This document discusses several clinical aspects of macronutrient metabolism. It begins by introducing inherited metabolic disorders and Garrod's hypothesis. It then covers clinical aspects of carbohydrate metabolism including lactase deficiency, glycogen storage diseases, and monosaccharide malabsorption. Clinical aspects of lipid metabolism discussed include lipid storage diseases and inborn errors of lipid metabolism. The document concludes by covering aspects of protein metabolism such as aminoacidurias, phenylketonuria, homocystinuria, and purine metabolism disorders.

1. Clinical Aspects of
Macronutrients
Submitted by
Kavita Kachhawa

2. Clinical Aspects
• Metabolic disorders
• Born error of metabolism/ inherited metabolic
disorders

3. • Garrod’s hypothesis (Inherited Metabolic
Disorders, 1908)
substrate excess
congenital metabolic diseases/ inherited metabolic diseases.
A
D
B C
toxic
metabolite
product
deficiency

4. Clinical Aspects of
Carbohydrates

5. Pathomechanisms
Activity of diasaccharidases is decreased
Decreased hydrolysis of disaccharide
Decreased resorbtion of substrate
Increased concentration of disaccharide in small intestine lumen
Increased osmotic activity of the lumen fluid
Diarrhoea
a) Activity of diasaccharidases is decreased

6. Activity of diasaccharidases is decreased
Activity of diasaccharidases is decreased
increased concentration of disaccharide in small intestine
lumen
increased concentration of disaccharide in large intestine
disaccharide fermentation by bacteria
increased concentration of lactic acid and fatty acids
stimulation of intestine wall
abdominal cramps, bloating, diarrhea, acidic stools, explosive
diarrhea

7. Causes of lactase deficiency:
1. genetic defect (primary)
2. secondary to a wide variety of gastrointestinal diseases that
damage the mucosa of the small intestine (secondary)
•Many persons showing milk intolerance prove to be lactase deficient
Lactase Deficiency Syndrome or hypolactasia
Causes of secondary lactase deficiency:
- Nontropical (celiac disease)and tropical sprue,
- Regional enteritis,
- Viral and bacterial infections of the intestinal tract,
- Giardiasis, cystic fibrosis, ulcerative colitis,
- Kwashiorkor, coeliac disease

8. The lactose is a good energy source for microorganisms in the colon,
and they ferment it to lactic acid while also generating methane
(CH4) and hydrogen gas (H2).
The gas produced creates the uncomfortable feeling of gut distention
and the annoying problem of flatulence.
The lactic acid produced by the microorganisms is osmotically
active and draws water into the intestine, as does any undigested
lactose, resulting in diarrhea.
If severe enough, the gas and diarrhea hinder the absorption of other
nutrients such as fats and proteins. The simplest treatment is to avoid
the consumption of products containing no lactose. Alternatively, the
enzyme lactase can be ingested with milk products.

9. • Small intestine ability to resorb glucose and galactose is
decreased
•Cause: Specific transport system for galactose and glucose
absorbtion in cells of small intestine is insufficient
•Results: Symptoms and signs similar to disaccharidase deficiency
syndrome
Monosaccharides Malabsorption

10. • Autosomal recessive disease (inborn errors of metabolism,
emzymopathy)
• There are defects in degradation of glycogen.
• The disturbances result in storage of abnormal glycogen, or storage
of abnormal amount of glycogen in various organs of the body
Results: Hypoglycemia in fasting individuals,
Hyperlipedmia,
Ketonemia
There are 9 other types of glycogenosis
Glycogenosis (Glycogen Storage Disease)

11. Frequently occurs in people suffering form visceral obesity
Characteristic features:
 insulin resistance
 compensatory hyperinsulinemia
 visceral obesity
 dyslipidemia ( LDL,  TG,  HDL)
 systemic hypertension
Increased probability of DM-type2 development
Syndrome X (metabolic X syndrome)

12. Cancer cells grow more rapidly than the blood vessels to nourish
them; thus, as solid tumors grow, they are unable to obtain oxygen
efficiently. In other words, they begin to experience hypoxia.
Under these conditions, glycolysis leading to lactic acid fermentation
becomes the primary source of ATP.
Glycolysis is made more efficient in hypoxic tumors by the action of a
transcription factor, hypoxia-inducible transcription factor (HIF-1).
In the absence of oxygen, HIF-1 increases the expression of most
glycolytic enzymes and the glucose transporters GLUT1 and GLUT3
These adaptations by the cancer cells enable the tumor to survive
until vascularization can occur.
Glycolysis and Cancer

13. HIF-1 also stimulates the growth of new tumors by increasing
the expression of signal molecules, such as :
vascular endothelial growth factor (VEGF), that facilitate the
growth of blood vessels.
Without such vascularization, the tumor would cease to grow
and either die or remain harmlessly small.
Efforts are underway to develop drugs that inhibit
vascularization of tumors.

14. Family of glucose transporters
GLUT1
GLUT3
Hexokinase
Phosphofructokinase
Aldolase
Glyceraldehyde 3-phosphate dehydrogenase
Phosphoglycerate kinase
Enolase
Pyruvate kinase
Lactate dehydrogenase
Glucose uptake and glycolysis proceed about ten times faster in most solid tumors than
in noncancerous tissues

15. Clinical aspects of
lipids

16. Lipid storage diseases
• Lipid storage diseases (Lipidoses) are a group of
diseases that arise from a deficiency of a specific
lysosomal hydrolase with a resulting
accumulation of the enzyme’s specific substrate.
• They are examples of lysosomal storage dx.
• The substrates share the ceramide molecule.
• Clinical symptoms of these disorders are mainly
from accumulation of the substrates in various
body organ-systems

17. • also known as sphingolipidoses
• genetically acquired
• due to the deficiency or absence of a catabolic enzymes
• examples:
• Tay Sachs disease
• Gaucher’s disease
• Niemann-Pick disease
• Fabry’s disease

18. Inborn Errors of Lipid Metabolism: Lysosomal (or
Lipid) Storage Diseases.
Disease Enzyme Defect Accumulated
Lipid
Tissues Involved
Tay–Sachs disease1 Hexosaminidase A GM2
ganglioside
Brain, retina
Gaucher's disease1 –Glucosidase
(glucocerebrosidase)
Glucocerebro
side
Liver, spleen, bone
marrow, brain
Neimann–Pick
disease1
Sphingomyelinase Sphingomyeli
n
Brain, liver, spleen
Metachromatic
leukodystrophy
Arylsulfatase A Sulfatide Brain, kidney, liver,
peripheral nerves
Fabry's disease –Galactosidase Ceramide
trihexoside
Skin, kidney
Krabbe's disease Galactosylceramidase Galactocerebr
oside
Brain

21. Genetic defects in ganglioside metabolism
• leads to a buildup of gangliosides (ganglioside
GM2) in nerve cells.
• Excess of ganliosides kill the nerve cells
NAc
Gal Gal Gal Glu
NAcNeu
enzyme that hydrolyzes here (beta hexosaminodase)
is absent in Tay-Sachs disease

22. Tay-Sachs disease
• A fatal disease which is due to the deficiency of
hexosaminidase A activity
• Accumulation of ganglioside GM2 in the brain of infants
• Mental retardation, blindness, inability to swallow
• A “cherry red “ spot develops on the macula (back of
the the eyes)
• Tay-Sachs children usually die by age 5 and often
sooner

23. Fabry’s disease
• Accumulation of ceramide trihexoside in kidneys
of patients who are deficient in lysosomal a-
galactosidase A sometimes referred to as
ceramide trihexosidas.
• Skin rash, kidney failure, pains in the lower
extremities.
• Now treated with enzyme replacement therapy:
agalsidase beta (Fabrazyme)

24. Genetic defects in cerebroside metabolism
• Krabbe’s disease:
• Also known as globoid leukodystrophy
• Increased amount of galactocerebroside in the white
matter of the brain
• Caused by a deficiency in the lysosomal enzyme
galactocerebrosidase
• Gaucher’s disease:
• Caused by a deficiency of lysosomal glucocerebrosidase
• Increase content of glucocerebroside in the spleen and
liver
• Erosion of long bones and pelvis
• Enzyme replacement therapy is available for the Type I
disease (Imiglucerase or Cerezyme)
• Also miglustat (Zavesca) – an oral drug which inhibits
the enzyme glucosylceramide synthase, an essential
enzyme for the synthesis of most glycosphingolipids

25. Genetic defects in ganglioside metabolism
• Metachromatic leukodystrophy
• accumulation of sulfogalactocerebroside (sulfatide) in the central
nervous system of patient having a deficiency of a specific
sulfatase
• mental retardation, nerves stain yellowish-brown with cresyl violet
dye (metachromasia)
• Generalized gangliosidosis
• accumulation of ganglioside GM1
• deficiency of GM1 ganglioside: b-galactosidase
• mental retardation, liver enlargement, skeletal involvement

26. Niemann-Pick disease
• principal storage substance: sphingomyelin
which accumulates in reticuloendothelial cells
• enzyme deficiency: sphingomyelinase
• liver and spleen enlargement, mental
retardation

27. CLINICAL ASPECTS OF PROTEIN
METABOLISM

28. Unique sequence of DNA
Specific sequence of RNA (mRNA)
Specific AA sequence of polypeptide
Specific Biochemical function

29. Introduction
a genetic disease
also known as biochemical genetics
Gene-level Gene mutation
Protein-level Abnormal protein
Transport Other
Enzyme protein protein
Metabolic-level Abnormal metabolites

30. AMINOACIDURIAS
Primary – Inborn errors of metabolism
Secondary – Hepatic, Renal, PEM

31. CNS Dysfunction –
mental retardation
seizure disorder
behavioral disturbances
Metabolic Ketoacidosis
Occasionally –
liver disease,
renal failure,
cutaneous abnormalities,
ocular lesions

32. AMINOACIDURIAS
Neurological
• Phenylketonuria
• Hypertyrosinemia
• Homocystinuria
• Maple-syrup urine
disease
• Hyperglycemia
• Methyl melonic aciduria
• Carnosinemia
• Citrullinemia
• Argininemia

33. Phenyl Ketonuria
CH2 CH COO
NH3
+
CH2 CH COO
NH3
+
HO
phenylalanine
tyrosine
O2 + tetrahydrobiopterin
H2O + dihydrobiopterin
Phenylalanine
Hydroxylase

34. Metabolic Pathways for Phe and Tyr

35. The PAH gene is located on chromosome 12 .
Several hundred DNA mutations in the phenylalanine hydroxylase
gene can cause PKU (98% of cases), as well as mutations in other
genes necessary for tetrahydrobiopterin production (2% of cases).
All newborns with PKU should be tested for tetrahydrobiopterin
defects.
Mutations in the GCH1, PCBD1, PTS and QDPR genes cause THB
deficiency.

36. Phenylketonuria is inherited in an autosomal recessive fashion
All genetic diseases, genetic counseling may be appropriate to help
families understand recurrence risks and ensure that they receive
proper evaluation and care.

38. Alkaptonuria is an inherited disorder first described by Garrod
(1902) and Willliam Bateson.
Infants have black urine, darkened ears and nose due to
homogentisic acid deposits.
Inheritance: The gene encoding the HGD enzyme is located on
chromosome 3
Alkaptonuria

39. • Dark urine
• Arthritis
• Musculoskeletal (muscle and ligament tears)
• Cardiovascular (valvulitis, fibrosis, calcification)
• Genitourinary (renal and prostatic calculi, renal failure)
• Hearing loss
Clinical Features of AKU

40. Alcaptonuria
Absence of homogentisate oxidase activity
urine
sclera

41. Albinism
• Albinism
– Autosomal recessive
– Results from loss of tyrosinase enzyme in skin, which converts
Tyr to DOPA and DOPA to Melanin pigments
– Loss of tyrosinase in brain causes Parkinson’s Disease (loss of
DOPA+ neurons).

42. Types of albinism
Ocular albinism : eyes
X-linked ocular: This type of albinism occurs mostly in males, who inherit the gene from
their mothers. It causes visual disabilities.
Oculocutaneous: Hair, skin, and eyes.
Tyrosinase-negative oculocutaneous: Also known as Type 1A, this is the most severe
form of albinism, marked by a total absence of pigment in hair, skin, and eyes. People
with this type of albinism have vision problems and sensitivity to sunlight. They also
are extremely susceptible to sunburn.
Tyrosinase-positive oculocutaneous: People with this type of albinism have light hair,
skin, and eye coloration and fewer visual impairments.

43. Hermansky-Pudlak syndrome (HPS):
This rare type of albinism is common in the
Puerto Rican community.
Approximately one person in every 1,800
people in Puerto Rico will be affected by it.
Chediak-Higashi syndrome:
A rare type of albinism that interferes with white
blood cells and the body’s ability to fight infection.
mutation in the lysosomal trafficking regulator
gene, LYST.

44. Maple syrup urine disease (MSUD)
Branched-chain ketoaciduria
Autosomal recessive
Branched-chain alpha-ketoacid dehydrogenase (BCKADH).
Chromosome 1, 6, 7, 19

45. Maple syrup urine disease

46. 1. Maple Syrup Urine Dz Maple syrup
2. Isovaleric acidemia Sweaty feet
3. Tyrosinemia Rancid butter
4. Beta-methylcrotonyl-
coenzyme A def. Tomcat’s urine
5. Phenylketonuria Mousy/Musty
6. Methionine malabsorption Cabbage
7. Trimethylaminuria Rotting fish

47. Homocystinuria
Autosomal recessive condition Incidence is one in 200,000
births Cystathionine synthase deficiency
It may be due to Cobalamin deficiency, N5, N10-Methylene THFA
Reductase deficiency
Urinary excretion of homocystine > 300 mg/24 h
Symptoms: Mental retardation, Flat foot, Charley Chaplin gait,
Skeletal deformities, Ectopia lentis, Myopia, Glaucoma
Treatment: Diet low in methionine and rich in cysteine

48. Methionine synthesis

52.  Gout: Gout is a systemic disease, deficient in
purine metabolism which will lead deposition of
uric acid in soft tissue as monosodium urate
crystals.
2. Leshnyhan syndrome
Purine Metabolism Disorders

53. Salvage pathway of purine
RPP Purine ribonucleoti
purine PPi
nine + PRPP Adenylate + PPi
(AMP)
Mg 2+
APRTase
Catalyzed by adenine phosphoribosyl transferase (APRTa

54. IMP and GMP interconversion
Hypoxanthine + PRPP
Inosinate + PPi
( IMP)
Mg 2+
HGPRTase
Guanine + PRPP Guanylate + PPi
(GMP)
Mg 2+
HGPRTase
HGPRTase = Hypoxanthine-guanine phosphoribosyl transferase

55. Silent tissue deposition
& Hidden Damage

56. Purine nucleotides
hypoxanthine
xanthine
Uric acid
Xanthine
oxidase
Alimentary
excretion
Urinary
excretion
Tissue deposition
in excess
Urate crystal microtophi
Phagocytosis
with acute
inflammation
and arthritis
uricosurics
colchicine NSAID
Allopurinol
Oxypurinol

57. Classification of Gout
Primary Gout:
Abnormal PRPP synthetase
Abnormal 5-phosphoribosyl amido transferase
Deficiency of enzymes of salvage pathway
Glucose 6-phosphate deficiency
Glutathione reductase variant
Secondary Gout:
1. Leukemia, lymphomas, polycythemia
2. Increased tissue breakdown after treatment of
large malignant tumors
3. Increased tissue damage due to trauma and
raised rate of catabolism as in starvation

58. Serum urate levels vary with age and sex.
Children: 3 to 4 mg/dL
Adult men : 3.5 to 7 mg/dL
Adult women: 2 to 5 mg/dL

59. • Defined as a plasma urate concentration > 7.0 mg/dl
• Can result from:
Increased production of uric acid
Decreased excretion of uric acid
Combination of the two processes
•Can occur in other joints, bursa & tendons

61. In severe
hyperuricemia, crystals
of sodium urate get
deposited in the soft
tissues, particularly in
the joints. Such
deposits commonly
known as Tophi.

63. Treatment
 Reduce dietary purine intake and restrict alchohol
 Increase renal excretion of urate by uricosuric drugs
 Allopurinol : Blocks conversion of hypoxanthine to uric acid
(Effective in overproducers, May be effective in
underexcretors and can work with renal insufficiency)

64. • X-linked recessive disorder
• Deficiency of HGPRT
• Males affected, female carriers
• Cerebellar dysfunction
• Genetic Counselling-study of females in
affected families
Lesch-Nyhan Syndrome

65. CONDITION DEFECTIVE
ENZYME
/SYSTEM
BIOCHEMICAL
FEATURES
CLINICAL
FEATURES
Gout Syn. of
UA from the
precursors
Con. Of
UA in serum &
urine
Arthritis, urinary
Urate calculi
renal damage
Xanthinuria Xanthine
oxidase, RT
reabsorption
Xanthine
excreted in
large amounts
Xanthine calculi in
urinary tract
Oroticaciduria Absence of
Pyrophosphoryla
se/decarboxyla
se or both
Orotic acid
accumulates &
is excreted in
urine
Megaloblastic
anaemia,
Orotic acid
Crystalluria
PURINE & PYRIMIDINE
METABOLISM –INBORN ERRORS

66. •CLINICAL ASPECTS ARISES
DUE TO ROLE OF MORE
THAN ONE
MACRONUTRIENT

68. DM is a chronic complex syndrome induced by absolute or relative
deficit of insulin which is characterized by metabolic disorders of
carbohydrates, lipids and proteins.
The metabolic disturbances are accompanied by
 Loss of carbohydrate tolerance
 Fasting hyperglycemia
 Ketoacidosis,
 Decreased lipogenesis,
 Increased lipolysis,
 Increased proteolysis and some other metabolic disorders
Diabetes Mellitus

69. The term Diabetes Mellitus describes a metabolic disorder with
heterogeneous etiologies which is characterized by chronic
hyperglycemia and disturbances of carbohydrate, fat and protein
metabolism resulting from defects in insulin secretion, insulin action or
both. (WHO 1999)
Global Burden of Diabetes
 366 million people have diabetes in 2011; by 2030 this will have risen
to 552 million
 80% of people with diabetes live in low- and middle-income countries
 The greatest number of people with diabetes are between 40 to
59 years of age
 183 million people (50%) with diabetes are undiagnosed
 Diabetes caused 4.6 million deaths in 2011
 78,000 children develop type 1 diabetes every year
World Diabetes Atlas 2011

70. Classification of Diabetes
Diabetes
Mellitus
Type 1 DM
(Insulin Dependent
DM)
Gestational Diabetes
Type 2 DM
(Non Insulin
Dependent DM)

71. Type 1 Diabetes

72. Physiology of development of Diabetes
Insulin binds to
extracellular subunit
of insulin receptor
Tyrosine kinase & IRS
1-4 are activated
IRS activates P13K/Akt
pathway: a critical signal
pathway
Pathway regulates
GLUT-4, for
transportation of
glucose into cells
P13K leads to
glycogen synthesis in
liver & reduce blood
glucose levels
Insufficiency of
Insulin OR
Resistance to Insulin
Defects in signal
pathway…… DIABETES
Chen & Raymond 2008

73. • High blood sugar that starts or is
first diagnosed during pregnancy.
• Body is unable to make and use
enough insulin needed for
pregnancy.
• Higher risk of developing type 2
diabetes later in life.
• Controlled through a healthy diet
• Babies born also have a higher risk
of obesity and developing type 2
diabetes as adults.
Gestational Diabetes Mellitus

74. Complications of Diabetes Mellitus
A. Acute complications
• Hypoglycemia
• Ketoacidosis
• Hyperosmolar hyperglycemic nonketotic coma
B. Chronic complications
• Diabetic micro- and macrovascular changes
• Diabetic neuropathy
• Diabetic retinopathy
• Diabetic nephropathy
• Other complications

75. Cardiovascular Disease
Cardiovascular diseases (CVD) is the
name for the group of disorders of the
heart and blood vessels and include
hypertension (high blood pressure),
coronary heart disease (heart attack),
cerebrovascular disease (stroke), heart
failure, peripheral vascular disease, etc.

76. Epidemiological transition
• with increasing rates of urbanization in India,
major changes in lifestyle patterns have
occurred for a large proportion of individuals.
• This has led to a trend toward decreasing
physical activity, increasing weight and,
consequently, increasing rates of diabetes,
hypertension and dyslipidemia in urban
populations.
• The shift from a predominance of infectious
diseases to a predominance of chronic
diseases, such as cardiovascular disease or
cancer, is called the “epidemiological
transition”

77. The major risk factors of CVD
high levels of low-
density lipoprotein
(LDL) cholesterol
smoking
hypertension diabetes
abdominal obesity
psychosocial factors
insufficient
consumption of
fruits and
vegetables
excess alcohol
lack of regular
physical activity

78. Cardiovascular diseases
• Coronary heart disease : Coronary heart disease (CHD) is
when your coronary arteries (the arteries that supply
your heart muscle with oxygen-rich blood) become
narrowed by a gradual build-up of fatty material within
their walls,
• This condition is called atherosclerosis and the fatty
material is called atheroma.
• In time, your arteries may become so narrow that they
cannot deliver enough oxygen-rich blood to your heart.
• The pain and discomfort you may feel as a result is
called angina.
• If a piece of atheroma breaks off it may cause a blood
clot(blockage) to form.
• If it blocks your coronary artery and cuts off the supply of
oxygen-rich blood to your heart muscle, your heart may
become permanently damaged . This is known as a heart
attack.

79. Cardiovascular diseases

80. Heart attack
• caused by coronary heart disease, which is
when your coronary arteries narrow due to a
gradual build-up of atheroma (fatty material)
within their walls. If the atheroma becomes
unstable, a piece may break off and lead to a
blood clot forming.
• This clot can block the coronary artery,
starving your heart of blood and oxygen
and causing damage to your heart muscle -
this is a heart attack. It is also called acute
coronary syndrome ,myocardial
infarction or coronary thrombosis.

81. • Stroke: cerebrovascular accident (CVA), is the rapid
loss of brain function(s) due to disturbance in the
blood supply to the brain. This can be due to ischemia
(lack of blood flow) caused by blockage (thrombosis,
arterial embolism), or a hemorrhage (leakage of
blood).
• Coronary artery disease: (CAD; also atherosclerotic
heart disease) is the result of the accumulation of
atheromatous plaques within the walls of the coronary
arteries that supply the myocardium(the muscle of the
heart) with oxygen and nutrients. It is sometimes also
called coronary heart disease(CHD). Although CAD is
the most common cause of CHD

82. • Coronary artery disease: (CAD; also
atherosclerotic heart disease) is the result of the
accumulation of atheromatous plaques within the
walls of the coronary arteries that supply the
myocardium(the muscle of the heart) with oxygen
and nutrients. It is sometimes also called coronary
heart disease(CHD). Although CAD is the most
common cause of CHD
• Cardiac arrest
It is totally different from a heart attack. A cardiac
arrest happens when your heart stops
pumping blood around the body. It can not contract
properly.

83. • Heart failure
Having heart failure means that for some
reason, your heart is not pumping
blood around the body as well as it used to.
The most common reason is that your heart
muscle has been damaged, for example,
after a heart attack.
• Alcoholic heart disease
This is pretty much self explanatory. But just
to be clear this form of the disease is due to
the overuse of alcohol.

84. Hypertensive heart disease
This is heart disease brought on by out of control,
long term high blood pressure. It is just one of many
diseases and conditions brought on by high blood
pressure. High blood pressure also affects the liver
very poorly among other organs.
Dilated Heart Disease
In this disease the heart (especially the left ventricle)
is enlarged and the pumping function limited causing
a loss of blood to the rest of the body.
Restrictive heart disease
This is the least common disease of the heart, the
walls of the heart ventricles are stiff, but may not be
thickened, and resists the normal filling of the heart
with blood.

85. Normal Blood parameters
Lipid profile
Total cholestrerol <200mg/dl
tryglycerides <150mg/dl
HDL-C >50mg/dl
LDL-C <130mg/dl
VLDL-C <30mg/dl