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Tuesday, September 29, 2009

UNIFESP

Universidade Federal de São Paulo - Escola Paulista de Medicina - Organização


Funcional do Corpo Humano - Casos Bioquímicos

Caso 5: Doença de Von Gierke

Desireé Lee
Giuliano Alkmin Bossolani
Jonathan Mamber Czeresnia
Lauro José R. Pajoli

Tuesday, September 29, 2009


Apresentação do Caso
Chiquinha: 13 anos, 128cm e 22.4kg
Paciente Normal

Apresenta abdome dilatado Glicose sérica (mM) 2.8 3.9-5.6

Relata fraqueza frequente, Lactato sérico (mM) 6.6 0.6-2.0


acompanhada de sudorese e
palidez que desaparecem com a Piruvato (mM) 0.43 0.05-0.1
ingestão de alimentos
Ácidos graxos livres
1.6 0.3-0.8
plasmáticos
Teve desenvolvimento lento e tem Triglicerídeio séricos
desempenho escolar insatisfatório 3.15 0.3-1.5
(mM)

Corpos cetônicos (mM) 70 < 7.0


Apresenta fígado aumentado, liso,
caído para a pelve
pH 7.25 7.35-7.45

Células hepáticas inchadas e CO2 total (mM) 12 24-30


dilatadas com áreas portais
comprimidas e enrugadas sem Glicogênio hepático (g/
11 ≤8
100 g de fígado)
reação inflamatória
Lipídeos (g/100g de
20 <5
fígado)
Grande quantidade de material
Glicose-6-fosfatase
hidrolisável por amilase salivar 22 160-260
(unidades/100g de fígado)

Tuesday, September 29, 2009


A doença de Von Gierke

Doença do metabolismo do
glicogênio que afeta a enzima
glicose-6-fosfatase

Incidência: 1 a cada 400.000


nascidos vivos

Herança recessiva autossômica,


localizada no cromossomo 17

Tuesday, September 29, 2009


branching enzyme moves six to eight units to form an ! (1,6) branch. Glycogen degradation is a phospho-
rolysis reaction (breaking of a bond
Glycogenolysis, the pathway for glycogen degradation, is not the reverse of the
using a phosphate ion as a nucle-
biosynthetic pathway. The degradative enzyme glycogen phosphorylase removes
ophile). Enzymes that catalyze phosphorolysis
glucosyl units one at a time from the ends of the glycogen chains, converting them reactions are named phosphorylase. Because

O Glicogênio
to glucose 1-phosphate without resynthesizing UDP-glucose or UTP. A debranch- more than one type of phosphorylase exists,
ing enzyme removes the glucosyl residues near each branchpoint. the substrate usually is included in the name of
Liver glycogen serves as a source of blood glucose. To generate glucose, the the enzyme, such as glycogen phosphorylase
glucose 1-phosphate produced from glycogen degradation is converted to or purine nucleoside phosphorylase.

CH
2 OH
O O
OH
CH
2 OH
O O
OH OH
α –1,6–Glycosidic
bond
α –1,4–Glycosidic OH O
bonds
CH2OH CH2 CH2OH
O O O

O OH O OH O OH

OH OH OH

Glucose residue linked α –1,4 Reducing end attached


to glycogenin
Glucose residue linked α –1,6 Nonreducing ends

Fig. 28.1. Glycogen structure. Glycogen is composed of glucosyl units linked by !-1,4-glycosidic bonds and !-1,6-glycosidic
bonds. The branches occur more frequently in the center of the molecule, and less frequently in the periphery. The anomeric car-
bon that is not attached to another glucosyl residue (the reducing end) is attached to the protein glycogenin by a glycosidic bond.
Polímero de glicose que armazena energia em animais
511
Formado por ligações do tipo α 1-4 (linear) e α 1-6 (ramificação) entre glicoses cíclicas

Encontrado principalmente no fígado (até 10% do peso úmido) e nos músculos (até 2% do
peso úmido)

Tuesday, September 29, 2009


(see Fig. 28.3). The biosynthetic pathway is an energy-requiring pathway; high-
energy phosphate from UTP is used to activate the glucosyl residues to UDP-
glucose (Fig. 28.4). In the degradative pathway, the glycosidic bonds between the
Síntese e Quebra do Glicogênio -
glucosy1 residues in glycogen are simply cleaved by the addition of phosphate to
produce glucose 1-phosphate (or water to produce free glucose), and UDP-glucose
is not resynthesized. The existence of separate pathways for the formation and
Glicogênese e Glicogenólise
degradation of important compounds is a common theme in metabolism. Because

Glycogen Glycogen Glycogen


degradation synthesis
debrancher glycogen synthase
enzyme 4:6 transferase
(branching enzyme)
D1 S3
Glycogen primer
Glucose UDP–G Other pathways
(small
amount) UDP–glucose
pyrophosphorylase
glycogen
phosphorylase UTP
S2
Glucose–1–P

phosphoglucomutase
Glycolysis
D2 Glucose–6–P Pentose–P pathway
glucose 6 – hexokinase Other pathways
phosphatase glucokinase
(liver only) (liver)
ATP
S1
Pi Glucose

Cell membrane

Glucose

Fig. 28.3. Scheme of glycogen synthesis and degradation. S1. Glucose 6-phosphate is formed
Tuesday, September 29, 2009 from glucose by hexokinase in most cells, and glucokinase in the liver. It is a metabolic branch-
Regulação Hormonal do
Glicogênio no Fígado
Jejum: Sangue: Fígado:
Glucagon Síntese de Glicogênio
Insulina Degradação de Glicogênio

Refeição: Sangue:
Glucagon
Insulina Fígado:
Glicose Síntese de Glicogênio
Degradação de Glicogênio
Tecido:
Glicose

Exercício e stress:
Sangue: Fígado:
Adrenanina Síntese de Glicogênio
Degradação de Glicogênio
Tuesday, September 29, 2009
Regulação Hormonal do
n state of glycogen phosphorylase in the degradative pathway and glycogen
in the biosynthetic pathway. An increase of glucagon and decrease of in
ng the fasting state initiates a cAMP-directed phosphorylation cascade, w
Glicogênio no Fígado
ts in the phosphorylation of glycogen phosphorylase to an active enzyme, an

Refeição Jejum
A ATP
P

Glycogen phosphorylase b Glycogen phosphorylase a


(inactive) (active)

B ATP
P

Glycogen synthase I (or a) Glycogen synthase D (or b)


(active) (inactive)

28.7. The conversion of active and inactive forms of glycogen phosphorylase (A


Tuesday, September 29, 2009
Regulação Hormonal do
Glicogênio no Músculo
Jejum:
Músculo:
Sangue: Síntese de Glicogênio
Insulina Transporte de Glicose

Refeição:
Sangue: Músculo:
Insulina Síntese de Glicogênio
Glicose Transporte de Glicose

Exercício e stress:
Sangue: Músculo:
Adrenalina Síntese de Glicogênio
Tecido: Degradação de Glicogênio
AMPc Glicólise

Tuesday, September 29, 2009


Manutenção da Glicemia
I. STRUCTURE OF GLYCOGEN
CHAPTER 28 / FORMATION AND DEGRADATION OF GLYCOGEN 513
Glycogen, the storage form of glucose, is a branched glucose polysaccharide com- Glycogen
posed body
Bodie, a 19-year-old of chains
builder,ofwas
glucosyl units
rushed to linked emer-
the hospital by !-1,4 bonds with branches
!-1,6treadmill
Jim Bodie’s everyand
exercise
8 toOne-half
room in a coma. 10 residues (see Fig.
hour earlier, 28.1).
his mother hadInheard
a molecule
a loud of this highly
most otherbranched structure,
types of moderate exer-

Pelo Glicogênio
Glucose–1–P
onlybasement
ng sound in the one glucosyl
where Jim residue haslifting
had been an anomeric
weights and carbon that is cisenot involving
linked towhole body move-
another glu-
ment (running, skiing, dancing, tennis)
daily workout on the
cose treadmill.
residue. ThisSheanomeric
found her son on theatfloor
carbon thehav-
beginning of the
increase the chain is of
utilization attached to theand
blood glucose
ing movements of all muscles (a grand mal seizure). Glucose–6–P
protein glycogenin. The other ends of the chains other
rgency room, the doctors learned that despite the objections of his
are called
fuels bynonreducing
skeletal muscles.ends
The(see
blood
glucose is normally supplied by the stimula-
Chapter
ends, Jim regularly used5). The branched
androgens structure
and other anabolic permits
steroids in anrapidtion
degradation and rapid synthesis Glycolysis
of liver glycogenolysis and gluconeoge-
up his muscleof glycogen because enzymes can work on severalnesis.
mass. chains simultaneously from the
hysical examination,
multiplehenonreducing
was comatose with ends.occasional involuntary ATP Lactate
ments of his extremities.
Glycogen FoamyGlicogênio
is saliva dripped
present muscular:
from
in tissueshis as
mouth. He é of very high molecular weight
polymers CO2
tongue and had lost bowel and bladder control at the height of the
(107–108) collectedparatogetherUSOinLOCAL, glycogen particles. The enzymes involved in glyco-
ory reported gen synthesis
a serum glucoseandleveldegradation, and somelow).
of 18 mg/dL (extremely of the regulatory enzymes, are bound to
us infusion ofthe
5% surface
glucose (5ofgportanto
the glycogen
of glucose NÃO mL ofTEM
particles.
per 100 solution),papel
na manutenção da
n started earlier, was increased to 10%. In addition, 50 g glucose was
seconds through the intravenous tubing.
glicemia
II. FUNCTION OF GLYCOGEN IN SKELETAL MUSCLE
AND LIVER
TURE OF GLYCOGEN
storage form Glycogen
of glucose, isisa branched Glycogen
found inglucose
most polysaccharide com- it serves as a reservoir
cell types, where Glycogen of glucosyl
s of glucosyl units linked by !-1,4 bonds with !-1,6 branches every
unitsInfora molecule
es (see Fig. 28.1). ATP generation frombranched
of this highly glycolysis.
structure, Glucose–1–P
Glucose–1– P
Glycogen is degraded mainly to glucose
syl residue has an anomeric carbon that is not linked to another glu- 1-phosphate, which is converted to glu-
This anomericcose
carbon6-phosphate.
at the beginning In ofskeletal
the chainmuscle andtoother
is attached the cell types, the glucose 6-phosphate Glucose–6–P
enin. The other ends the
of the chains are pathway
called nonreducing ends (see Glucose– 6 – P
enters glycolytic (Fig. 28.2). Glycogen is an extremely important fuel glucose 6–phosphatase
he branched structure permits rapid degradation and rapid synthesis
source for skeletal muscle when ATP demands are high and when Glycolysis glucose 6-phos- Gluconeo- Glucose
Glicogênio hepático:
ecause enzymes can work on several chains simultaneously from the
ducing ends. phate is used rapidly in anaerobic glycolysis. In many other cell types,
ATP Lactatethe small genesis
s present in glycogen responsável pela
reservoirofserves
tissues as polymers very higha similar
molecularpurpose;
weight it is an emergency CO2
fuel source that
ected togethersupplies
in glycogenglucose
particles.for
Thethe generation
enzymes involvedof ATP in the absence of oxygen or during
in glyco-
and degradation, manutenção da glicemia
and someblood
restricted of the regulatory
flow. In enzymes,
general,areglycogenolysis
bound to and glycolysis are activated
Fig. 28.2. Glycogenolysis in skeletal muscle
the glycogen particles.
porcells.
together in these meio da glicogenólise and liver. Glycogen stores serve different func-
Glycogen serves a very different purpose in liver than in skeletal muscle and other
ON OF GLYCOGEN
em28.2).
tissues (seeINFig.
períodos
SKELETAL Liver
de jejum
glycogen is the first and immediate source of glucose
MUSCLE
tions in muscle cells and liver. In the muscle
and most other cell types, glycogen stores
VER (entre
for the maintenance 2h glucose
of blood e 30h) levels. In the liver, the glucose 6-phosphate that serve as a fuel source for the generation of
ound in most iscell
generated from
types, where glycogen
it serves as a degradation is hydrolyzed to glucose
reservoir of glucosyl Glycogen by glucose 6-phos- ATP. In the liver, glycogen stores serve as a
generation phatase,
from 29,an
glycolysis.
Tuesday, September enzyme present only in the liver and kidneys.Glucose–1–
2009 Glycogen P degradation thus source of blood glucose.
Neoglicogênese

Tuesday, September 29, 2009


Glucose

Pi
glucose 6 –phosphatase

Glucose 6–phosphate

Fructose 6–phosphate

Pi
fructose 1,6 –bisphosphatase

Fructose 1,6–bisphosphate

Dihydroxyacetone–P Glyceraldehyde–3–P

Liberação de reservas Glycerol Glycerol–3–P

Phosphoenolpyruvate
Produzido no músculo a partir
phosphoenolpyruvate
carboxykinase de outros AA ou de glicose
TCA Oxaloacetate
Amino cycle Amino
acids acids
Alanine
pyruvate
carboxylase Pyruvate

Lactate Glicólise Anaeróbica


Tuesday, September 29, 2009
Retomando o Caso
Chiquinha: 13 anos, 128cm e 22.4kg
Paciente Normal

Apresenta abdome dilatado Glicose sérica (mM) 2.8 3.9-5.6

Relata fraqueza frequente, Lactato sérico (mM) 6.6 0.6-2.0


acompanhada de sudorese e
palidez que desaparecem com a Piruvato (mM) 0.43 0.05-0.1
ingestão de alimentos
Ácidos graxos livres
1.6 0.3-0.8
plasmáticos
Teve desenvolvimento lento e tem Triglicerídeio séricos
desempenho escolar insatisfatório 3.15 0.3-1.5
(mM)

Corpos cetônicos (mM) 70 < 7.0


Apresenta fígado aumentado, liso,
caído para a pelve
pH 7.25 7.35-7.45

Células hepáticas inchadas e CO2 total (mM) 12 24-30


dilatadas com áreas portais
comprimidas e enrugadas sem Glicogênio hepático (g/
11 ≤8
100 g de fígado)
reação inflamatória
Lipídeos (g/100g de
20 <5
fígado)
Grande quantidade de material
Glicose-6-fosfatase
hidrolisável por amilase salivar 22 160-260
(unidades/100g de fígado)

Tuesday, September 29, 2009


Sintoma: Abdome Dilatado e
Fígado Inchado
Biópsia mostra: acúmulo de glicogênio e de lipídeos no parênquima hepático

Glucagon Lipídeos
Teor baixo de
promove acumulam-se
glicose no
liberação de no fígado
sangue
lipídeos

Glicerol usado na
Neoglicogênese e Inchaço do fígado gliconeogênese e
glicogenólise não e dilatação do ácidos graxos são
ocorrem abdome acumulados no
fígado para
serem reduzidos
a corpos
cetônicos
Acúmulo de
Falta da enzima
glicogênio no
glicose-6-fosfatase
fígado

Tuesday, September 29, 2009


Sintoma: fraqueza,
sudorese, palidez
São todos sintomas de hipoglicemia, então desaparecem com a
ingestão de alimentos

Teor baixo de
Neoglicogênese e
Falta da enzima glicose no
glicogenólise não
glicose-6-fosfatase sangue -
ocorrem
hipoglicemia

ALIMENTO =
ENTRADA DE
GLICOSE NO
Normalização da
SANGUE
glicemia =
desaparecimento
dos sintomas

Tuesday, September 29, 2009


Sintoma: Desenvolvimento lento, baixo
peso e baixa estatura

O cérebro é o orgão com maior


demanda por glicose. Como
Chiquinha tem hipoglicemia sempre
que fica algumas horas sem comer,
seu cérebro não se desenvolveu
como deveria

Além do cérebro, Chiquinha tem


problemas de crescimento. Com a
falta de glicose, o crescimento dos
tecidos é mais lento, o que explica
seu baixo peso e sua baixa
estatura

Tuesday, September 29, 2009


Exames
Paciente Normal

Glicose sérica (mM) 2.8 3.9-5.6 OK


Lactato sérico (mM) 6.6 0.6-2.0

Piruvato (mM) 0.43 0.05-0.1

Ácidos graxos livres plasmáticos 1.6 0.3-0.8

Triglicerídeio séricos (mM) 3.15 0.3-1.5

Corpos cetônicos (mM) 70 < 7.0

pH 7.25 7.35-7.45

CO2 total (mM) 12 24-30

Glicogênio hepático (g/100 g de


fígado)
11 ≤8
OK
Lipídeos (g/100g de fígado) 20 <5
OK
Glicose-6-fosfatase (unidades/100g
de fígado)
22 160-260 OK
Tuesday, September 29, 2009
Níveis de Lactato e Piruvato

Neoglicogênese e
Falta da enzima glicogenólise param Acúmlo de
glicose-6-fosfatase no estágio de glicose-6-fosfato
glicose-6-fosfato

562 SECTION FIVE / CARBOHYDRATE METABOLISM

Lactato Piruvato
A
CH3 lactate CH3
dehydrogenase
H C OH C O
COO– NAD+ NADH+ + H+ COO–
Lactate Pyruvate

B CH3 alanine CH3


+ aminotransferase
H C NH3 C O
Sofre o
COO– COO–
resto da
Alanine Pyruvate
glicólise
C CH2OH CH2OH
Tuesday, September 29, 2009
HO C H C O
Exames
Paciente Normal

Glicose sérica (mM) 2.8 3.9-5.6 OK


Lactato sérico (mM) 6.6 0.6-2.0 OK
Piruvato (mM) 0.43 0.05-0.1
OK
Ácidos graxos livres plasmáticos 1.6 0.3-0.8

Triglicerídeio séricos (mM) 3.15 0.3-1.5

Corpos cetônicos (mM) 70 < 7.0

pH 7.25 7.35-7.45

CO2 total (mM) 12 24-30

Glicogênio hepático (g/100 g de


fígado)
11 ≤8
OK
Lipídeos (g/100g de fígado) 20 <5
OK
Glicose-6-fosfatase (unidades/100g
de fígado)
22 160-260
OK
Tuesday, September 29, 2009
Níveis de Ácidos Graxos
Livres e Corpos Cetônicos

Glucagon
Teor baixo de promove Níveis de
glicose no liberação de ácidos graxos
sangue ácidos graxos sobem
livres

Fígado converte
ácidos graxos a
corpos cetônicos

Os corpos cetônicos
são usados pelo
cérebro como
substrato
alternativo à glicose

Tuesday, September 29, 2009


Blood Glycogen Acetyl CoA
Glucose
Liver 2 3
1 Insulin Glucose Brain
TCA
Glucose
Glucagon
12 CO2 [ATP]
[ATP]

FA Acetyl CoA
4
7 11
Glycerol KB
Lactate RBC
Lactate
Urea
10
Adipose 9
KB
5 AA Kidney
TG FA
8

6
AA

Acetyl CoA Protein

Urine
TCA
Muscle CO2 [ATP]

Tuesday, September 29, 2009


pH e níveis de CO2
Acidose metabólica

HCO3+ + H+ CO2 + H2O


Excesso de
corpos Diminuição do pH
cetônicos

Ácidos
relativamente
Abaixa
fortes
[bicarbonato]
tamponados por
bicarbonato

Descolamento do
Excesso equilíbrio bicarbonato
de lactato Neurônios são muito sensíveis à - gás carbônico -->
acidose, portanto, esse diminuição da
fenômeno também compromete concentração de CO2
o desenvolvimento nervoso

Tuesday, September 29, 2009


Exames
Paciente Normal

Glicose sérica (mM) 2.8 3.9-5.6 OK


Lactato sérico (mM) 6.6 0.6-2.0 OK
Piruvato (mM) 0.43 0.05-0.1
OK
Ácidos graxos livres plasmáticos 1.6 0.3-0.8 OK
Triglicerídeio séricos (mM) 3.15 0.3-1.5 OK
Corpos cetônicos (mM) 70 < 7.0 OK
pH 7.25 7.35-7.45 OK
CO2 total (mM) 12 24-30 OK
Glicogênio hepático (g/100 g de
fígado)
11 ≤8
OK
Lipídeos (g/100g de fígado) 20 <5
OK
Glicose-6-fosfatase (unidades/100g
de fígado)
22 160-260
OK
Tuesday, September 29, 2009
s inhibited, and vice versa. liver, glucokinase (Fig. 28.3). Glucose 6-phosphate is the precursor of glycolysis,
the pentose phosphate pathway, and of pathways for the synthesis of other sugars.
In the pathway for glycogen synthesis, glucose 6-phosphate is converted to glucose
1-phosphate by phosphoglucomutase, a reversible reaction.
Glycogen is both formed from and degraded to glucose 1-phosphate, but the

Outras enzimas do
biosynthetic and degradative pathways are separate and involve different enzymes
(see Fig. 28.3). The biosynthetic pathway is an energy-requiring pathway; high-
energy phosphate from UTP is used to activate the glucosyl residues to UDP-
glucose (Fig. 28.4). In the degradative pathway, the glycosidic bonds between the
glucosy1 residues in glycogen are simply cleaved by the addition of phosphate to

metabolismo do glicogênio
produce glucose 1-phosphate (or water to produce free glucose), and UDP-glucose
is not resynthesized. The existence of separate pathways for the formation and
degradation of important compounds is a common theme in metabolism. Because

Glycogen Glycogen Glycogen


degradation synthesis
debrancher glycogen synthase
enzyme 4:6 transferase
(branching enzyme)
D1 S3
Glycogen primer
Glucose UDP– G Other pathways
(small
amount) Quantidades
Quantidades UDP – glucose
pyrophosphorylase são normais
são normais glycogen
em pacientes
phosphorylase
em pacientes UTP
afetados
afetados S2
Glucose–1– P

phosphoglucomutase
Glycolysis
D2 Glucose– 6 – P Pentose– P pathway
glucose 6 – hexokinase Other pathways
phosphatase glucokinase
(liver only) ( liver )
ATP
S1
Pi Glucose

Cell membrane

Glucose

Fig. 28.3. Scheme of glycogen synthesis and degradation. S1. Glucose 6-phosphate is formed
Tuesday, September 29, 2009 from glucose by hexokinase in most cells, and glucokinase in the liver. It is a metabolic branch-
Tratamento - Dieta
Objetivo: manter os níveis de glicose
sérica

Lactose, galactose, frutose e sacarose


devem ser evitados pois também
dependem da glicose-6-fosfatase para
serem metabolizados

Uma dieta rica em proteínas não é


recomendável, já que a
neoglicogênese é afetada

Deve-se ingerir amido de milho não


cozido (maizena) ou maltodextrina

Tuesday, September 29, 2009


Tratamento -
Administração Parenteral
Desaparecimento Normalização da
de fraqueza e liberação de
sudorese corpos cetônicos

Administração
Normalização da
contínua de Controle da
liberação de
glicose glicemia
ácidos graxos
endovenosa
livres
Diminuição da
acidose

Maior dano
tecidual
Maior
armazenamento
de glicogênio

Continuidade da
produção de
lactato

Tuesday, September 29, 2009


Outras anomalias do
metabolismo do glicogênio

Tuesday, September 29, 2009


Bibliografia

Mark’s Basic Medical Biochemistry - Smith, C; Marks A.D; Liberman,


M

Lehninger Princípios de Bioquímica - Nelson, D.L; Cox, M.M

Manual de Bioquímica com Correlações Clínicas - Devlin, T.M

Bioquímica: Uma Aborgagem Dirigida por Casos - Montgomery, R.

www.uptodate.com

www.pubmed.com

Tuesday, September 29, 2009