chymotrypsinogen, proelastase and procarboxypedtidase. Trypsinogen is converted via brush
border enzymes (enterokinases) in the intestine into trypsin and converts other zymogens into
their active forms. A protective enzyme trypsin inhibitor protein is also secreted to prevent
activation of trypsin in the ducsts and pancreas.
Functions of the zymogens are as follows:
Trypsin – cleaves lysine and arginine residues
Chymotrypsin – cleaves large bulky aromatic residues
Elastase – cleaves glycine, alanine and serine residues
Carboxypedtidases – cleaves even smaller strands of protein into individual absorbable residues
Lipids:
Pancreatic secretions in charge of lipid digestion include pancreatic lipase, colipase and
phospholipase A, the latter two are also secreted in the inactive forms of procolipase and
prophospholipase A. These require activation via cleavage by trypsin.\
Pancreatic lipase and colipase - cleaves TAG
Phospholipase A – cleaves phospholipids\
Secretin and Cholecystokinin are GI hormones that are used to modify contents of the intestine.
Secretin is secreted by S cells in the duodenum in response to the acidic contents of the stomach.
Secretin increases HCO3- secretion on order to neutralize the acid from the stomach. CCK is
secreted by the I cells in the duodenum and the jejunum in response to increased levels or
proteins, nuclei acids and lipids. It increases the pancreatic secretions mentioned above as well as
reduce gastric emptying in order to increase the effectiveness for absorbtion.

4. Explain the surgical significance of "McBurney’s point".

A common surface projection of the appendix, which is one-third of the way up along a
line from the right anterior superior iliac spine to the umbilicus. If an open laparotomy is
preformed McBurney’s point is where a 2-3 inch incision would be made. A more
current method of appendectomy is laparoscopic, which involves three 0.25-0.5 inch
incisions.

5. Explain the surgical approach through the layers of the abdominal wall to
approach an inflamed appendix and the surgical significance of the muscle fiber
orientation.

Perform an open appendectomy starting with incision of the skin (No. 10 Blade). Next,
use an (Bovie) electrocautery to incise through the superficial (camper) and deep
(Scarpa) fasca. Now the external oblique aponeurosis is exposed and you want to split
the external oblique fibers bluntly using (Kelly) clamps or (Roux) retractors. Repeat this
splitting and retraction of the internal oblique muscles and the transversus abdominis
muscles to expose the transverasalis fascia and the peritoneum. Make a craniocaudal
incision in the pericardium with (Metzenbaum) scissors allowing access to the peritoneal
cavity. The importance of splitting the muscles along the length of the fibers is to
preserve the integrity of the abdominal wall and prevent incisional hernias occurring
later as complication of the procedure.

Case 4

1.Describe histological differences in different parts of esophagus. Describe the

structure and functions of upper and lower esophageal sphincters.

The esophagus consists of:

-mucosa - contains stratified non-keritinaized squamous cells, lamina propria, and
muscularis mucosa (smooth muscle)

-submucosa - mucous secreting glands and connective tissue)

-muscularis externa - this layer varies depending on the area of the esophagus. Upper
1/3 is skeletal muscle, middle 1/3 is mixed skeletal and smooth, bottom 1/3 is smooth
muscle.

-adventitia

UES – since it is part of the upper 1/3 of the esophagus, it consists of skeletal muscle
and is under conscious contol. Part of the inferior pharyngeal constrictor muscle. The
UES opens during swallowing to allow the bolus of food passage into the esophagus.
LES – ring of smooth muscle which opens into the cardia of the stomach. Remains
closed except during swallowing and protects from regurgitation of gastric contents back
into the esophagus.

2) Explain physiology of swallowing including stages, mechanisms involved, reflex arc,

esophageal pressure recordings and timings of opening and closure of upper/lower
esophageal sphincters.
Swallowing

It is coordinated in the medulla and travels via fibers in the glossopharyngeal and vagus nerves.
The sequence is:

1. The nasopharynx closes and breathing is inhibited.

2. The laryngeal muscles contract to close the glottis and elevate the larynx
3. Peristalsis begins in the pharynx and propels the food bolus toward the esophagus at the
same time, the UES relaxes and the food bolus enters
Esophageal Motility
Is based on slow wave contractions of oscillating membrane potentials as dictated by the
interstitial cells of Cajal. The Cajal cells are the pace maker of GI contraction and determine the
pattern of the action potentials. These slow waves are bring the membrane potential up to -40
mv. At the threshold, the calcium channels open, and the depolarization and contraction can
occur. Therefore the rate of slow waves will dictate the rate of action potentials and therefore
contraction. The number of action potentials/contractions will vary along the GI tract. It is
important to note that neural and hormonal input affect only the frequency of the action
potentials, not the frequency of slow waves.
Continuing from above, as part of swallowing, the UES relaxes and swallowed food enters the
esophagus. The primary peristaltic contraction creates an area of high pressure behind the food
bolus and moves the bolus along, constantly contracting behind it. A secondary peristaltic
contraction clears any remaning food in the esophagus. As the bolus approaches the LES, it
relaxes via vagally meditated VIP. From there the food bolus enters the stomach.
Just a note:
Depolarization of Circular muscle- leads to contraction of the ring of smooth muscle and a
decrease in DIAMETER
Depolarization of the Longitudinal Smooth muscle- leads to a decrease in LENGTH.

3. Describe the pathogenetic mechanism, morphology and, signs and symptoms of achalasia
and scleroderma (systemic sclerosis) involving esophagus.
Achalasia is the failure of the LES to relax d/t loss of Auerbach’s plexus, high LES opening
pressure combined with uncoordinated peristalsis. Barium swallow will show dilated esophagus
with an area of distal stenosis, bird’s beak appearance. Symptoms will be progressive dysphagia.
Systemic scleroderma is a systemic connective tissue disease of autoimmune origin causing an
overproduction of collagen. T cells accumulate in the skin and produce cytokines stimulating
collagen deposition especially from activation of fibroblasts. In the esophagus it can cause reflux
esophagitis complicated with narrowing of the esophagus, strictures (fibrosis). Also causes
decreased motility in the LES causing dysphagia and chest pain.

4. Describe the mechanism for development of megacolon (Hirchsprung’s disease).

Development of Hirchsprung’s is caused by failure of neural crest cells to migrate. It is
characterized by lack of ganglion cells in the enteric plexus, Auerbach’s and Meissner’s
plexuses, in a segment of the colon. This will present as dilation of the colon proximal to the
aganglionic segment with severe constipation.

5. Describe the boundaries of the inguinal triangle of Hesselbach and its clinical
significance.

The inguinal triangle is bounded by the rectus abdominus muscle medially, the inferior
epigastric vessels superior and laterally, and the inguinal ligament inferiorly. Clinically
significant because a direct inguinal hernia will protrude through the inguinal triangle.

6) Explain the difference between a direct and an indirect inguinal hernia.

INDIRECT INGUINAL HERNIA

 Goes INTO the INTERNAL INGUINAL RING, to the external ring and INTO the
scrotum
 Enters the internal ring lateral to the inferior epigastic artery
 Occurs in INFANTS due to the process vaginialis failing to close
 Follows the decent of testes and is covered by all 3 layers of spermatic fascia
DIRECT INGUINAL HERNIA

 Goes through the external superficial ring only

 Protrudes through abdominal wall medial to the inferior epigastric
 Covered only by external spermatic fascia
 Older men
MDs don’t Lie
Direct hernia- media to the IEA
Indirect hernia- lateral to the IEA

MALE GENITAL
Case 1
Q1. Describe the genetic basis, histopathological findings in the testis, clinical
features and the pathophysiological basis for the clinical features in a patient
with Klienefelter’s syndrome.
Genetic basis: caused by nondisjunction, XXY karyotype
Histophathological findings: testes are largely atrophic, hyalinized seminferous tubules
(due to fibrosis), loss of sertoli cells, increased number leydig cells (functionally
abnormal, as testosterone is decreased with increased LH and FSH)
Clinical features and pathophysiological basis: Infant has usually normal male external
genitalia at birth and diagnosis suspected in adolescence.
a. Atrophy of the seminiferous tubules: absence of spermatogenesis, infertility
 b. Primary hypogonadism (testosterone deficiency): female secondary sex characteristics
at puberty including gynecomastia, soft skin, and female hair distribution
c. Loss of sertoli cells: decreased inhibin  causes increased FSH (due to loss of negative
feedback with inhibin)  increased FSH causes increased synthesis of aromatase in
Leydig cells aromatase converts testosterone to estradiol  estradiol causes
feminization (decreased testosterone)
- increased LH (due to loss of negative feedback with testosterone)
d. Higher number of X chromosomes: associated with subnormal intelligence or mental
retardation

Q2 Describe the development of the testis, internal genitalia and external genitalia
in a male fetus.
The gonads are from three sources:
1) mesoderm
2) mesenchyme
3) primordial germ cells

Begins during the fifth week of life. A bulge in the middle of Mesonephros, gonadal
ridge, forms and gonadal cords grow into the mesenchyme. The medulla differentiates
into a testis. The SRY gene for the testis-determining factor (TDF) on the short arm of
the Y chromosome directs the development of the indifferent gonad into a testis. Fetal
testis produces Mullerian-inhibiting substance that suppresses the development of
paramesonephric (Mullerian ducts).
Primordial germ cells originate in the wall of the umbilical vesicle and migrate along the
dorsal mesentery of the gut to the gonadal ridges. During the sixth week the primordial
germ cells are incorporated into the gonadal cords and eventually differentiate into
sperm.
Testosterone stimulates the mesonephric ducts to form male genital ducts
Mesonephric ducts form:
- Ureter
- Seminal gland
- Ejaculatory duct
- Ductus deferens
- Efferent ductules and duct of epididymis
Urogenital sinus forms:
- urinary bladder
- Prostate
- Prostatic and penile urethra
- Bulbourethral glands

External genitalia are fully differentiated in the 12 th week. Proliferating mesenchyme

produces a genital tubercle and Labioscrotal swellings and urogenital folds develop on
each side. The genital tubercle elongates to form a primordial phallus. As the phallus
develops, the urethral folds fuse along the ventral surface of the penis and form the
spongy urethra.
Labioscrotal swellings fuse to form the scrotum (the line of fusion is the scrotal raphe).
Genital tubercle forms the glans of the penis.
The corpora cavernosa and and corpus spongiosum develop from mesenchyme in the
phallus.
(Before we were born, p. 173-183).

Q3(a) Describe histology of human testis.

1. The capsule of the testis contains three layers.

 Tunica vaginalis = mesothelium (outer layer)
 Tunica albuginea = dense regular collagenous CT
 Tunica vasculosa = thin layer of vascularized loose CT
2. The human testis has a lobular organization.
 The human testis is subdivided into approximately 250 lobules by septal extensions
from the tunica albuginea.
 Each lobule contains 1 to 4 seminiferous tubules embedded in a stroma of loose CT
(interstitial connective tissue) which contains blood and lymphatic vessels and
macrophages, but lacks typical fibroblasts and other loose CT cells.
 The Leydig endocrine cells are located in the interstitial CT.

3. Seminiferous tubules fill most of the volume in the testis.

 Seminiferous tubules consist of loops (no free ends).
 Seminiferous tubules are composed of a complex epithelium surrounded by
peritubular "connective" tissue (sometimes called lamina propria).
 Two major epithelial cell types occur in seminiferous tubules.
(1) Sertoli cells (sustentacular or supporting cells)
 form a simple tall columnar epithelium (this arrangement is usually not apparent due
to spermatogenic cells)
 have pale staining cytoplasm which is extensively branched and extends between the
spermatogeneic cells
 have relatively basally located nuclei which are predominately euchromatic with
prominent nucleoli
 attach to one another by zonula occludens

(2) Spermatogenic cells

 Spermatogenic cells are spherical until the later stages of sperm differentiation, then
become very elongated cells.
 Spermatogenic cells have pale cytoplasm and nuclei which are initially a mixture of
heterochromatin and euchromatin and become heavily heterchromatic during sperm
differentiation.
 Interconnected clusters of spermatogenic cells are enfolded by Sertoli cells.
 The spermatogonia which divide to produce the clusters of spermatogenic cells are
enfolded by the basal region of the Sertoli cells.
 Three clusters of spermatogenic cells (each at a different stage in spermatogenesis)
are typically observed in a given location at one time.
 The most mature clusters are located closest to the lumen of the seminiferous tubule.

Peritubular "connective" tissue (tunica propria or "lamina propria") surrounds each

seminiferous tubule.
 A thin basal lamina surrounds the epithelial components of each seminiferous tubule.
 3 to 5 layers of myoid cells (smooth muscle-like cells) surround the basal lamina.
 The myoid cells are interspersed with fine collagen fibers- Rhythmic contractions of
the myoid cells create peristaltic waves that help move spermatozoa and testicular
fluid through the seminiferous tubules to the excurrent duct system.

4. Interstitial connective tissue (stromal connective tissue) occurs between seminiferous

tubules in the testis.
 Testicular interstitial tissue resembles highly vascular loose CT with fine collagen
fibers and macrophages, but few or no typical fibroblasts occur.
  Interstitial cells of Leydig (Leydig cells) are distributed singly or in small clusters in
interstitial stromal tissue.
a. Leydig cells are large cells with pale vacuolated cytoplasm containing
extensive sER and occasional crystals of Reinke (refractile crystals of
unknown function).
b. Leydig cells have spherical nuclei with both euchromatin and heterochromatin
and distinct nucleoli.

Q3(b) Discuss the physiological functions of the Sertoli and Leydig cells.
Sertoli cells
 Secrete inhibin which inbibit FSH
 Secrete androgen binding protein (ABP) which maintains levels of testosterone
 Tight junctions between adjacent Sertoli cells form blood-testis barrier- isolate gametes
from autoimmune attack
 Support and nourish developing spermatozoa
 Regulate anti-mullerian hormone

Leydig cells
 Secrete testosterone

Q3(c) Explain the interrelationship between the Sertoli and Leydig cells and the importance of
this regarding male reproductive function

Source: Medical Physiology: Principles for Clinical Medicine, 3rd Edition

 Leydig cells do not have FSH receptors, but FSH can increase the number of developing
Leydig cells by stimulating the production of growth stimulators from Sertoli cells, which
subsequently enhance the growth of the Leydig cells.
 In addition, androgens stimulate the proliferation of developing Leydig cells. Estrogen
receptors are present on Leydig cells and reduce the proliferation and activity of these
cells.
  Leydig cells have LH receptors, and the major effect of LH is to stimulate androgen
secretion via a cAMP-dependent mechanism. The main product of Leydig cells is
testosterone, but two other androgens of less biological activity, dehydroepiandrosterone
(DHEA) and androstenedione, are also produced.
 The Sertoli cell is incapable of producing testosterone but contains testosterone receptors
as well as FSH-dependent aromatase.
 The Leydig cell does not produce estradiol but contains receptors for it, and estradiol can
suppress the response of the Leydig cell to LH.
 Testosterone diffuses from the Leydig cells, crosses the basement membrane, enters the
Sertoli cell, and binds to ABP. As a result, androgen levels can reach high local
concentrations in the seminiferous tubules.
 Testosterone is obligatory for spermatogenesis and the proper functioning of Sertoli cells.
In Sertoli cells, testosterone also serves as a precursor for estradiol production. The daily
role of estradiol in the functioning of Leydig cells is unclear, but it may modulate
responses to LH.

Case 2
Q1 Risk Factors For Testicular Tumours

1.     White, Family history (Klinefelter’s Syndrome - XXY)

2.     Cryptorchidism increases the risk of germ cell tumors (especially intra-abdominal cryptorchid testis)

3.     Testicular feminization = deficiency of androgen receptors, fetal DHT and Testosterone are unable to function,
Mullerian structures absent due to MIF, external genitalia is female, vaginal ends in a blind pouch

4.     Trauma and radiation

5.     Trimodal age distribution

   Q2 Describe histopathological findings in the following tumors of testis:  Seminoma,

choriocarcinoma and teratoma.

Testicular Germ Cell Tumors (95%) Testicular non-germ cell tumors (5%)
Seminoma = malignant, painless, homogenous Leydig cell = reinke crystals, androgen
testicular enlargement, MOST COMMON testicular producing, gynecomastia, precocious
tumour affecting males 15 – 35. Large cells in puberty
lobules with watery cytoplasm and a “fried egg”
appearance similar to koilocytes and  
oligodendroglioma, radiosensitive, late metastasis,
excellent prognosis Sertoli cell  = sex cord stroma, benign,
visible calcifications, advanced
Choriocarcinoma = malignant, increased hCG, may spermatogenesis
ave gynecomastia, disordered syncytiotrophoblastic
and cytotrophoblastic elements, hemorrhagic necrosis  
with sheets of small cuboidal cells with multiple dark
pleiomorphic nuclei, hematogenous metastasis to the Testicular lymphoma = COMMON in
LUNGS older men

Teratoma = from somatic cell lines, multiple tissue

 types (along any cell lineage – skin, cartilage, bone,
epithelium), unlike in females, a mature teratoma is
MALIGNANT

Embryonal carcinoma = painful, worse prognosis,

may be associated with an increase in AFP, hCG,
large angry looking hyperchromatic nuclei

Yolk sac = common in children up to 3 years,

increasedAFP, Schiller-Duval bodies (resemble
glomeruli, cancer cells around a vessel)

Q3 Explain the developmental mechanism responsible for the formation of

hypospadias and epispadias.
Epispadias: the spongy urethra opens as a groove on the dorsum of the penis
Hypospadias: the urethra opens on the underside of the penis because of a failure of the
two urethral folds to fuse completely. As a result, more urine exits from the underside of
the penis than from its tip
Q4 Describe histology, nerve supply, blood supply and lymphatic drainage of penis.
Histology:
Prepuce (skin above the -retractile fold of skin that contains connective tissue with
foreskin) smooth muscle on its interior
Corpus cavernosa (of -covered by a resistant layer of dense CT (tunica albugenia)
the penis and urethra) -composed of erectile tissue (large # of venous spaces lined
with endothelial cells and separated by CT fibers and smooth
muscle cells)
Penile urethra -most lined by pseudostratified columnar epithelium
-glans penis: becomes stratified squamous epithelium
-mucus-secreting glands of Littre throughout

Nerve supply: S2-S4pudendal nervedorsal nerve of penisruns between the two

layers of the suspensory ligament of the penisinnervates the skin, prepuce and glans
-parasympathetics (arise from the pelvic splanchnic nerves)erection
-sympatheticsejaculation
Blood supply: abdominal aortacommon iliac vesselsinternal iliacinternal pudendal
(runs over superior aspect of the perineal membrane)
first gives off the artery of the bulbsupplies the bulb of the penis and the
bulbourethral glands
deep artery of the penis (terminal branch of internal pudendal)runs through
the center of the corpus cavernosum of the penis and supply its erectile tissue
dorsal artery of the penispasses through suspensory ligament of the
penissupplies the glans and prepuce

Lymphatic drainage: superficial inguinal lymph nodesexternal iliac nodeslumbar

(aortic) nodes
Q5 Describe synthesis, transport, metabolism and physiological actions of
testosterone.
SYNTHESIS:
-occurs in primarily in the Leydig cells (>95%)
-hypothalamusreleases GnRHacts on anterior pituitaryrelease LHbinds
interstial Leydig cells w/LH receptorsLH stimulates cholesterol desmolase
-also occurs in zona reticularis of the adrenal cortex (contain 21 beta hydroxylase and 11-
beta hydroxylase so can make glucocorticoids/mineralocorticoids as well)
-17 hydroxylase used here to get to andostenedioneuses 17-β hydroxysteroid
dehydrogenase to get to testosterone

-Cholesterol desmolase: rate limiting step

TRANSPORT/PHYSIOLOGICAL ACTIONS:
-testosterone released from testislipophilic; binds steroid protein (albumin, sex steroid
binding protein)enters the target cell (anywhere but fetal external genitalia; male body,
scalp and facial hair; prostate; sebaceous gland)combines directly with the nucleus or
converts into dihydrotestosterone first (via 5 alpha hydroxylase)physiological actions
-actions of testosterone:
 Differentiation of epididymis, vas deferens, seminal vesicles
 Pubertal growth spurt
 Cessation of pubertal growth spurt (epiphyseal closure)
 Libido
 Spermatogenesis in Sertoli cells (paracrine effect)
 Deepening of voice
 ↑ muscle mass
 Growth of penis and seminal vesicles
 Negative feedback on anterior pituitary

-actions of DHT
 Differentiation of penis, scrotum, prostate
 Male hair pattern
 Male pattern baldness
 Sebaceous gland activity
 Growth of prostate

METABOLISM:
-~7% of testosteroneDHT
-~0.3% of testosteroneestradiol (via aromatase in liver and adipose tissues)
-testosterone negatively feedsback on the hypothalamus and anterior pituitary
Case 3:
Q1-2 Describe pathogenesis, histopathology, clinical features and laboratory
findings in a patient with benign prostatic hypertrophy. List the lobes of the prostate
and the symptoms most commonly involved in benign prostatic enlargement.
Pathogenesis: DHT and ↑ DHT receptors due to age-related ↑ in estradiol causes prostate to
hypertrophy. Hypertrophy compress urethra leading to symptoms.
Histopathology: Hyperplastic glands of the middle lobe (transitional zone) lined by tall
columnar cells (2 cell layers). Proliferating stroma surrounds glands.
Clinical Features: usually > 50 y/o, Voiding symptoms (difficulty in starting and stopping
urine flow, reduced flow, dribbling once stopped) then Storage symptoms (frequency,
urgency, nocturia) then Complications (infection, hydronephrosis, dilated bladder)
Laboratory Findings: ↑ PSA (usually between 4ng-10ng)
Q3 Describe the histology, blood supply and lymphatic drainage of the prostate. List
the common sites of metastases of carcinoma prostate and give anatomical
basis for it.
Histology:

The prostate is the largest accessory sex gland in men (about 2 × 3 × 4 cm). It contains 30 -
50 tubuloalveolar glands, which empty into 15 - 25 independent excretory ducts. These
ducts open into the urethra. The glands are embedded into a fibromuscular stroma, which
mainly consists of smooth muscle separated by strands of connective tissue rich in
collagenous and elastic fibers. The muscle forms a dense mass around the urethra and
beneath the fairly thin capsule of the prostrate.

A characteristic feature of the prostate is the appearance of corpora amylacea in the

secretory alveoli. They are rounded eosinophilic bodies. They appear already in the
seventh month of foetal development. Their number increases with age - in particular past
50. They may undergo calcification. Corpora amylacea may also appear in semen.

Blood supply:

The main arterial supply to the prostate gland is from the prostatic artery, a branch off of
the inferior vesical artery, and it is also supplied by small branches from the middle rectal
and pudendal vessels.

Lymphatic drainage: obturator lymph nodes and internal iliac nodes (hypogastric chain)

Prostate Cancer metastasis:

* Bones (spinal column): via Batson’s venous plexus (valveless veins connecting the deep
pelvic veins and thoracic veins to the internal vertebral venous plexuses)

Q4 Explain why the common symptoms of prostate cancer usually involve erectile
and urinary dysfunction.

Erectile dysfunction can be caused by the treatment of prostate cancer:

· Surgery - may disrupt nerves and blood vessels supplying the penis

· Radiation therapy (develops 6 months post surgery) – damages blood vessels supplying
the nerves responsible for erection
· Cryosurgery (freezing of cancerous tissue) – freezing may damage nerves

· Hormone therapy – results in decreased levels of testosterone which affects sex drive
and the ability to achieve an erection

Urinary dysfunction can be caused by direct damage to the sphincter or it may result due to
instability of the detrusor muscle.

Q5 Describe the nerves that might be compromised during open prostatectomy and
the consequence on sexual functioning and urinary continence.
Prostatectomy-surgical removal of all parts of the prostate (open prostatectomy=the
incision is done below the navel and prostate is removed)
Care must be taken to spare pelvic plexus and the two plexuses it gives rise to: prostatic
plexus and vesical plexus.
Sexual Dysfucnction:
Must spare pelvic and prostatic plexuses
Inferior hypogastric (Pelvic) plexus lies against the posteriolateral pelvic wall, lateral to
rectum and base of the bladder.
-formed by the union of hypogastric, pelvic splanchnic (contains parasympathetics), and
sacral splanchnic (contains sympathetics) nerves. The pelvic plexus gives rise to the
prosthetic plexus. The nerves from the prostatic plexus pass to the corpora cavernosa, the
erectile tissue of the penis. As a result erection (ruled by parasympathetic nerves S2-S4)
and ejaculation (ruled by sympathetic nerver (L1-L2) can become dysfunctional upon
damage of pelvic or prostatic plexuses.
Urinary Incontinence:
Must spare pelvic and vesical plexus
Similarly to prostatic plexus, vesical plexus also arises from form pelvic plexus. Damage
will result in urinary incontinence.
Q6 List the target tissues which form dihydrotestosterone from testosterone. Name the
enzyme involved. Mention its clinical importance.
Testosterone is not active in all androgenic tissues. In some target tissues,
dihydrotestosterone (DHT) is the active androgen. In those tissues, testosterone is
converted to DHT by 5α-reductase.
Target Tissues of DHT:
1) Fetal External Genitalia (differentiation of penis, scrotum, prostate)
2) Male body, scalp and facial hairs (male pattern baldness)
3) ↑ sebaceous gland activity
4) ↑ prostate growth

Clinical importance:
1) Congenital 5α-reductase deficiency-ambigous genitalia before puberty (b/c penis,
scrotum and prostate cannot differentiat w/t DHT) but after puberty when testosterone
starts increasing→masculinzation and ↑ growth of external genitalia as well as
development of secondary male sex characteristics. It becomes evident when that the child
is a boy. “Penis at 12” syndrome
2) Since growth of prostate and male pattern baldness depend on DHT rather than
testosterone, 5α-reductase inhibitors can be used in treatment of BPH and hair loss in men.
Case 4:
Q1 Define dementia and list the most common causes of dementia in an
elderly.
Dementia – the development of memory impairment and other cognitive deficits
with preservation of a normal level of consciousness (Robbins)

Major Causes of Dementia:

Primary Neurodegenerative Disorders:
Alzheimer disease
Pick disease and other frontaltemporal degenerations
Parkinson disease and diffuse Lewy body degenerations
Progressive supranuclear palsy
Huntington disease
Motor neuron disease

Also, infections (Prions, HIV, etc…), vascular and traumatic diseases (multi-
infarct, subdural hematoma, etc…), metabolic and nutritional diseases, brain
tumors, neuronal storage disease and toxic injury.

Q2 List the anatomical areas of the brain involved in Alzheimer’s disease. Relate the
signs and symptoms to the anatomical areas involved in a patient involved with
Alzheimer’s disease.

The anatomical areas showing a build up of abnormal protein in Alzheimer’s disease are
the hippocampus, neocortex, amygdale, basal forebrain, locus ceruleus, raphne nuclei amd
entorhinal cortex. Of these areas, the loss of neurons are most noticeable in the
hippocampus, the association cortices, some areas of the limbic system as well as the basal
nucleus of Meynert.

The most noticeable symptom of Alzheimer patients are their loss of memory and later in
the course of disease, the inablilty to work on complex tasks and emotional probelms.
The loss of areas that secret neurotransmitters correspond to the changes in mood:
Raphne nucleus – serotonin
Locus cereleus –norepinephrine
Basal nucleus of Meynert – achetylcholine
The loss of memory and emotion corresponds to lesions in the limbic system, and most
importantly the hippocampus which establishes long term memory.

Q3
Sporadic Alzheimer disease onset is rarely before 50 yrs old. Earlier onset can be seen in
heritable forms of Alzheimer disease, which are the minority. From a biochemical and
genetic standpoint there is evidence that accumulation of the peptide β-amyloid (Aβ) can
initiate a chain of events leading to the morphologic changes and dementia seen in
Alzheimer disease. Aβ is derived from an amyloid precursor protein (APP) which when
cleaved normally by α-secretase and γ-secretase prevents the formation of Aβ.
Alternatively, APP can be cleaved by β-site APP-cleaving enzyme and γ-secretase
generating Aβ (peptide that accumulates in Alzheimer disease).
Generation and accumulation of Aβ occurs slowly with advancing age. Mutations in APP
(chromosome 21) or in components of γ-secretase (presenilin-1 found on
chromosome 14 or presenilin-2 found on chromosome 1) lead to early onset of
Alzheimer disease by increasing the rate of Aβ accumulation. Alzheimer disease is seen in
almost all Down syndrome patients that live past the age of 45. Two genes, Apoε4 and
SORL 1, are thought to be associated with the more common sporadic form of Alzheimer
disease.
Extracellular accumulation of Aβ causes problems with neuronal function. Aggregates of
Aβ can alter neurotransmission and be toxic to neurons. The presence of Aβ leads to the
hyperphosphorlation of microtubular binding protein tau. The hyperphosphorylation
causes redistribution of tau inside the neuron to form neurofibrillary tangles. This
process causes neuronal dysfunction and cell death.
Histology: We see extracellular neuritic plaques, which are focal, spherical collections of
dilated, tortuous, silver staining neuritic processes around a central amyloid core (Aβ)
found in the hippocampus, amygdyla and neocortex. There can also be Aβ without the
neuritic surrounding called disuse plaques. Neurofibrillary tangles (not specific to
Alzheimer disease) are bundles of paired helical filaments visible as basophilic fibrillary
structures in the cytoplasm of the neurons that displace or encircle the nucleus. A major
component of paired helical filament is abnormally hyperphosphorylated forms of the
protein tau. These tangles are found in cortical neurons, especially in the entorhinal
cortex, as well as in other sites such as pyramidal cells of the hippocampus, the amygdala,
the basal forebrain, and the raphe nuclei

Q4 Define an amyloid. Mention the different types. Describe how the amyloid bodies
are demonstrated in a histological specimen.

Amyloids are extracellular, proteinacious deposits which stain apple-green with Congo Red
under polarized light. They all take on a molecular B-pleated sheet structure. This
characteristic histological picture is diagnostic for Amyloidosis.

B-Amyloid - derived from Amyloid precursor protein (APP) - Alzheimer's disease

AL - derived from Ig light chains (Multiple myeloma) - Primary
AA - derived from serum amyloid-associated protein (SAA) - Secondary
Transthyretin - derived from AF - Senile Cardiac
Amylin - derived from AE (endocrine) - Type II Diabetes
A-CAL - derived from calcitonin - Medullary carcinoma of the thyroid
B2-Microglobulin - derived from MHC I - Dialysis Aquired

Q5 Define urinary continence. With the help of a micturition reflex arc, describe
factors contributing to the continence and how they are affected in elderly.
-Urinary continence is the control of the elimination of urine from the bladder.
-The muscles of the bladder, urethra and pelvic floor are under the control of the nervous
system. A simplified picture would be that as the bladder fills, sensory receptors in the
bladder wall trigger the micturition reflex - a simultaneous contraction of the detrusor and
relaxation of the urethral and periurethral muscles. The neurological signals for these
actions are co-ordinated by a micturition centre. During voiding afferent pelvic nerve
discharges ascend in spinal cord, synapse in pontine micturition centre Descending
efferent pathways cause
Inhibition of pudendal firing - relaxation of sphincter, Inhibition of sypathetic firing - opens
bladder neck
pelvic parasypathetic firing - detrusor contraction and voiding through urethra.
-In elderly pts

Transient urinary incontinence

Transient urinary incontinence is often seen in both elderly and hospitalized patients. The
mnemonic DIAPPERS is a good way to remember most of the reversible causes of
incontinence

 D: Delirium or acute confusion

 I: Infection (symptomatic UTI)
 A: Atrophic vaginitis or urethritis
 P: Pharmaceutical agents
 P: Psychological disorders (depression, behavioral disturbances)
 E: Excess urine output (due to excess fluid intake, alcoholic or caffeinated beverages,
diuretics, peripheral edema, congestive heart failure, or metabolic disorders such as
hyperglycemia or hypercalcemia)
 R: Restricted mobility (limits ability to reach a bathroom in time)
 S: Stool impaction

Overflow incontinence:
The major contributing factor to overflow incontinence is incomplete bladder emptying
secondary to impaired detrusor contractility or bladder outlet obstruction. Factors
involved in the development of overflow incontinence are physical obstruction such as
pelvic organ prolapse and enlarged prostate, and neurological abnormalities, such as spinal
cord injuries. It is also commonly associated with bladder neuropathy that occurs in the
setting of diabetes mellitus.
Patients often complain of continuous small-volume leakage associated with weak urinary
stream, dribbling, hesitancy, frequency, and nocturia.
Other less frequent causes of urinary incontinence include trauma from pelvic fracture,
complications of urologic procedures, and fistulas. In the pediatric population, it includes
enuresis and congenital abnormalities of the genitourinary system. Older adults can have
transient incontinence from medication, decreased mobility, and fecal impaction.

Q 6:

Osteoporosis- is the reduction in primary trabecular (spongy ) bone mass in spite of

normal mineralization. There are two types
 Type 1- Seen in postmenopausal women due to increased bone resorption due to
decreased estrogen levels.
  Type 2- in senile osteoporosis and affects both men and women over the age of 70
equally.

Both cause an increased risk of vertebral crush fractures, acute back pain, loss of height, kyphosis

Osteomalacia- is the defective mineralization of bone. Usually due to a vitamin D def. This will cause a
decrease in calcium, and an increase in PTH excretion. It is reversible

Osteoblasts – are responsible for bone formation, by producing osteoid (Type 1 collagen) and allow for
mineralization
Osteoclasts- are responsible for bone reabsorption, remove the mineralized matrix and break up the
organic bone.
As one ages, the osteoblasts don’t fxn as well while the osteoclasts continue to reabsorb.

RENAL

Hepatobiliary Renal Pt 1
Group 18
Group members listed at end

Case 1:
1. Describe the contents of the liver segment (include zone1, zone2 and zone3) -
include the structures such as bile ductule, bile canaliculus, sinusoids, Kupffer cell,
space of Disse, hepatic artery, portal vein, and central vein.

Refer to p. 308 in First Aid.

A hepatic lobule is a small division of the liver

defined on a histological scale. The classical
lobule, hepatic lobule, is hexagonal in shape
and divided into three zones:
Zone 1(periportal zone): encircles the portal
triad (hepatic artery, hepatic portal vein and bile
ductule) where oxygenated blood from hepatic
arteries enter; hepatocytes are specialized for
oxidative liver functions (eg. Gluconeogenesis
and beta-oxidation)
Zone 2 (intermediate zone):
Zone 3 (pericentral vein or centrilobular zone):
around central vein and where oxygenation is
poor, affected 1st by ischemia, contains P-450
system, most sensitive to toxic injury
 Each liver cell borders a vascular space, sinusoid, on at least one side and other
hepatocytes on its remaining side. The sinusoids drain to the central veins. Where
2 hepatocytes adjoin, they delimit a small intercellular space, bile canaliculus, into
which bile is delivered. Since sinusoids are lined by endothelial cells (sinusoidal
lining cells) and macrophages (Kuppfer cells), hepatocytes do not come into contact
with the bloodstream. Space of Disse intervenes between hepatocytes and
sinusoidal cells. This houses microvilli of hepatocytes, occasional fat storing cells
(ito cells) and slender reticular fibers that help form the supporting network of the
liver.

2.

Explain the biochemical basis for clinical manifestations of deficiencies of vitamin

A, D and K in patients with bile duct obstruction.

Vitamins A, D, E, and K are lipid soluble vitamins. Bile duct obstruction results in fat
malabsorption and deficiency in fat soluble vitamins.

Vitamin A: Hydroxyl (Retinol), Carboxyl (Retinoic Acid), and aldehyde (retinal).

Function:
- Antioxidant
- Constituent of visual pigments (retinal and a protein form Rhodopsin, a receptor
for light photons that changes from Trans to Cis-Retinal and results. In the dark,
glutamate is continuously released and inhibits the optic nerve bipolar cells.
When light activates the Rhodopsin receptor, it hyperpolatizes the rod cell
membrane, light stops glutamate release, and the optic nerve is no longer
inhibited and sends a signal to the brain.)
 - Essential for normal growth, maintenance, and differentiation, of epithelial cells
into specialized tissue (pancreatic cells, mucus-secreting cells) Retinol and
retinoic acid bind intracellular receptors (family of Zn finger proteins), and they
regulate transcription through specific response elements.

Decifiency:
- night blindness
- dry skin/ hyperkeratosis

Vitamin D: (D2 = ergocalciferol; D3 = cholecalciferol; 25-OH D3 = storage form; 1,25 –

(OH)2 D3 = calcitriol = active form.
Function:
- ↑ intestinal absorption of Ca2+ and phosphate
- ↑ bone resorption (activates osteoclasts)
- Biochem: 1,25-(OH)2 acts on duodenal epithelial cells as a lipid soluble hormone
and binds the intracellular receptor (Zn-finger protein), which binds to response
elements in enhancer regions of the DNA to induce the synthesis of calcium
binding proteins that are important in stimulating calcium uptake from the GI
tract.

Deficiency:
- Rickets in children (bending bones)
- Osteomalacia in adults (soft bones)
- Hypocalcemic tetany

Vitamin K:
Function:
- Catalyzes γ-carboxylation of glutamic acid residues (enzyme: γ-Glutamyl
Carboxylase) on various proteins concerned with blood clotting (clotting factors:
II, VII, IX, X, and protein C and S)
- Synthesized by intestinal flora

Deficiency:
- Neonatal hemorrhage with ↑ PT and ↑ aPTT but normal bleeding time (neonates
have sterile intestines and are unable to synthesize Vit. K)
- Can occur after prolonged use of broad-spectrum antibiotics

First Aid 2010 p. 90, 93, 94.

3. Review the breakdown of heme and excretion of end products of heme degradation in feces
and urine. Include the role of UDP glucuronyl transferase in bilirubin metabolism.
(from: Lippincott's Illustrated Reviews: Biochemistry, 4th Edition, pg 283)
After approximately 120 days in the circulation, red blood cells are taken up and degraded by the
reticuloendothelial system, particularly in the liver and spleen . Approximately 85% of heme
destined for degradation comes from red blood cells, and 15% is from turnover of immature red
blood cells and cytochromes from extraerythroid tissues.
1. Formation of bilirubin: The first step in the degradation of heme is catalyzed by the
microsomal heme oxygenase system of the reticuloendothelial cells. In the presence of
NADPH and O2, the enzyme adds a hydroxyl group to the methenyl bridge between two
pyrrole rings, with a concomitant oxidation of ferrous iron to Fe3+. A second oxidation by
the same enzyme system results in cleavage of the porphyrin ring. The green pigment
biliverdin is produced as ferric iron and CO are released [Note: The CO has biologic
function, acting as a signaling molecule and vasodilator.] Biliverdin is reduced, forming
the red-orange bilirubin. Bilirubin and its derivatives are collectively termed bile
pigments. [Note: The changing colors of a bruise reflect the varying pattern of
intermediates that occur during heme degradation.]

2. Uptake of bilirubin by the liver: Bilirubin is only slightly soluble in plasma and,
therefore, is transported to the liver by binding non-covalently to albumin. [Note: Certain
anionic drugs, such as salicylates and sulfonamides, can displace bilirubin from
albumin, permitting bilirubin to enter the central nervous system. This causes the
potential for neural damage in infants.] Bilirubin dissociates from the carrier albumin
 molecule and enters a hepatocyte, where it binds to intracellular proteins, particularly the
protein ligandin.

3. Formation of bilirubin diglucuronide: In the hepatocyte, the solubility of bilirubin is

increased by the addition of two molecules of glucuronic acid. [Note: This process is
referred to as conjugation.] The reaction is catalyzed by microsomal UDP glucuronyl
transferase using uridine diphosphate-glucuronic acid as the glucuronate donor. [Note:
Varying degrees of deficiency of this enzyme result in Crigler-Najjar I and II and Gilbert
syndrome, with Crigler-Najjar I being the most severe deficiency.]

4. Secretion of bilirubin into bile: Bilirubin diglucuronide (conjugated bilirubin) is

actively transported against a concentration gradient into the bile canaliculi and then into
the bile. This energy-dependent, rate-limiting step is susceptible to impairment in liver
disease. [Note: A deficiency in the protein required for transport of conjugated bilirubin
out of the liver results in Dubin-Johnson syndrome.] Unconjugated bilirubin is normally
not secreted.

5. Formation of urobilins in the intestine: Bilirubin diglucuronide is hydrolyzed and

reduced by bacteria in the gut to yield urobilinogen, a colorless compound. Most of the
urobilinogen is oxidized by intestinal bacteria to stercobilin, which gives feces the
characteristic brown color. However, some of the urobilinogen is reabsorbed from the gut
and enters the portal blood. A portion of this urobilinogen participates in the
enterohepatic urobilinogen cycle in which it is taken up by the liver, and then resecreted
into the bile. The remainder of the urobilinogen is transported by the blood to the kidney,
where it is converted to yellow urobilin and excreted, giving urine its characteristic color.

(Diagram and text from Lippincott's Illustrated Reviews: Biochemistry, 4th Edition, pg 282-284)

4.

Describe how ammonia is detoxified in the liver (revise urea cycle). (First Aid 105)
The urea cycle (ornithine cycle) produces urea ((NH2)2CO) from ammonia. (NH3).
Amino acid catabolism results in the formation of common metabolites (e.g. pyruvate
acetyle-CoA), which serve as metabolic fuels. Excess nitrogen (NH4+) generated by this
process is converted to urea and excreted by the kidneys as urea.
 Ordinarily Careless Crapper Are Also Frivolous About Urination
Ornithine, Carbamoyl phosphate, Cirtulline, Aspartate, Argininosuccinate,
Fumarate, Arginine, Urea

CPS1 = Carbamoyl phosphate synthetase

OTC = Ornithine transcarbamoylase
ASS = Argininosuccinate synthase
ASL = Argininosuccinate lyase

Reactants Products Catalyzed Locat

1 NH4+ + HCO3− + 2ATP carbamoyl phosphate + 2ADP + Pi CPS1 mt

2 carbamoyl phosphate + ornithine citrulline + Pi OTC mt

3 citrulline + aspartate + ATP argininosuccinate + AMP + PPi ASS cytosol

4 argininosuccinate Arg + fumarate ASL cytosol

5 Arg + H2O ornithine + urea ARG1 cytosol

ARG1 = Arginase
Hyperammonemia = liver disease or hereditary diseases such as ornithine transcarbomoylase
(OTC) deficiency lead to an increase in ammonia in the blood which depletes alpha-ketoglutarate
and leads to the inhibition of the TCA cycle (Tx: limit protein diet)

Ammonia intoxication = tremor, slurring of speech, somnolence, vomiting, cerebral edema,

blurring of vision

5.
Name the primary and secondary bile salts. Indicate the rate-limiting enzyme in synthesis
of bile salts.
BILE is composed of bile salts (bile acids conjugated to glycine or taurine, making them water
soluble), phospholipids, bilirubin, water, and ions. BILE is the only significant mechanism for
cholesterol excretion and is needed for the digestion of triglycerides and micelle formation in the
small intestine.

Bile salts are bile acids (made by the liver by cytochrome P450 metabolization of cholesterol)
conjugated to taurine and glycine. They are stored in the gallbladder. Conjugated bile acids are
more efficient at emulsifying fats because at intestinal pH, they are more ionized than
unconjugated bile acids.

An important function of bile salts is formation of micelles. This way bile salts keep hydrophobic
substances like cholesterol in aqueous solution. In the intestine bile salts are essential to emulsify
the lipids. Bile salts are also responsible for absorption of fat-soluble vitamins A, D, E, and K by
forming mixed micelles. Bile salts also help in activation of pancreatic lipase. Bile salts act as
mild cathartics.

Primary bile acids = cholic acid and chenodeoxycholic acid

Secondary bile acids = formed in the intestine as a result of bacterial action on primary bile
acids and these are deoxycholic acid (from cholic acid) and lithocholic acid (from
chenodeoxycholic acid)

7 alpha-hydroxylase is the rate-limiting enzyme in the synthesis of bile acid from cholesterol

7 alpha-hydroxylase
Cholesterol  alpha-hydroxycholesterol

Case 2

1.
Describe the anatomical relation between liver, gallbladder, pancreas, small
intestine and the connecting ducts.
Image source: http://www.caring4cancer.com/go/liver/basics/what-is-liver-cancer.htm

Anatomical relationship:
Liver -surrounded by peritoneum
-attached to diaphragm by coronary and falciform ligaments and
the right and left triangular ligaments
Gallbladder -located at the junction of the right ninth costal cartilage and lateral
border of the rectus abdominis
-lies on inferior surface of the liver between the right and quadrate
lobes
-in contact with the duodenum and transverse colon
Pancreas -lies largely in the floor of the lesser sac in the epigastric and left
hypochondriac regions—forms a major portion of the stomach bed
-retroperitoneal (except for a portion of the tail)
-head: lies within the C-shaped concavity of the duodenum
-unicate process (projection of the lower part of the head): lies
behind the superior mesenteric vessels
-body: lies behind the stomach
-tail: in contact with the spleen (splenic artery runs superior to
pancreas, posterior to stomach)
Small -retroperitoneal (except for the beginning of the first part, which is
intestine connected to the liver by the hepatoduodenal ligament)
(duodenum) -C-shaped tube surrounds the head of the pancreas

Connecting ducts:
-right and left hepatic ducts drain bile from the bile ductules from with in the liverjoin to
form common hepatic duct
-bile backs up in to the gallbladder via the cystic duct (passes upward)the cystic duct
ultimately joins the common hepatic ductforms the common bile ductcommon bile
duct merges with pancreatic duct forms the hepatopancreatic duct (ampulla of
Vater)enters the 2nd part of the duodenum at the greater papilla (descending part of
duodenum)

Cystic duct Common site for gallstone impaction

Common bile duct -runs behind the first part of the duodenum and through
the head of the pancreas
-runs lateral to the proper hepatic artery and anterior to
the portal vein in the right free margin of the lesser
omentum
-sphincter of Boyden: circular muscle layer around the
lower end of the duct
Pancreatic duct -begins in the tailruns along the entire pancreas
-carries pancreatic juice containing enzymes
Hepatopancreatic duct -sphincter of Oddi: circular muscle layer around the duct
(ampulla of Vater) in the greater duodenal papilla

2.
Describe the contents of the hepatoduodenal ligament which will be gripped
during a Pringle maneuver.

Pringle’s maneuver: cross-clamping of the hepatoduodenal ligament containing portal triad

(hepatic portal vein, common bile duct, proper hepatic artery) at the foramen of Winslow
-hepatoduodenal ligament: part of the lesser omentum
-used for control of hepatic bleeding during liver surgery or donor hepatectomy for living
liver transplantation
3.
List the 3 common sites where gall stones can be impacted (lodged) and
explain the effects of each on the bile flow.

 Cystic duct: Causes intermittent biliary colic or acute cholecystitis. Bile flow is only
obstructed from the gallbladder, not from liver.
 Common bile duct: Causes acute cholecystitis and jaudice. Bile flow is completely
stopped.
 Ampulla of Vater (Hepaticopancreatic ampulla): Causes acute cholecystitis, jaudice,
and acute pancreatitis. Bile flow and pancreatic secretions are completely stopped.

4.
List the areas of portal-systemic anastomoses, identify the veins being
connected
and describe how these areas may decompress (alleviate) portal
hypertension.
From Essential Clinical Anatomy K. Moore page 174
For rapid review the important notes are either highlighted or in bold
  Bet ween the esopha geal vei ns dra ining into either the azygos vein (syste mic
system) or the left gas tric vein (p ortal syst em); when d ilated these are
eso phageal varices.
 Bet ween the rectal veins , the in ferio r and mid dle ve in s d raining into the IV C
(syste mic system) and the supe rior re ctal vein con tinu ing as the infe rior
mesen teric vein (portal system); when abnorma lly dilate d the se are
he morrh oids.
 Paraumbi lical vei ns of the anterio r abdo minal wa ll (po rta l syste m)
ana stomosing with supe rficial epi gas tric veins (syste mic syste m); whe n d ila ted
the se vein s produ ce caput me dusae —va rico se veins ra dia tin g f rom the
u mbilicu s. The se dilated ve ins were ca lled caput med usae becau se of the ir
rese mb lan ce to the serpent s on the head of Medu sa, a cha ra cte r in Gree k
myth olog y.

Portal venous system. A. The

venous system is demonstrated.
B. Portal–systemic anastomoses
provide collateral circulation in
cases of obstruction in the liver
or portal vein. Darker blue, portal
tributaries; lighter blue, systemic
tributaries; A, anastomoses
between esophageal veins; B,
anastomoses between rectal
veins; C, anastomoses between
the paraumbilical veins (portal)
and small epigastric veins of the
anterior abdominal wall; D,
anastomoses between the twigs
of colic veins (portal) and the
retroperitoneal veins.

describe how these areas may decompress (alleviate) portal hypertension.

P ortal–Sy ste mic Anastomos es

Th e co mmun ications between the po rta l venous syst em and the systemic venous
system a re imp ortant clin ically in the ad vent of an int rahep atic or ext rahep atic portal
ven ous blo ck. When port al circu lat ion through the liver is obst ru cted becau se of liver
d isea se or physical p ressure fro m a tu mor, for exa mp le, blo od f ro m the a limen tary tra ct
can st ill reach the right side of the hea rt thro ugh the IV C by way of seve ra l colla teral
route s. These a lternate rou tes are ava ilab le beca use the porta l vei n and i ts
tri buta ries have no valv es; he nce bl ood can fl ow in a reve rse di rection to the IV C.

5.

Explain which caval vein can be anastomosed with the splenic vein to create a
portocaval shunt to decompress portal hypertension.
P ortal Hy perte nsi on
When sca rrin g and f ibrosis f rom cirrh osis of the live r obst ru ct the po rta l vein, pre ssu re
rises in the portal ve in and its t ributa ries, p roducing porta l hy pe rte nsi on. At the sites
of anasto mo ses bet ween portal and syste mic veins, po rta l hyperten sio n p roduces
en larged varicose ve in s and blood f low f rom the po rta l to the syste mic syste m of vein s.
Th e ve in s may beco me so dilated that the ir walls ruptu re, resu lt ing in hemorrhag e.
B leeding fro m esophagea l va rice s (dila ted esophagea l veins) at the dista l end of the
eso phagus is often seve re and may be fatal. A commo n method fo r redu cing po rta l
hyp ertension is to divert blood f rom the po rtal ve nous syste m to the syste mic ven ous
system by creat ing a co mmun ication bet ween the portal vein and the IV C or by
j oining the s plenic and le ft re nal veins—a portacaval anas tomosis or
portosys temic s hunt.

Case 3

1.
List the sites of constriction of the ureter and explain their relationship to kidney
stones.
Obstruction of the ureter is most likely to occurs by renal calculi at the narrowest areas of
the ureter where:
1) ureter joins the renal pelvis (ureteropelvic junction)
2) ureter crosses the pelvic brim over the distal end of common iliac artery
3) ureter enters the wall of the urinary bladder (uterovesicular junction)

2) Identify, in radiological
images, the structures in the
posterior abdominal wall.

3 Liver (right lobe)

8 Rib
10 Abdominal Aorta
12 Spleen
15 Body Of Vertebra
19 Head of Pancreas
21 Duodenum
23 Kidney
29 Cauda Equina
30 Right Renal Vein
31 Small Intestine
(Taken from Rohan’s Atlas of Anatomy)

3.

Identify the structures and regions seen grossly in a frontal section of a kidney
and describe their organization and general function.

a) Cortex – contains the renal corpuscle (glomerulus and Bowman’s capsule), and renal
tubules except the loop of Henle which enters the renal medulla.
b) Medulla – innermost part of the kidney which splits into a number of sections called renal
pyramids. The renal medulla contains the vasa rectae, venule rectae, medullary capillary
plexus, the loop of Henle and the collecting tubule.
c) Pyramids – cone shaped tissues of the kidney, the striped appearance is formed by
straight parallel segments of nephrons. The base of each pyramid starts at the
corticomedullary border and the apex terminates in a papilla, within a minor calyx.
d) Pelvis – the dilated prximal part of the ureter in the kidney. This is the point of
convergence of two or three major calyxes. Main function is to funnel the urine into the
ureter.
 e) Calyx – there are the major and minor calyx. Urine flows through a papilla at the apex
into the minor calyx then into the major calyx and finally into the pelvis.
f) Ureter – muscular tubes that propel urine from the kidneys to the urinary bladder.
g) Renal artery/vein – carry blood to the kidneys from the abdominal aorta and drain the
kidney to the inferior vena cava.

4.
Describe the structure, function and location of each component of a nephron
and the urinary tract into which the nephrons empty.

Structure Function
Proximal Tubule Cuboidal epithelial cells Reabsorption of solutes
with long microvilli and water. Most
reabsorbing occurs here.

Descending thin loop of
Henle
Ascending thin loop of
Henle
Thick ascending loop of
Henle
Distal convoluted tubule
Cortical collecting ducts
Medullary collecting ducts
Some secretion is also
involved
Squamous epithelial cells Reabsorption of water only
Squamous epithelial cells Reabsorption of solutes
only
Cuboidal epithelial cells Resbosorption of solutes
Cuboidal epithelial cells Reabsorption of solutes
with short microvilli and also where the macula
densa is and therefore
senses the GFR
Cuboidal epithelium Reabsorption of solutes
and water. This area also
controls the acidity of the
urine and blood.
Cuboidal epithelium Reabsorption of water
through aquaporins

5.
Describe the components and functions of the juxtaglomerular apparatus.

The juxtaglomerular apparatus consists of afferent arterioles, the modified smooth

muscle cells (also called JG cells) and the macula densa. The juxtaglomerular
apparatus is used to monitor the GFR. This translates to the blood pressure of the body
and therefore maintains blood pressure. The JG cells produce the enzyme called renin
and activate the RAS.

6.

Renal agenesis is associated with oligohydramnios (small

amount of amniotic fluid) because little or no fluid is
excreted into the amniotic cavity. Failure of the
metanephric diverticulum (An outgrowth from the
mesonephric duct that gives rise to the ureter, renal
pelvis, calyces, and collecting tubules; also called uteric
bud) to penetrate the metanephrogenic blastema (The
mesoderm covering the distal end of the metanephric
diverticulum; it gives rise to the nephrons in the
permanent kidneys) results in an absence of renal
development because no nephrons are induced by the
collecting tubules to develop from the metanephrogenic
blastema.
Question 7

In a discoid kidney there is complete fusion of the kidneys

while in the pelvis. While, in a horseshoe kidney there is only
fusion of the inferior poles of each kidneys and the ascending
kidneys are stopped when the fused portion reaches the
inferior mesenteric artery (pg. 134, 2010 FA; pg. 133 2009
FA)

Case 4

1.

Describe in sequence the tubular segments through which ultrafiltrate flows from
Bowman’s capsule to the ureter. Identify the cortical/medullary location of each
renal tubule segment

There are two types of nephrons, juxtaglomerular and cortical. Cortical nephrons have all
portions of its tubule in the cortext except for the loop of henle and collecting duct.

For a juxtaglomerular nephron:

Glomerulus - Cortex (will filter anything under 30Kd or without a strong (-) charge)
Proximal Tubule - Cortex (Creatinine, antibiotics, diuretics, uric acid are filtered.   Bicarb,
Glucose, AA, NaCl, K, H20 are reabsorbed).
Descending tubule - Medulla (Na, K, H20 reabsorbed)
Loop of Henle - Medulla (Mg, Ca reabsorbed)
Ascending tubule - Medulla (Na reabsorbed)
Distal Tubule - Cortex (K, H, Urea filtered, NaCl, Ca, H20 reabsorbed)
Collecting duct - Medulla (H20 reabsorbed)
Ureter – Pelvis

2.

Renal clearance is the measurement of renal excretion ability. Clearance is a

function of glomerular filtration, secretion from the peritubular capillaries to the nephron,
and reabsorption from the nephron back to the peritubular capillaries.
Cx = Ux V / Px -Volume of plasma from which the substance is completely cleared
- per unit time

Cx = clearance of X
Ux = Urine concentration of X
V = Urine flow rate
Px = Plasma concentration of X

Creatinine Clearance (mL/min) =
          Urine Creatinine (mg/dL) TotalVolume(mL)
          Serum Creatinine(mg/dL) X Time (min)

Reference intervals for corrected creatinine clearances differ between sexes:

                   Males:          71 - 135 mL/min/1.73 m2
                   Females:      78 - 116 mL/min/1.73 m2

3.
Creatinine clearance of the patient is:

192 * 1 / 3.2 = 60

Cx = 60 mL/min

4.

Define and mention the formula to calculate:

FILTERED LOAD = GFR X plasma concentration
EXCRETION RATE = V x U(x)
 V=Urine Flow Rate
U(x)= Urine Concentration
NET TUBULAR REABSORPTION RATE=FILTERED – EXCRETED
Filtered = GFR x plasma concentration
Excreted= Urine Flow rate x urine concentration
Given: GFR, Urine Flow Rate, Plasma and Urine concentrations of a substance.

5)
Assuming creatinine clearance is equal to GFR, calculate filtered load of creatinine, urea,
sodium and potassium in this patient.
Filtered Load= GFR x plasma concentration
GFR= 192 mg/dL
Creatinine: 192 mg/dL x 3.2 mg/dL=614.4
Sodium = 192 md/dL x 142 meq/ L
Potassium= 192 x 5.8 meq/L
Urea= 192 x 80 mg/dl

CASE 1

Case 1:
1. Describe the clinical manifestations of nephrotic syndrome and their pathophysiological
basis. Explain the etiology, pathogenesis, morphological changes, electron microscopy and
immunofluorescence microscopy in: i) Minimal change disease and ii) Membranous
glomerulonephritis.

Nephrotic syndrome is a glomerular diseases characterized by glomerular injury due to

cytokines not neutrophils. The cytokines damage podocytes causing them to fuse
together and the negative charge of the GBM is also destroyed.
Clinical findings:
a. Key finding is proteinuria >3.5g/24hrs
b. generalized pitting edema and ascites – due to hypoalbuminemia
c. hypertension – due to sodium rentenion
d. hypercoaguable state due to loss of antithrombin III – can lead to renal vein thrombosis
e. hypercholesterolemia – hypoalbuminemia increases synthesis of cholesterol (unknown
mechanism)
f. hypogammaglobulinemia – due to loss of gamma-globulins in the urine
g. fatty casts with maltese cross and oval fat bodies  key finding of nephritic syndrome

Minimal Change Disease Membranous Glomerulonephritis

(diffuse membranous
glomerulopathy)
Etiology - triggered by recent infection - caused by drugs (eg. Captopril),
or an immune stimulus infections (eg. HBV), SLE, and solid
 - most common in children
Pathogenesis T-cell cytokins cause the
GBM to lose its negative
charge; selective proteinuria
(albumin, not globulins) due
to GBM polyanion loss
Morphological changes Structurally normal glomeruli
Electron Microscopy Fusion of podocytes and no
deposits
Immunoflourescence Negative IF
Microscopy
tumors (eg. Hodkin’s lymphoma)
- most common cause of adult
nephritic syndrome
Immunologically mediated disease in
which immune complexes deposit in
the subepithelial space
Antigen-antibody complexes can
develop by the production of immune
complexes in situ or by deposition
Mesangium is normal, no
hypercellularity;
Diffuse thickening of membranes
“spike and dome” appearance with
subepithelial deposits
Subepithelial ICs with granular IF

Case 1, question 2
Trace the circulation of blood through the kidney. Describe in sequence the blood
vessels through which blood flows when passing from the renal artery to the
renal vein, including the glomerular blood vessels, peritubular capillaries and
vasa recta.

Renal artery → Interlobar artery → (Arcuate artery) → Interlobular artery → afferent

arteriole → glomerular capillaries → efferent arteriole → vasa recta (in the renal
medulla) → venulae recta → (arcuate vein) → interlobular vein → interlobar vein → renal
vein

(First Aid 2010, p. 458, Netter plate 337)

3. Identify the components of the glomerular filtration barrier.

The filtration apparatus enclosed by the parietal layer of the Bowman’s consists of three
components;

1. Endothelium of the glomerular capillaries

 Possess fenestrated capillaries which are larger (70 to 90 nm in diameter), more
numerous, and more irregular in outline than fenestrations in other capillaries
 Moreover, the diaphragm that spans the fenestrations in other capillaries is absent
in the glomerular capillaries
 Endothelial cells of glomerular capillaries possess a large number of aquaporin-1
(AQP-1) water channels that allow the fast movement of water through the
epithelium

2. Glomerular basement membrane (GBM)

 A thick (300 t0 350nm) basal lamina that is the joint product of the endothelium
and the podocytes, the cells of the visceral layer of Bowman’s capsule
  Principal component of the filtration barrier
GBM: size and charge determine protein filtration

a. Composed of type IV collagen

b. Size and charge are the primary determinants of protein filtration.
o (1) Heparan sulfate produces the negative charge of the GBM.
o (2) Cationic proteins of low molecular weight (LMW) are permeable.
o (3) Albumin has a strong negative charge and is not permeable.

Albumin: negative charge; repelled by negatively charged GBM

 (a) Loss of the negative charge causes loss of albumin in the urine.
 (b) Called selective proteinuria (e.g., minimal change disease)
o (4) GBM is permeable to water and LMW (<70,000 daltons) proteins (e.g., amino
acids).
c. Causes of GBM thickening
o (1) Deposition of immunocomplexes
 Example-membranous glomerulopathy
o (2) Increased synthesis of type IV collagen
 Example-diabetes mellitus

3. Visceral Layer of Bowman’s capsule

 Contain specialized cells called podocytes or visceral cells which extend
processes around the glomerular capillaries and secondary processes called
pedicels or foot processes
 The foot processes interdigitate with foot process of neighboring podocytes and
the spaces between them is called filtration slits, which are about 25nm wide and
allow the ultrafiltrate from the blood to enter Bowman’s space.
 The foot processes contain numerous actin filaments that are thought to help
regulate the size and patency of the filtration slits.

a. Fusion of the podocytes: sign of nephrotic syndrome

o Serve as a distal barrier for preventing protein loss in the urine
b. Fusion of the podocytes is present in any cause of the nephrotic syndrome
 .

4. Compare and contrast the structure and function of cortical and juxtamedullary
Nephrons
1. Subcapsular or cortical nephrons
 Have their renal corpuscles located in the outer part of the cortex
 They have short loops of Henle extending only into the outer medulla

2. Juxtamedullary nephrons
 Make up about one eighth of the total nephron count
 Their renal corpuscles occur in proximity to the base of a medullary pyramid
 They have long loops of Henle and long ascending thin segments that extend well into
the inner region of the pyramid
 These structures features are essential to the urine concentrating mechanism .
 http://oracle3927.tripod.com/nephron.htm

Case #1: Question 5

Alisha Razack

Given the capillary and Bowman’s capsule hydrostatic and oncotic pressures, calculate the
net filtration pressure at the glomerular capillaries. Predict the effect on glomerular filtration
rate caused by changes in any of these driving forces.
(Physiology BRS: pg 158 – 159)

GFR = Kf [(PGC – PBS) – (GC - BS)]

(GFR is filtration across the glomerular capillaries)
(+) net pressure = FILTRATION
(-) net pressure = REABSORPTION

Kf is the filtration coefficient = 1 in glomerulus

 Glomerular barrier consists of capillary endothelium, basement membrane, and filtration slits
of podocytes. Normally, anionic glycoproteins line the filtration barrier and restrict the filtration
 of plasma proteins (usually negatively charged). In glomerular disease, anionic charges are
removed resulting in proteinuria.

PGC = glomerular capillary hydrostatic pressure which is constant along the length of the
capillary. It is increased by dilation of the afferent arteriole (prostaglandins) or constriction of
the efferent arteriole (angiotension II)  both increased blood flow through the glomerulus. If
PGC increases, GFR increases as well.

PBS = Bowman’s space hydrostatic pressure and is analogous to Pi in systemic capillaries. It is

increased by constriction of the ureters (ureteral stone). If PBS increases, GFR will decrease.

GC = glomerular capillary oncotic pressure and it normally increases along the length of the
capillary because filtration of water increases the protein concentration of the glomerular
capillary blood. An increase in GC will decreased GFR

BS = Bowman’s space oncotic pressure. It is usually ZERO because only a small amount of
protein is normally filtered. An increase in BS will increase GFR.

Case 2

1)Describe the etiology, pathogenesis, morphology of the glomerular lesion,

electron microscopy, immunofluorescence microscopy and clinical features of: i)
Poststreptococcal glomerulonephritis ii) Goodpasture’s syndrome.

-both produce nephritic syndrome: proliferation of cells within glomeruli + neutrophilic

infiltrationinflammation reaction injures capillariesallows RBCs to leak out; induces
hemodynamic changes that cause ↓GFR
-hypertension: d/t ↓ GFR (Na and fluid retention) + ↑ renin release when kidneys
become ischemic
-periorbital puffiness: d/t Na retention (sometimes edema can be more
generalized)
-oliguria (~400mL urine/day): d/t ↓GFR from inflamed glomeruli
-hematuria: injured capillariesRBCs in urineRBCs dysmorphic w/irregular
membranes
-RBC casts in urine
-mild proteinuria >150mg/day (<3.5g/day)
-azotemia: ↑ serum BUN, Cr; BUN:Cr>15; d/t ↓ GFR

Post-streptococcal GN Goodpasture’s syndrome

 Etiology -follows Group A strep infection
of skin (ie. scarlet fever) or
pharynx
Pathogenesis Type III hypersensitivity:
antibody made against strep
(IgG)ag/ab immune complexes
formcirculate and deposit
beneath podocytes
Morphology of -diffuse: all glomeruli affected
glomerular -proliferative (hypercellular
lesion glomerulus): d/t proliferation of
endo and epi cells w/in glomeruli
+ neutrophilic infiltration + ↑
mesangial cells
Electron -electron dense subepithelial
microscopy depositions
Immuno- Granular (irregular immune
fluorescence complex deposits in the
microscopy capillaries)
Clinical -hematuria 1-3 wks post-infection
features w/a nephritogenic strain (never
cause rheumatic fever)
-↑ anti-DNase B titers
-streptolysin O degraded by skin
oils (so anti-b not seen)
-usually resolves
-genetic: HLA-BR2 + (80%)
-M>F
-rare
Type II hypersensitivity: anti-
basement membrane antibodies
(IgG) against alpha3 chain of
collagen in glomerular and
pulmonary capillaries
-cresentic (5%): proliferation of
parietal epithelial cells in
Bowman’s capsuleoccupies
~1/2 the urinary spacecells
encase, compress glomerular tuft
-NO electron dense deposits
Linear (antibodies line up against
evenly distributed antigens in BM)
-begins with hemoptysis,
pulmonary hemorrhage (crackles
on P/E)
-ends with renal failure
-rapidly progressive: acute renal
failure over days to weeks
-poor prognosis

2. Describe the development of the kidney from the metanephric diverticulum and the
metanephric mass of mesoderm.

Metanephric diverticulum (ureteric bud):

- Dervied from caudal end of mesonephros
- Give rise to ureter, pelvises, calyces, and collecting ducts

Metanephric mass:
- Ureteric bud interacts and induces the mass to differentiate
- Give rise to glomerulus and renal tubules up to the distal convoluted tubules

3. Explain how changes in plasma flow rate affect glomerular filtration rate.

Renal plasma flow (RPF) is the amount of plasma that perfuses the renal tubules per unit
time. Best estimated with para-aminohippuric acid (PAH) clearance. PAH is both filtered
and actively secreted.
GFR is the measure of fluid filtered from the renal glomerular capillaries into the
Bowman's capsule per unit time. Creatinine clearance is typically used to estimate GFR.
Creatinine is filtered and only slightly secreted.

Filteration Fraction (FF) = GFR / RPF. RPF affects GFR differently in different settings
(afferent vs. efferent). See table.

Effect RPF GFR FF

Afferent arteriole constriction ↓ ↓ Constant
Afferent arteriole dilation ↑ ↑ Constant
Efferent arteriole constriction ↓ ↑ ↑
Efferent arteriole dilation ↑ ↓ ↓

4)

Describe the renal transport of following substances in the PCT: glucose,

bicarbonate, phosphate, amino acids.

From medical physiology Boron

Glucose reabsoption:
Secondary active transport
Luminal membrane-Cotransport with Na
Basolateral membrane -GLUT2
Renal threshold =300 mg/dl
375 mg/min (TmG) divided by 125 ml/min (GFR)
Actual renal threshold = 200 mg/dl

The threshold for glucose is affected by the following:

GFR – a low GFR causes an increased threshold because the filtered glucose is
decreased and the kidney can reabsorb the filtered glucose even though the plasma
glucose is increased (more time for reabsorption)
TmG – a decreased TmG lowers the threshold because the tubules have a
reduced capacity to reabsorb glucose.
Splay – “rounded” as it approaches its maximum which is caused by different
nephrons having different reabsorption and filtering capacities.
 Amino acid reabsorption
• All filtered AAs are reabsorbed in PCT
• Luminal membrane
– Cotransport with Na
• Basolateral membrane
– Diffusion

Bicarbonate reabsorption:
• 90% of filtered is reabsorbed in PCT
• Filtered HCO3 + H2O ®H2CO3
• H2CO3 ® H2O + CO2 in the presence of carbonic anhydrase
• CO2 diffuses into the cell + H2O®H2CO3
• H2CO3 ® CA ® H + HCO3
• HCO3 is reabsorped
H+ is secreted in exchange for Na +
 Phosphate reabsorption:
• Bones, teeth & skeleton (80%)
• Intracellular P (20%)
• Plasma P 1mmol/l freely filtered
• 1/3 of filtered is excreted in urine
• Cotransported with Na
• Rate of absorption is under the
control of PTH & VD (¯rate of absorption)
• Compete with glucose: blocking glucose ® P reabsorption

5) Describe the renal transport of following substances in the PCT: glucose,

bicarbonate, phosphate, amino acids.
Early PCT reabsorbs all the glucose and AAs and most phosphate via a coupled
cotransport with Na+. In each case, Na moves into the luminal cell and down its
electrochemical gradient while glucose, phosphate, AAs move into the cell against their
electrochemical gradients.

The HCO3- story is a bit more complex….

The only Na+ driven countertranport mechanism in the early PCT is the Na+-H+
antiporter (Na into the luminal cell, H+ into the tubular lumen). In the lumen, H+ combines
with filtered HCO3- forming CO2 & H2O→both move from lumen into the luminal cell→
reconverted to H+ & HCO3- (with help of carbonic anhydrase). HCO3- reabsorbed into the
blood by facilitated diffusion. Net Result: reabsorbtion of filtered HCO3-

6) Describe the mechanisms for NaCl absorption along the different segments of
the renal tubule such as PCT, Henle’s loop, distal convoluted tubule and
collecting duct. Summarize the humoral factors which regulate NaCl reabsorption
along the nephron.

Segment Cellular Mechanism Hormone Actions

Early proximal tubule Na-glucose (SGL2
tranporter), Na-AA, Na-
phosphate cotransport
Na-H+ countertransport
Late proximal tubule NaCl reabsorbtion driven by
Cl gradient (Note: 2
separate channels Na-H via
NHE3 countertranporter
and Cl-formate anion
countertransport)
Thick Ascending Loop of Na-K-2Cl cotransport
Henle (NKCC2 tranporter)
Early DCT Na-Cl contransport (NCCT
transporter)
Collecting Duct Reabsorb Na (ENaC) in
exchange for secretion of K
(ROMK) & H.
PTH inhibits Na+-
phosphate contransport
Angiotensin II stimulates
Na+-H+ exhanger→↑ Na &
H2O excretion
ADH stimulates this
cotransprot
PTH-↑ Ca/Na exhange→
↑Ca reabsorbtion
Aldosterone stimulate K &
H secreton and Na
reabsorbtion

CASE 3.

1. Discuss the causes, pathogenesis, morphological changes and clinical features of

acute tubular necrosis.
Disease: Acute Tubular Necrosis (ATN)
Etiology:  Most common cause of acute renal failure
 A period of inadequate blood flow to the peripheral organs
 (i.e. hypotension and shock also blood transfusion
mismatch, hemolytic crisis and myoglobinuria) 
ischemic ATN
 Poisons, heavy metals (e.g. mercury), organic solvents
(e.g. carbon tetrachloride and drugs (i.e. gentamicin, other
antibiotics) and radiographic contrast agents 
nephrotoxic ATN
Pathogenesis:  Tubular injury  persistent and severe disturbances in
blood flow  diminished oxygen and substrate delivery to
tubular cells
 Loss of cell polarity: epithelial cell detachment, necrosis,
granular (“muddy brown”) casts
Morphological  Ischemic ATN: necrosis of short segments of the tubules
Changes: usually seen in straight portions of the proximal tubule and
ascending thick limbs (“skip lesions”)
 Proteinaceous casts in distal tubules and collecting ducts
(Tamm-Horsfall protein w/ hemoglobin and plasma
proteins)
 Interstitium: mild inflammatory infiltrate (PMNs, leukocytes,
lymphocytes and plasma cells)
 Toxic ATN: similar, necrosis is in proximal tubule
Clinical features:  3 stages: inciting event  maintenance (low urine) 
recovery (2-3) weeks
 Initiation (36 hours): inciting event
 Maintenance (2nd to 6th day): urine output falls, oliguria (50-
400mL per day), signs and symptoms of uremia and fluid
overload (patients may die during this phase)
 Recovery: steady increase in urine, electrolyte imbalances
may occur, about 25% of ATN deaths occur in this phase

2)Explain the distribution of pain from kidney stones that are impacted (lodged) in
the ureter.

There are 3-4 areas that kidney stones are usually lodged at, these would be the
uretopelvic junction (UPJ), the top ridge of the ilium, the area where the ureter passes
by the iliac arteries and the uretovesico junction (UVJ). The pain that occurs is often
described as from loin to groin and follows the general path of the urinary tract, the pain
is caused by ureteric peristalisis.

3)Describe the layers that would be cut when harvesting a donor kidney using a
posterior approach.
 The layers would be :
1) Renal Capsule
2) Peri-renal fat
3) Renal Fascia
4) Pare-renal fat
5) Tendon of the transversalis muscle
6) Latissimus Dorsi muscle
7) Skin and Subcutaneous fat

Case 3 - Question 4

Describe the relative resistances of the afferent

and efferent arterioles and the effects of selective
changes in each on renal blood flow and
glomerular filtration.

The vascular resistance in the renal vasculature is

controlled at the level of the afferent and efferent
arterioles. These arterioles have the largest
vascular resistance and hence the largest drop in
renal blood pressure occurs at these vessels.

With afferent arteriole constriction there will be a decrease in renal plasma flow (RPF) as
well as a decrease in the glomerular filtration rate (GFR) resulting in no change in the
filtration fraction (FF = GFR/RPF). With efferent arteriole constriction there will be a
decrease iin RPF, but an increase in GFR. As a result, the FF will decrease. ( pg. 458 FA
2010; pg. 438 FA 2009)

5. Identify the two most potent stimuli for ADH release and the negative feedback
mechanism for each. Explain the mechanisms by which ADH causes formation of
concentrated urine.

A. The most important stimuli for secretion of ADH from the posterior pituitary is
increased plasma osmolarity detected by osmoreceptors in the hypothalamus. ADH then
acts on collecting ducts by increasing the expression of aquaporin channels. As the filtrate
flows down the collecting tubule, the concentration gradient outside the tubule favors
water reabsoption (as long as aquaporins are present) and leaves behind concentrated
urine. The increase in water content will bring the osmolarity of plasma back to normal,
and decrease osmoreceptor firing.

B.A decrease in plasma volume is sensed by baroreceptors in the aortic arch and
carotid arteries, which will influence an increase in ADH secretion, and an increase of
plasma volume through water reabsorption.
CASE
1. Describe four primary acid-base disturbances – Respiratory acidosis and
alkalosis, metabolic acidosis and alkalosis. Explain the compensatory changes
that take place in each of these conditions.

- Metabolic acidosis  dereased pH, decreased Pco2, decreased Bicarbonate

- Metabolic alkalosis  increased pH, increased Pco2, Increaed Bicarbonate
- Respiratory acidosis  decreased pH, Increased Pco2, increased Bicarbonate
- Respiratory alkalosis  increased pH, Decreased Pco2, decreased Bicarbonat

Red primary disturbance

Green  compensatory response

Compensatory Changes
-M. Acidosis  Hyperventilation
-M. Alkalosis  Hypoventilation
-R. Acidosis  Increased renal bicarb reabsorption
-R. Alkalosis  Decreased renal bicarb reabsorption

2.
Draw Davenport diagram showing relationship between arterial pH, arterial
PCO2 and Bicarbonate. Insert points in it to show various acid-base
disturbances.
 CASE
4
3) Mention primary acid base disturbances in the following conditions. Pg 463- First Aid
Resp. Muscle Paralysis- Resp Acidosis
Hysterical Hyperventilation-Resp. Alkalosis
Diabetic Ketoacidosis-Met Acidosis
Vomiting-Met Alkalosis
High altitude-Resp. Alkalosis
Upper airway obstruction-Resp acidosis
Antifreeze poisioning- Met. Acodid
NG tube aspiration-Resp acidosis

4)From arterial blood gas values, id simple and mixed metabolic resp.acid base disturbances
Again See pg 463 in first aid. They have helpful charts.
pH PCO2 [HCO3-] Compensation
Met acidosis Decreased Low low Hyperventilate
Met alkalosis Increased Increased high hypoventilate
Resp acidosis decreased Increased Increased Increase
HCO3- reabs
Resp alkalosis increased decreased Decreased. Decrease renal
HCO3 reabs
Note: the ones in bold are the key changes that dictate the response