530
UNIT FOUR
In George III’s time, physicians were permit-
ted to do little to the royal body, basing diagnoses
on what the patient told them. Twentieth-century
researchers found that George III’s red urine was
caused by an inborn error of metabolism. In por-
phyria variegata, because of the absence of an
enzyme, part of the blood pigment hemoglobin,
called a porphyrin ring, is routed into the urine
instead of being broken down and metabolized
by cells. Porphyrin builds up, causing many of
the nervous system symptoms. Examination of
the medical records of King George III’s descen-
dants reveals several of them also had porphyria
variegata. The underlying defect in red blood cell
recycling had appeared in its various guises as
diF
erent problems.
King George III’s porphyria, however, was
highly unusual—it appeared later in life, with
frequent, severe episodes. In 2005, British and
Australian researchers sought another causative
factor—heavy metal poisoning. Arsenic disturbs
hemoglobin synthesis and in combination with
lead found in certain alcoholic beverages of the
time, triggers severe porphyria symptoms.
Clues to arsenic poisoning came from the
king’s hair, which had been on exhibit at the
K
ing George III, who ruled England at the
time of the American revolution, inherited
an abnormality of hemoglobin synthesis
that, combined with arsenic poisoning, caused a
strange sequence of signs and symptoms.
At age fifty, the king first experienced
abdominal pain and constipation, followed by
weak limbs, fever, a rapid pulse, hoarseness, and
dark red urine. Next, nervous system symptoms
began, including insomnia, headaches, visual
problems, restlessness, delirium, convulsions,
and stupor. His confused and racing thoughts,
combined with his ripping off his wig and run-
ning about naked while at the peak of a fever,
convinced court observers that the king was mad.
Just as Parliament was debating his ability to rule,
he mysteriously recovered.
But George III’s plight was far from over. He
suF
ered a relapse thirteen years later, then again
three years after that. Always the symptoms
appeared in the same order—abdominal pain,
fever, and weakness progressing to the nervous
system symptoms. When an attack in 1811 caused
permanent stupor, the Prince of Wales dethroned
him. George III lived for several more years, expe-
riencing further episodes.
Science Museum in London since 1928. The hairs
had failed to yield DNA, but they did have whop-
ping levels of arsenic—17 parts-per-million
(ppm), compared to 0.05 ppm in control hairs.
A level above 1 ppm is considered evidence of
poisoning!
The presence of arsenic throughout the royal
hairs indicated a slow, steady exposure, rather
than contamination. Researchers identified the
source of the poison in the king’s medical records.
While at a “provincial madhouse,” he had been
given “emetic tartar,” a concoction of potassium
antimony tartrate. When mined, the antimony is
often contaminated with arsenic. The king was
forced to take the medication, which, in combina-
tion with his mutant genes, caused the episodes
of porphyria.
People with various porphyria-related
symptoms, including reddish teeth, pink urine,
excess hair, and photosensitivity (avoidance of
daylight), may have inspired the vampire and
werewolf legends (see ±
g. 4.26). Today, porphy-
ria variegata remains rare, and people who have
it are often misdiagnosed with a seizure disor-
der. Unfortunately, some seizure medications
and anesthetics worsen symptoms.
14.1
CLINICAL APPLICATION
King George III and Porphyria Variegata
Heme further decomposes into iron and a greenish
pigment called
biliverdin.
The iron, combined with a pro-
tein called
transferrin,
may be carried by the blood to the
hematopoietic (red blood cell-forming) tissue in the red bone
marrow and reused in synthesizing new hemoglobin. About
80% of the iron is stored in the liver cells in the form of an
iron-protein complex called
ferritin.
In time, the biliverdin is
converted to an orange pigment called
bilirubin.
Biliverdin
and bilirubin are excreted in the bile as bile pigments (see
F g. 14.7 and
f g. 14.9
).
The polypeptide globin chains break down into amino
acids. The individual amino acids are metabolized by the
macrophages or released into the blood.
Table 14.3
summa-
rizes the process of red blood cell destruction.
PRACTICE
14
What happens to damaged red blood cells?
15
What are the products of hemoglobin breakdown?
Types of White Blood Cells
White blood cells,
or
leukocytes
(lu
ko-sı¯tz), protect against
disease. Leukocytes develop from hematopoietic stem cells
in the red bone marrow in response to hormones, much as
red cells form from precursors upon stimulation from EPO.
These hormones fall into two groups—
interleukins
(in
ter-lu-
kinz) and
colony-stimulating factors
(CS±s). Interleukins are
numbered, while most colony-stimulating factors are named
for the cell population they stimulate. Blood transports white
blood cells to sites of infection. White blood cells may then
leave the bloodstream, as described later in this chapter.
Normally, five types of white cells are in circulating
blood. They differ in size, the composition of cytoplasm, the
shape of the nucleus, and their staining characteristics, and
are named for these distinctions. ±or example, leukocytes
with granular cytoplasm are called
granulocytes
(gran
u-
lo-sı
¯tz
), whereas those without cytoplasmic granules are
called
agranulocytes
(a-gran
u-lo-sı¯tz).
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