Mariam Raed Radwan 122
CLINICAL NOTES FOR BIOCHEMISTRY
“Midterm material”
Chapter 7
Abnormal degradation of disaccharides : any defect in a specific disaccharidase activity causes
the passage of undigested carbohydrate into the large intestine.
Consequence:
1. Osmotic diarrhea : the presence of this osmotically active material ( undigested
disaccharides) draws water from the mucosa into the large intestine.
2. Abdominal cramps, diarrhea, and flatulence: Diarrhea is reinforced by the bacterial
fermentation (= large volumes of CO2 and H2 ).
Disaccharidase deficiencies (disaccharide intolerance) Reasones:
1. Hereditary deficiencies
2. Intestinal diseases:enzymes are rapidly lost in normal individuals with severe diarrhea
causing a temporary, acquired enzyme deficiency.
3. Malnutrition.
4. Drugs that injure the mucosa of the small intestine.
Lactose intolerance:
1. Over 60% of the worlds
2. In certain populations (90% of adults of African or Asian descent are Lactase deficient).
3. Age-dependent loss of lactase activity starting at age 2 represents a reduction in the
amount of enzyme produced.
4. Caused by a small variations in the DNA sequence of a region on Chromosome 2 that
controls expression of the gene for lactase
5. Treatment:
1. Reduce milk intake. eat yogurts and some cheeses (bacterial action and aging
process decrease lactose content) green vegetables to ensure adequate calcium intake.
2. Use /lactase-treated products.
3. Take /actase in pill form prior to eating.
[Note: Because the loss of lactase is the norm for most of the world's adults, use of the terms
adult type hypolactasia or lactase non persistence rather than lactose intolerance is becoming
more common.] Rare cases of congenital Lactase deficiency are known.
Congenital sucrase-isomaltase deficiency
1. Autosomal recessive disorder.
2. Results in an intolerance of ingested sucrose.
3. Congenital SI deficiency is more common in the Inuit people of Greenland and Canada
than individuals of European descent.اتوقع بس للعلم مش ضروري
4. Treatment: dietary restriction of sucrose and enzyme replacement therapy.
Diagnosis:
1. Identification of a specific enzyme deficiency by performing oral tolerance tests with the
individual disaccharides.
2. Measurement of H2 in the breath for determining the amount of ingested carbohydrate
not absorbed by the body, but which is metabolized instead by the intestinal flora
Chapter 8
Lactic acidosis:
1. Elevated concentrations of lactate in the plasma (a type of metabolic acidosis)
2. Occur when there is a collapse of the circulatory system, such as with myocardial
infarction, pulmonary embolism, and uncontrolled hemorrhage, or when an individual is
in shock.
3. Reason: The failure to bring adequate amounts of oxygen to the tissues results in
impaired oxidative phosphorylation and decreased ATP synthesis. The cells rely on
anaerobic glycolysis for generating ATP, producing lactic acid as the end product.
[Note: Production of even meager amounts of ATP may be lifesaving during the period required
to reestablish adequate blood flow to the tissues.]
4. **oxygen required to recover from a period when oxygen availability has been
inadequate is termed the oxygen debt.
[Note: oxygen debt is often related to patient morbidity or mortality. In many clinical situations,
measuring the blood levels of lactic acid allows the rapid, early detection of 02 debt in patients
and the monitoring of their recovery.]
**Glucokinase functions as a glucose sensor in blood glucose homeostasis. Inactivating
mutations of glucokinase are the cause of a rare form of diabetes, maturity onset diabetes of
the young type 2 (MODY 2) that is characterized by impaired insulin secretion and
hyperglycemia.
Arsenic poisoning:
1. The toxicity of arsenic due to the inhibition by trivalent arsenic (arsenite) of enzymes
such (PDHC), which require lipoic acid as a coenzymes.
2
2. Pentavalent arsenic (arsenate) prevent net ATP and NADH production by competing
with Pi as a substrate for glyceraldehyds 3-phosphate dshydrogenase, forming a
complex that hydrolyzes to form 3-phosphoglycerate.
3. The cell is deprived of energy obtained from the glycolytic pathway.
[Note: Arsenate also competes with Pi binding to the F1 domain of ATP synthase resulting in
formation of ADP-arsenate that is rapidly hydrolyzed.]
Pyruvate kinase deficiency:
1. Mature RBC lack mitochondria, they are completely dependent on glycolysis for ATP
production. ATP is required to meet the metabolic needs of RBC and to fuel the ion
pumps necessary for the maintenance of the flexible, biconcave shape that allows them
to squeeze through narrow capillaries.
2. The anemia observed in glycolytic enzyme deficiencies is a consequence of the reduced
rate of glycolysis, leading to decreased ATP production by substrate-level
phosphorylation.
3. The resulting alterations in the RBC membrane lead to changes in cell shape and,
ultimately, to phagocytosis by cells of the mononuclear phagocyte system, particularly
splenic macrophages.
4. The premature death and lysis of RBC result in mild-to-severe nonspherocytic hemolytic
anemia, with the severe form requiring regular transfusions.
5. Among patients with rare genetic defects of glycolytic enzymes, the majority has a
deficiency in PK.
[Note: Liver PK is encoded by the same gene as the RBC isozyme. However, liver cells show no
effect because they can synthesize more PK and can also generate ATP by oxidative
phosphorylation.]
6. Severity depends both on the degree of enzyme deficiency (generally 5%-35% of
normal levels) and on the extent to which RBC compensate by synthesizing increased
levels of 2,3-BPG .
7. Almost all individuals with PK deficiency have a mutant enzyme that shows altered
kinetics or decreased stability.
8. Individuals heterozygous for PK deficiency have resistance to the most severe forms of
malaria.
9. The tissue-specific expression of PK in RBC and the liver results from the use of
different start sites in transcription of the gene that encodes the enzyme.
**
PK gene mutation→ altered primary structure of the enzyme → altered folding → PK deficiency
(Hemolytic Anemia)
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Chapter 9
**Deficiencies of thiamine or niacin [ cause serious central nerwus system problems because
brain cells are unable to produce sufficient ATP (via the TCA cycle) if the PDHC is inactive].
Wernicke-Korsakoff
1. Encephalopathypsychosis syndrome due to thiamine deficiency
2. May be seen with alcohol abuse
DEFICIENCY:
*A deficiency of the a subunits of the tetrameric E1 component of the PDHC, though
very rare, is the most common biochemical cause of congenital lactic acidosis.
- The deficiency results in a decreased ability to convert pyruvate to acetyl CoA, causing
pyruvate to be shunted to lactate via lactate dehydrogenase.
- This creates particular problems for the brain, which relies on the TCA cycle for most of
its energy and is particularly sensitive to acidosis.
- Symptoms include neurodegeneration, muscle spasticity, and, in the neonatal-onset
form, early death.
- X linked, and because both males and females may be affected, the deficiency is
classified as X-linked dominant.
- There is no proven treatment for PDHC deficiency but dietary restriction of carbohydrate
and supplementation with thiamine may reduce symptoms in select patient.
Leigh syndrome
1. (Subacute necrotizing encephalomyelopalhy) is a rare.
2. Progressive, neurodegenerative disorder caused by defects in mitochondrial ATP
production
3. A result of mutations In genes that encode proteins of PDHC, the ETC, or ATP synthase.
4. Both nuclear and mibitchonclrial DNA can be affecled.
Arsenic poisoning:
1. Pentavalent arsenic (arsenate) can interfere with glycolysis at the glyceraldehyde
3-phosphate step →decreasing ATP production.
2. Arsenic poisoning is due primarily to inhibition of enzyme complexes that require lipoic
acid as a coenzyme, including PDH, a-ketaglutarate delrydrogenase .
3. Arsenite (the trivalent form of arsenic) forms a stable complex with the thiol (-SH) groups
of lipoic acid, making that compound unavailable to serve as a coenzyme. When it binds
to lipoic acid in the PDHC, pyruvate (and, consequendy, lactate) accumulates.
4. As with PDHC deficiency, this particularly affects the brain, causing neurologic
disturbances and death.
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Chapter 11
GLYCOGEN STORAGE DISEASES
1. GSD are a group of genetic diseases caused by defects in enzymes required for
glycogen degradation or, more rarely, glycogen synthesis.
2. They result either in formation of glycogen that has an abnormal structure or in the
accumulation of excessive amounts of normal glycogen in specific tissues as a result of
impaired degradation.
3. A particular enzyme may be defective in a single tissue, such as the liver (resulting in
hypoglycemia) or muscle (causing muscle weakness), or the defect may be more
generalized, affecting a variety of tissues, such as the heart and kidneys.
4. Severity ranges from fatal in early childhood to mild disorders that are not life
threatening.
[Note: Only GSD II is lysosomal because glycogen metabolism occurs primarily in the cytosol.]
McArdle disease(type V)
(SKELETAL MUSCLE GLYCOGEN PHOSPHORYLASE OR llYOPHOSPHORYLASE
DEFICIENCY)
1. Affect skeletal muscles
2. Liver enzyme normal
3. No rise In blood lactate during strenuous exercise
4. Myogloblnemla and myogloblnurla may be seen
5. Relatively benign, chronic condition
6. High level or glycogen with normal atructure In muscle
7. Deficiency of the liver isozyme causes type VI: Hers disease with mild fasting
hypoglycemia.
TYPE II: POMPE DISEASE
(LYSOSOMAL a(1-+4)-GLUCOSIDASE DEFICIENCY)
1. Only GSD that is lysosomal storage disease
2. Excessive glycogen in lysosomes
3. Normal glycogen structure
4. Normal blood suger levels
5. Hypotonia and muscle weakness
6. Infantile form : frequently fatal due to heart failure
7. Enzyme replacement therapy available
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TYPE Ill: CORI DISEASE
(4."4 TRANSFERASE and/or AlfYLD-a(1-+6)-GLUCOSJDASE DEFICIENCY)
1. Fasting hypoglycemia
2. Abnormal Glycogen structure with four or one glucosyl residues at branch point
TYPE la: VON GIERKE DISEASE
(GLUCOSE 6-PHOSPHATASE DEFICIENCY) TYPE lb: GWCOSE &PHOSPHATE
TRANSLOCASE DEFICIENCY
1. Affects liver and kidney
2. Fating hypoglycemia:sever
3. Fatty liver, hepato- and runomegaly
4. Progressive renal disease
5. Growth retardation and delayed puberty
6. Lactic acidmis, hyperlipidemia, and hyperuricemia
7. Normal glycogan structurere lncreased glycogen stored
8. Type lb also characterized by neutropenia and recurrent Infections.
9. Tretltment: nocturnal gastric Infusions of glucoae or regular administration of uncooked
cornstarch .
**Lysosomal storage diseases
are genetic disorders characterized by the accumulation of abnormal amounts of
carbohydrates or lipids primarily due to their decreased lysosomal degradation resulting
from decreased activity or amount of lysosomal acid hydrolases.
Chapter 12
A deficiency of one of the key enzymes required for the entry of fructose into metabolic
pathways.
FRUCTOSE
Essential fructosuria
1. Deficiency of fructokinase
2. Autosomal recessive
3. More common than HFI
4. Benign
5. Fructose accumulate in urine
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Hereditary fructose intolerance
1. Autosomal recessive
2. Deficiency in aldolase B leads to intercellular trapping of fructose 1 P
3. Causes:
● Severe hypoglycemia.
● Vomiting ( decreased availability of hepatic ATP decreases gluconeogenesis)
● Jaundice , hemorrhage( decreased availability of protein synthesis causing a
decrease in blood-clotting factors and other essential proteins)
● Hepatomegaly (enlarged liver)
● Renal dysfunction (Renal reabsorption of P1 is decreased)
● Hyperuricemia, and lactic acidemia (Fructose 1-phosphate accumulates, drop
in the level of inorganic phosphate (Pi) and ATP production as a result.(AMP)
rises. The AMP is degraded → hyperuricemia. The drop in P1 also inhibits
glycogenolysis).
4. Fructose, sucrose. and sorbitol can cause hepatic failure and death.
5. Treatment: removal of fructose and sucrose from the diet.
6. Diagnosis of HFI can be made on the basis of fructose in the urine, enzyme assay using
liver cells, or by DNA-based testing .
[NOTE:The first symptoms of HFI appear when a baby is weaned from lactose-containing milk
and begins ingesting food containing sucrose or fructose].
[Note: Individuals with HFI display an aversion to sweets and, consequently, have an absence of
dental caries.]
GALACTOSE
CLASSIC GALACTOSEMIA
1. Galactose 1-phosphate uridylyltransferase deficiency galactose accumulates.
2. Autosomal recessive disorder
3. This reaction is catalyzed by aldose reductase, the same enzyme that reduces glucose
to sorbitol.causing galactosemia and galactosuria
4. Physiologic consequences are similar to those found in HFI but a broader spectrum of
tissues is affected.
Accumulation of galactose 1-phosphate and galactitol In the liver (liver damage), brain
(brain damage), and eyes (cataracts)
5. Prenatal diagnosis by chorionic villus sampling /newborn screening available
6. Treatment: removal of galactose from diet
7. Despite adequate treatment, at risk for cataracts / developmental delay / In female,
premature ovarian failure.
[Note: Deficiencies in galactokinase and the epimerase result in less severe disorders of
galactose metabolism, although cataracts are common]
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GALACTOKINASE DEFICIENCY
1. Rare autosomal recessive disorder
2. Elevation of galactose In blood (galactosemia) and urine (galactosuria )
3. Galactitol accumulation if galactose present In diet (elevated galactitol causing cataracts)
4. Treatment: dietary restriction
Chapter 13
G6PD DEFICIENCY
1. Hereditary condition
2. Characterized by hemolytic anemia caused by the inability to detoxify oxidizing agents.
3. The most common disease-producing enzyme abnormality in humans ( highest
prevalence in the Middle East, tropical Africa and Asia, and parts of the Mediterranean)
4. X linked and is, in fact, a family of deficiencies caused by a number of different mutations
in the gene encoding G6PD. Only some of the resulting protein variants cause clinical
symptoms.
5. Most individuals who have inherited one of the G6PD mutations do not show clinical
manifestations (that is, they are asymptomatic).
6. Some patients with G6PD deficiency develop hemolytic anemia if they are treated with:
● Oxidant drug
(AAA: antibiotics -sulfamethoxazole and chloramphenicol-, antimalarials-
primaquine but not chloroquine or quinine-, antipyretics - acetanilide but not
acetaminophen-.)
● Ingest fava beans :
Favism, the hemolytic effect of ingesting fava beans, is not observed in all
individuals with G6PD deficiency, but all patients with favism have G6PD
deficiency.
● Contract a severe infection:
- Most common precipitating factor of hemolysis in G6PD deficiency.
- The inflammatory response to infection results in the generation of free
radicals in macrophages.
- The radicals can diffuse into the RBC and cause oxidative damage
[Note: In addition to hemolytic anemia, a clinical manifestation of G6PD deficiency is neonatal
jaundice appearing 1-4 days after birth. The jaundice, which may be severe, typically results
from increased production of unconjugated bilirubin]
7. The life span of individuals with a severe form of G6PD deficiency may be somewhat
shortened as a result of complications arising from chronic hemolysis.
8. This negative effect of G6PD deficiency has been balanced in evolution by an advantage
in survival, an increased resistance to Plasmodium falciparum malaria.
[Note: Sickle cell trait and the thalassemias also confer resistance to malaria.]
