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chapter 37
Mineral Metabolism
characterized by hyperplasia or tum ors (or both) involv-
ing tw o or m ore endocrine glands in the sam e individual.
M E N syndrom es are inherited as an autosom al dom inant
trait; however, they m ay also arise sporadically. M E N I
syndrom e is characterized by tum ors o f the parathyroid,
pancreatic islet cells, and anterior pituitary. The M E N I
gen e located on chrom osom e
1
lq l3 , w hich is thought to
be a putative tum or suppressor gene, en cod es for a novel
610-am ino-acid protein. The precise role o f M E N I protein
in endocrine cell growth and regulation is not understood.
In patients w ith M E N I syndrom e, several inactivating
m utations in the gen e, nam ely, nonsense, m issense, d ele-
tions, insertions, and donor-splice m utations, have been
identified.
M E N II syndrom e is characterized by m edullary thy-
roid carcinom a, with or without pheochrom ocytom a and
hyperparathyroidism . U nlike M E N I inactivating muta-
tions that results in inactive putative tum or supressor pro-
tein, M E N II is caused by activating m utation o f the RET
(REarranged during Transfection) proto-oncogene, w hich
cod es for a m em brane-bound receptor tyrosine kinase.
T he RET gene is developm entally regulated and the RET-
encoded tyrosine kinase is expressed primarily in neural
crest and urogenital precursor cell. Under normal condi-
tions, glial-derived neurotrophic factor along with other
cell surface com ponents, by binding to tyrosine kinase,
transmits growth and differentiation signals via a num -
ber o f downstream signaling pathways. T he intracellular
signaling pathways involve adapter proteins containing
SH 2 dom ain, w hich interacts with am ino acid residues
surrounding phosphorylated tyrosine residues o f tyrosine
kinase. T hese interactions with adapter proteins stim ulate
R A S-m ediated activation o f the M A P kinase pathway, as
w ell as other signaling pathways. G erm line m utations o f
RET proto-oncogene can give rise to a constituitively acti-
vated tyrosine kinase (gain in function m utation), resulting
in the transm ission o f unregulated growth and differenti-
ation signals. In all these conditions, PTH secretion is not
affected by serum calcium concentration. The signs and
sym ptom s are due to hypercalcem ia, hypophosphatem ia,
hypercalciuria, and hyperphosphaturia. N ephrocalcinosis,
or urolithiasis progressing to nephrolithiasis, is the m ost
com m on com plication and can lead to renal failure. B one
involvem ent results in
osteitis fibrosa cystica,
in which
normal bone is replaced by fibrous tissue. Serum intact
PTH levels are used in the assessm ent o f primary hy-
perparathyroidism . In addition m easurem ent o f PTH in
venous blood draining individual parathyroid gland has
been used for preoperative localization o f m alfunctioning
glands.
A nother exam ple o f a constitutively activated tyro-
sine kinase that results from a B C R -A B L fusion gene
causes
chronic myeloid leukemia.
The fusion gene occurs
due to reciprocal translocation bew een the lon g arms o f
chrom osom e 9 and 22. A n inhibitor (a phenylam inopy-
rim idine derivative) o f the B C R -A B L tyrosine kinase
has produced rem ission o f clinical and hem atological
abnorm alities.
Secondary hyperparathyroidism
develops w henever
hypocalcem ia occurs. This condition frequently arises
from chronic renal failure or intestinal m alabsorption. In
chronic renal failure, the hypocalcem ia is secondary to
hyperphosphatem ia caused by inability o f the diseased
kidneys to excrete phosphate. T he loss o f renal tissue
also decreases la-hyd roxylase activity, w hich leads to
decreased intestinal calcium absorption. This situation
b ecom es clinically important w hen on ly about 25% o f re-
nal function rem ains. In long-term hem odialysis, hypocal-
cem ia can be prevented by adequate am ounts o f ion -
ized calcium in the d ialysis fluid; decrease o f phosphate
intake; decrease o f intestinal phosphate absorption; in-
gestion o f alum inum hydroxide, calcium carbonate, or
calcium lactate; and administration o f la -(O H )D , 1,25-
(O H )
2
D , or dihydrotachysterol. H owever, chronic use
o f alum inum -containing agents can cause toxicity (see
b elow ). If secondary hyperparathyroidism is long stand-
ing,
norm alization
o f
serum
calcium
level
follow -
ing successful renal transplantation m ay not result in
im m ediate norm alization o f serum PTH concentration, al-
though serum PTH usually returns to normal within several
months.
Hypoparathyroidism
is characterized by hypocalcem ia,
hyperphosphatem ia and decrease in circulating PTH. E c-
topic calcification is com m on. The m ost com m on form is
due to inadvertent rem oval o f or dam age to the parathyroid
glands during thyroid gland surgery or surgery to rem ove
m alignant tumors in the neck. T he congenital absence o f
the parathyroids com bined with thym ic agenesis is known
as
diGeorge’s syndrome.
This condition is usually fatal
by age
1 - 2
years because o f hypocalcem ia and im m un-
odeficiency.
Familial hypoparathyroidism
may be an au-
toim m une disease, but its inheritance is com plex and the
presence o f circulating antiparathyroid antibodies does not
alw ays correlate w ell with occurrence o f the disease.
In
pseudohypoparathyroidism,
hypocalcem ia, and hy-
perphosphatem ia are accom panied by normal or high con -
centrations o f PTH in plasm a. In som e form s, resistance
to PTH is due to deficiency o f a G -protein that couples
PTH -receptor binding to cA M P synthesis (Chapter 30).
Pseudopseudohypoparathyroidism
is a variant that o c-
curs in som e relatives o f patients w ith pseudohypoparathy-
roidism . T hese individuals have developm ental and skele-
tal defects w ithout clinical or m etabolic evidence o f
hypoparathyroidism .
