Lipid metabolism and its disorders.pdf

Disorders of Lipids – Plasma lipoproteins, cholesterol, triglycerides and phospholipids in health and disease, hyperlipidemia, hyperlipoproteinemia, Gaucher’s disease, Tay-Sach’s and Niemann-Pick disease, ketone bodies.

1. Lipid Metabolism and its Disorders
Dr.Shiny C Thomas, Department of Biosciences, ADBU

2. Overview
Fatty acids (F.A.s) are taken up by cells.
They may serve as:
•precursors in synthesis of other compounds
•fuels for energy production
•substrates for ketone body synthesis.
Ketone bodies may be exported to other tissues: used for
energy production.
Some cells synthesize fatty acidsfor storage or export.

3. Energy
Fats are an important source of calories.
Typically 30-40% of calories in American diet are from
fat.
Fat is the major form of energy storage.
Typical body fuel reservesare:
fat: 100,000 kcal.
protein: 25,000 kcal.
carbohydrate: 650 kcal.
Provides 60% of energy needs for body at rest
TAG reserves would enable someone to
survive starvation for ~30 days

4. Digestion and Absorption of Lipids
•98% of ingested lipids are
triacylglycerols (TAGs)
•Digestion in the Mouth:
enzymes are aqueous
-little effect on lipids
•Digestion in the Stomach:
causes a large physical
change:
-Churned into droplets:“Chyme”

5. Gastric Lipase:
Begins actual
lipid digestion.
~10% of TAGs are
hydrolyzed
in the stomach.
Chyme stimulates
cholecystokinin
(CCK) to release bile
from gallbladder.
Bile is an emulsifier

6. Pancreatic lipase (PL) hydrolyzes insoluble triglyceride
by binding to the bile-salt micelles
TAGs are partiallyhydrolyzed: 2 of the 3 F.A.s have
ester linkages hydrolyzed and are released.
Monoacylglycerolremains = glycerol and 1 fatty acid

7. Oil droplets will form
spherical micelleshapes.
Bile salts aid this process
clumping fatty acids and
monacylglycerols.

8. Fatty acid micelle:
hydrophobic fatty acids &
monoacylglycerols
are in the interior.
Bile salts on exterior.
Micelles are small
enough to penetrate
membrane of
intestinal cells.
Free fatty acids & monoacylglycerols are reformed
into triacylglycerols.

9. TAGs are combined with
membrane & water soluble
proteins to form a
chylomicron, a lipoprotein.
Chylomicronscarry TAGs from
intestinal cells into bloodstream
via the lymph system.

10. Triacylglycerols reach bloodstream
& are hydrolyzed down to glyceroland fatty acids.
These are absorbed by cells and
processed further for energy by forming acetyl CoA.
or
Stored as lipids in fat cells (adipose tissue)

11. Summary of events that must occur before triacyglycerols (TAGs) can
reach the bloodstream through the digestive process.

12. Disorders of Lipid Metabolism
•Lipids play a critical role in almost all aspects of biological life –they are
structural components in cells and are involved in metabolic and hormonal
pathways.
•Lipids are defined as organic compounds that are poorly soluble in water
but miscible in organic solvents.
•Lipidologyis the study of abnormal lipid metabolism.
•An understanding of the pathophysiology of plasma lipid metabolism is
usefully based on the concept of lipoproteins, the form in which lipids
circulate in plasma.

13. PLASMA LIPIDS
The chemical structures of the four main forms of lipid
present in plasma are illustrated in Figure.

14. FATTY ACIDS
•These are straight-chain carbon compounds of varying lengths. They may
be saturated, containing no double bonds, monounsaturated, with one
double bond, or polyunsaturated, with more than one double bond
(Table 13.1).
•Fatty acids can esterify with glycerol to form triglycerides or be non-
esterified (NEFAs) or free.
•Plasma NEFAs liberated from adipose tissue by lipase activity are
transported to the liver and muscle mainly bound to albumin.
•The NEFAs provide a significant proportion of the energy requirements of
the body.
Summary diagrams of fatty acid synthesis and oxidation
are shown in Figures 13.2 and 13.3.

15. •Triglycerides are transported from the intestine to various tissues, including
the liver and adipose tissue, as lipoproteins. Following hydrolysis, fatty
acids are taken up, re-esterified and stored as triglycerides.
Table 13.1 Some of the major fatty acids found in the plasma

16. •Plasma triglyceride concentrations rise after a meal, unlike that of plasma
cholesterol.
•Phospholipids are complex lipids, similar in structure to triglycerides but
containing phosphate and a nitrogenous base in place of one of the fatty
acids.
•They fulfil an important structural role in cell membranes, and the
phosphate group confers solubility on nonpolar lipids and cholesterol in
lipoproteins.

18. Summary of fatty acid
oxidation.CoA, coenzyme A.

19. CHOLESTEROL
•Cholesterolisasteroidalcoholfoundexclusivelyinanimalsandpresentin
virtuallyallcellsandbodyfluids.
•Itisaprecursorofnumerousphysiologicallyimportantsteroids,includingbile
acidsandsteroidhormones.
•AsummaryofthecholesterolsyntheticpathwaysisshowninFigure13.4.
Therate-limitingenzymeis3-hydroxy-3-methylglutarylcoenzymeA
reductase(HMG-CoAreductase),whichiscontrolledbynegativefeedbackby
theintracellularconcentration.
•Abouttwo-thirdsoftheplasmacholesterolisesterifiedwithfattyacidsto
formcholesterolesters.

20. Figure 13.4 Summary of pathways of cholesterol synthesis.

21. LIPOPROTEINS
•Becauselipidsarerelativelyinsolubleinaqueousmedia,theyare
transportedinbodyfluidsas,oftenspherical,solubleproteincomplexes
calledlipoproteins.
•Lipidscanbederivedfromfood(exogenous)orsynthesizedinthebody
(endogenous).Thewater-soluble(polar)groupsofproteins,phospholipids
andfreecholesterolfaceoutwardsandsurroundaninnerinsoluble
(nonpolar)coreoftriglycerideandcholesterolesters.

22. DISORDERS OF LIPID METABOLISM
1. Chylomicron syndrome
•This can be due to familial lipoprotein lipase deficiency,
an autosomal recessive disorder affecting about 1 in
1 000 000 people.
•The gene for lipoprotein lipase is found on chromosome 8, and genetic
studies have shown insertions or deletions within the gene.
•Lipoprotein lipase is involved in the exogenous lipoprotein pathway by
hydrolysing chylomicrons to form chylomicron remnants, and also in the
endogenous pathway by converting VLDL to IDL particles.
•Presentation as a child with abdominal pain (often
with acute pancreatitis) is typical.

23. •Gross elevation of plasma triglycerides due to the accumulation of
uncleared chylomicron particles occurs.
•Treatment of the chylomicron syndrome involves a low-fat diet, aiming for
less than 20 g of fat a day, if possible.
2. Familial hypercholesterolaemia
•This condition is usually inherited as an autosomal dominant trait and was
described by Goldstein and Brown.
•The inheritance of one mutant gene that encodes for the LDL receptor
affects and resulting in impaired LDL catabolism and
hypercholesterolaemia.
•About 1 in every 500 people

24. •At least five types of mutation of the LDL receptor have been described,
resulting in reduced synthesis,
•failure of transport of the synthesized receptor to the Golgi complex within
the cell,
•defective LDL binding
•or inadequate expression
•or defective recycling of the LDL receptor at the cell surface.
•Definite familial hypercholesterolaemia (FH) is defined as a plasma cholesterol
concentration of more than 7.5 mmol/L in an adult (more than 6.7 mmol/L in
children under 16 years)
•or a plasma LDL cholesterol concentration of more than 4.9 mmol/L in an
adult in the presence of tendon xanthoma.

25. •Typically, patients manifest severe hypercholesterolaemia, with a relatively
normal plasma triglyceride concentration in conjunction with xanthomata,
which can affect the back of the hands, elbows, Achilles tendons etc.
Tendinousxanthomasin familial
hypercholesterolaemia.

26. Hyperlipidemias
•Hyperlipidemiasare disorders of the rates of synthesis or clearance of
lipoproteins from the bloodstream.
•Usually they are detected by measuring plasma triacylglycerol and cholesterol
and are classified on the basis of which class of lipoproteins is elevated.
Type I hyperlipidemiais due to accumulation of chylomicrons. Two genetic
forms are known: lipoprotein lipase deficiency and ApoCIIdeficiency. ApoCIIis
required by lipoprotein lipase for full activity.
•Patients with type I hyperlipidemiahave exceedingly high plasma
triacylglycerol levels (over 1000 mg dL–1) and suffer from eruptive xanthomas
(triacylglycerol deposits in the skin) and pancreatitis.

27. •Type II hyperlipidemiais characterized by elevated LDL levels.
•Most cases are due to genetic defects in the synthesis, processing, or function
of the LDL receptor.
•Heterozygotes have elevated LDL levels; hence the trait is dominantly
expressed.
•Homozygous patients have very high LDL levels and may suffer myocardial
infarctions before age 20.
Type III hyperlipidemiais due to abnormalities of ApoE, which interfere with the
uptake of chylomicron and VLDL remnants.
Hypothyroidism can produce a very similar hyperlipidemia. These patients have
an increased risk of atherosclerosis.

28. Type IV hyperlipidemiais the commonest abnormality.
•The VLDL levels are increased, often due to obesity, alcohol abuse, or diabetes.
•Familial forms are also known but the molecular defect is unknown.
Type V hyperlipidemiais, like type I, associated with high chylomicron
triacylglycerol levels, pancreatitis, and eruptive xanthomas.
•Hypercholesterolemia also occurs in certain types of liver disease in which
biliary excretion of cholesterol is reduced.
•An abnormal lipoprotein called lipoprotein X accumulates. This disorder is not
associated with increased cardiovascular disease from atherosclerosis.

29. Hyperlipoproteinemia
•Hyperlipoproteinemiais a common disorder.
•It causes an inability to break down lipids or fats in the body, specifically
cholesterol and triglycerides.
•Hyperlipoproteinemiais often genetic and caused by a defect.
•High levels of cholesterol and/or triglycerides are serious because they are
associated with heart problems.
•There are several types of hyperlipoproteinemia, depending on the
concentration of lipids.

30. Types of hyperlipoproteinemia
There are five types of hyperlipoproteinemia:
Type 1(pure hypercholesterolemia) is characterized by high cholesterol levels
and normal triglycerides.
LDL (low-density lipoprotein), considered the “bad” cholesterol.

31. Type 2is characterized by high triglyceride levels and normal cholesterol. There
are two Type 2 subtypes: one with increased VLDL (very low-density
lipoproteins) and one with normal VLDL levels.
Type 3is characterized by high triglyceride levels and high cholesterol levels.
Type 4is characterized by high VLDL levels with normal LDL levels.
Type 5is characterized by increased VLDL levels and the presence of
chylomicrons, another kind of lipoprotein.

32. What causes Hyperlipoproteinemia?
•Hyperlipoproteinemiacan be a primary or secondary condition.
•Primary conditions are caused by problems with lipids in the body or lifestyle
choices that affect lipids.
•Primary hyperlipoproteinemia can be genetic and a result of a defect in
lipoproteins.
•Environmental factors can also cause primary hyperlipoproteinemia. These
include diet, alcohol, and drug use.
•Secondary disorders are the result of other health conditions, such as
diabetes, hypothyroidism, or pancreatitis.
Some common prescription drugs that cause lipid problems include
contraceptives and steroids.

33. Symptoms
Lipid deposits are the main symptom of hyperlipoproteinemia.
•The location of lipid deposits can help to determine the type. Some lipid
deposits, called xanthomas, are yellow and crusty. They occur on the skin.
•Many people with hyperlipoproteinemiaexperience no symptoms, but
become aware of the condition when they develop a heart condition.

34. Other signs and symptoms of hyperlipoproteinemiainclude:
•pancreatitis (type 1)
•abdominal pain (types 1 and 5)
•enlarged liver or spleen (type 1)
•lipid deposits or xanthomas(type 1)
•family history of heart disease (types 2 and 4)
•family history of diabetes (types 4 and 5)
•heart attack stroke

35. Hypolipoproteinemias
•A beta lipoproteinemiais a genetic disease that is characterized by absence of
chylomicrons, VLDLs, and LDLs due to an inability to synthesize apolipoprotein
B100.
•Patients show accumulation of lipid droplets in small intestinal cells,
malabsorptionof fat, acanthocytosis(spiny shaped red cells), and neurological
disease (retinitis pigmentosa, ataxia, and retardation).
•Tangier disease, an a lipoprotein deficiency, is a rare autosomal recessive
disease in which the HDL level is 1–5% of its normal value.

36. •Clinical features are due to the accumulation of cholesterol in the
lymphoreticularsystem, which may lead to hepatomegaly and splenomegaly.
•In this disease the plasma cholesterol and phospholipids are greatly reduced.
•Deficiency of the enzyme lecithin: cholesterol acyltransferaseis a rare disease
that results in the production of lipoprotein X.
•Also characteristic of this disease is the decrease in the alpha lipoprotein and
pre beta lipoprotein (lipoprotein X) in electrophoresis.

37. Gaucherdisease: Gaucherdisease is a rare inherited enzyme deficiency, which
researchers estimate may be present in 10,000 -20,000 Americans.
•It is a panethnicdisorder, with highest prevalence in the Ashkenazi Jewish
population.
•Gaucherdisease is characterized by a remarkable degree of variability in its
clinical signs and symptoms, ranging from severely affected infants to
asymptomatic adults.
•Many patients suffer from anemia, bone damage, and enlarged livers and
spleens; a few develop severe central nervous system damage.

38. •Gaucherdisease is a potentially lethal disorder.
•All patients with Gaucher disease have a genetic defect in the enzyme
glucocerebrosidase,which results in the accumulation of the lipid
glucocerebroside within intracellular structures known as lysosomes.
•Patients with Gaucherdisease have been classified into three major types on
the basis of clinical signs and symptoms:
type 1, non-neuronopathic(adult);
type 2, acute neuronopathic(infantile);
and type 3, subacuteneuronopathic(juvenile).
All types of Gaucherdisease can be diagnosed by demonstrating a deficiency of
glucocerebrosidaseactivity.

39. •Gaucherdisease, the most common lysosomalstorage disorder, is caused by
the defective activity of the lysosomalenzyme, acid-b-glucosidase(GlcCerase),
leading to accumulation of glucosylceramide(GlcCer), particularly in cells of
the macrophage lineage.
•Nearly 200 mutations in GlcCerasehave been described, but for the most
part, genotype-phenotype correlations are weak, and little is known about the
down-stream biochemical changes that occur upon GlcCeraccumulation that
result in cell and tissue dysfunction.

40. •The gene for glucocerebrosidase, which is located on chromosome 1q21, has
been characterized and sequenced.
•Many mutations in the glucocerebrosidasegene have been identified in DNA
from different patients; several of these mutations are frequent.
•Although some patients with the same DNA mutations have similar clinical
courses, other patients with the same mutations have very different clinical
manifestations.
•It is still not clear to what extent a persons clinical features (phenotype) or
prognosis can be accurately predicted through current mutation analysis.

41. •Although the molecular techniques can be used for early prenatal diagnosis,
detection of individuals carrying the disease gene, and population screening,
the appropriate clinical application of these molecular techniques remains
unresolved.

42. Treatment
•enzyme replacement therapy.
•One other treatment, substrate reduction therapy, has recently been
marketed, and others are in early stages of development.
•Gaucherdisease has been traditionally managed by supportive therapy
including total or partial removal of the spleen, blood transfusions,
orthopedicprocedures, and occasionally bone marrow transplantation.
•More recently, enzyme replacement therapy has become available and has
proven effective in many patients.

43. •Tay-Sachs Disease is an autosomal recessive neurodegenerative disorder that
is typically fatal within the first two or three years of life.
•Its incidence is highest among Ashkenazi Jews (Jews of Eastern European
descent), approximately 100 times higher than in the general population.
•The disease was characterized by two doctors working independently,
resulting in its hyphenated name; a British physician named Warren Tay, and
an American physician named Bernard Sachs.

44. Tay--‐Sachs Disease
What is Tay--‐Sachs Disease?
•Tay--‐Sachs disease is a neurodegenerative disorder caused by a deficiency of
an enzyme called hexosaminidaseA, or HEXA.
•Lack of this enzyme causes rapid and progressive deterioration of the brain
and nervous system through the build up of toxic substances called
gangliosides.
•Infants with Tay--‐Sachs diseases appear to develop normally for the first few
months of life with rapid decline of mental and physical abilities occurring
around 4-6 months of age, leading to blindness, deafness, and an inability to
swallow.

45. •Mascularatrophy leads to paralysis and other neurological symptoms
(dementia, blindness and paralysis). Life expectancy is typically less than 5
years of age.
What cause Tay-Sachs Disease?
•Tay-Sachs disease is a hereditary disorder caused by a change, or mutation, in
both copies of the HexosaminidaseA (HEXA) gene, which causes these genes
to work improperly or not work at all.
•Individuals with Tay-Sachs disease have two non-working copies of this gene.
Tay-Sachs disease is inherited in an autosomal recessive manner.

46. Biochemistry and Genetics
Tay-Sachs is classified as a lysosomalstorage disease. The normal function of
the affected protein, β-hexosaminidaseA, is to degrade a compound called
GM2-ganglioside, a fatty-acid derivative.
Without this degradation, GM2-ganglioside builds up in the lysosomes of
neuronal tissue, leading to the neurodegenerative effects of the disease.
While massive neuronal apoptosis is observed in patients with Tay-Sachs, the
exact method through which the GM2-gangliosides cause this has yet to be
determined.
TheGM2 gangliosidosesare a group of three related genetic disorders that result from a
deficiency of the enzymebeta-hexosaminidase. Thisenzymecatalyzes thebiodegradationof
fatty acid derivatives known asgangliosides.The diseases are better known by their individual
names.

47. •Individuals carrying Tay Sachs mutations show a reduced level of the enzyme
HexosaminidaseA which is essential for breaking down fatty substances in
neural tissue.
•As a result these lipid molecules build up in the CNS and gradually destroy
neural structures. A routine and inexpensive carrier test is a blood test
measuring the level of hexosaminidaseactivity.
Besides enzyme assays of hexosaminidaseA acitivity, diagnosis can also be done
via genetic testing using polymerase chain reaction.

48. Symptomology
•A thorough understanding of the symptoms of the disease is essential for the
physician in order to arrive at a correct diagnosis.
•Symptoms typically found include retardation beginning early in infancy
followed by dementia, blindness, and paralysis. Infantile Tay-Sachs usually
proves to be fatal by the age of three.
A study done by Rapinet al. in 1976, assessed the condition of a brother and
two sisters of Ashkenazi descent who were diagnosed with Tay-Sachs.

49. •Early in childhood, the children lost their ability to walk and maintain posture.
Furthermore they showed loss of muscle mass, foot drop, muscle spasms, as
well as loss of coordination in their trunk and extremities.
•Although the muscle atrophy began in the lower limbs, it soon reached the
upper body, causing stuttering due to the denervation of laryngeal muscles.
•Furthermore, a characteristic "cherry-red" spot in the back of their retina was
discovered as a consequence of the neural degeneration in the CNS.

50. •Although displaying many of the signs of classical Tay-Sachs, these children
did not display the usual loss of optic acuity and intelligence.
•After one of the children died, biochemical studies showed that this family
did indeed have an allelic variant of the disease.

51. Diagnosis, Testing, and Prevention
•Tay-Sachs is most prevalent in the Ashkenazi Jewish population with a carrier
rate of 1 in 25, as opposed to the rate of 1 in 250 in the general population.
•This high carrier rate has caused the Jewish population, in both Israel and
around the world, to place more emphasis on genetic screening and testing.
•In fact, Tay-Sachs screening in the Jewish community is one of the first
successes for genetic screening for a specific genetic disorder.
•Carrier detection and prevention programs have proven dramatically effective
and have established the paradigm for the prevention of recessive diseases.

53. Treatment
•At the present time there is no successful cure or treatment to halt the rapid
progression of Tay-Sachs disease.
•A number of different therapies are being evaluated; however, none have
proven effective in curing this devastating illness.
•Some of the potential therapies currently under study are enzyme
replacement, bone marrow transplant, and gene therapy.

54. Niemann-Pick Disease
•A metabolic defect: sphingomyelinasedeficiencies
•the heterogenousgroup of Niemann-Pick disease
•types A and B, C
Clinical Presentation
Sphingomyelinasedeficiencies have historically been categorized into a severe,
acute neuronopathicform, or type A, and a non-neuronopathicform, or type B.
•Type A has its highest prevalence in Ashkenazim
•Type B does not have an Ashkenazi Jewish predilection and appears more
frequent in Southern Europe, North Africa, Turkey and the Arabian peninsula
than in Northern Europe.

55. Classical type A patients have a quite uniform presentation.
•First symptoms are often vomiting, diarrhoea, or both, and failure to thrive,
often appearing in the first weeks of life.
•Prominent and progressive hepatosplenomegaly (liver and spleen swell and
enlarge)and lymphadenopathy(Swelling in an arm or leg caused by a
lymphatic system blockage) occur in most cases before 3 to 4 months of age,
and sometimes in the neonatal period.
•Hypotonia(lack of oxygen at birth) and muscle weakness are common.
Psychomotor retardation becomes evident around 6 months of age.
•A cherry-red spot in the retina is detected in about half of the patients.
•Loss of motor function and intellectual deterioration.

56. •Brownish-yellow discoloration and xanthomasmay be detected in the skin.
•Death usually occurs between 1.5 to 3 years.
Type B is a chronic disease.
•Most typically, the presenting sign is splenomegalyor hepatosplenomegalyin
late infancy or childhood, but the age of discovery may occur from birth until
late adulthood.
•Hepatosplenomegaly(HPM) is a disorder where both the liver and spleen
swell beyond their normal size, due to one of a number of causes.
•The most constant associated signs are radiographic abnormalities of the lung
(diffuse, reticulonodularinfiltrations) and interstitial lung disease with variable
impairment of pulmonary function.

57. •In cases presenting in infancy or childhood, growth
restriction is common in late childhood and adolescence, with delay in skeletal
age and puberty.
•Abnormal lipid profiles, mildly elevated liver transaminases, low platelet count
are other common findings.
•In adult patients, pulmonary reticular fibrosis may be the initial sign.
The disease is also characterized by hepatosplenomegalywith progressive
hypersplenism, worsening atherogeniclipid profile, gradual deterioration in
pulmonary function and stable liver dysfunction.

58. •Metabolic derangement: A primary deficiency of the lysosomal(or acid)
sphingomyelinaseresulting from mutations on the SMPD1 gene leads to the
progressive accumulation of sphingomyelinin systemic organs in all types of
the disease, and in brain in the neuronopathicforms.
•Sphingomyelinstorage is massive in liver and spleen in type A and slightly less
in type B. A significant increase of unesterifiedcholesterol occurs secondarily.

59. Diagnostic Tests
The diagnosis is made by demonstration of a deficiency in sphingomyelinase
activity in leukocytes (or lymphocytes) or in cultured cells.
Treatment and Prognosis
No specific therapy is yet available.
•Experience of bone marrow transplantation (BMT) is limited but did not
appear to improve symptoms in type A patients.
•In type B, splenectomymay have a deleterious effect on the lung disease.

60. •Preclinical trials using the human recombinant enzyme
have been conducted in a knock-out mouse model, that led to correction of the
storage process in liver, spleen and lung (but, as expected, not in brain),
providing the proof of principle for enzyme replacement therapy for type B.

61. Ketone bodies:
•Under certain metabolic conditions associated with a high rate of fatty acid
oxidation, liver produces considerable quantities of compounds like
acetoacetate and β-OH butyric acid, which pass by diffusion into the blood.
•Acetoacetate continually undergoes spontaneous decarboxylation to produce
acetone.
These three substances are collectively known as “ketone bodies” (or
“acetone bodies”). Liver appears to be the only organ which produces ketone
bodies and add to the blood.

62. Inter-relationship of these three substances are shown
below:

63. Concentration of Ketone Bodies
Concentration of total ketone bodies in the blood of well fed individuals does
not normally exceed 1 mg/100 ml
(as acetone equivalents).
Urine: Loss via urine is usually less than 1 mg/ 24 hrsin
humans.
Ketonaemia: Rise of ketone bodies in blood above normal level is known as
ketonaemia.
Ketonuria: When the blood level of ketone bodies rises above the renal
threshold, they are excreted in urine and is called as ketonuria.
Ketosis: Accumulation of abnormal amount of ketone bodies in tissues and body
fluids is termed as ketosis, where the urinary excretion of β-OH butyric acid
exceeds 200 mg daily (normal 5 to 10 mg). The overall pattern is called ketosis.

64. Causes
1. Starvation: Simplest form of ketosis occurs in starvation.
Mechanism: Involves depletion of available carbohydrate reserve, coupled with
mobilisation of FFA and oxidation to produce energy.
2. In Pathologic States
• In Diabetes mellitus: Clinical and experimental.
• In some types of alkalosis: Ketosis may develop.
• Pregnancy toxaemia in sheep and in lactating cattle.
3. In prolonged ether anaesthesia.
4. Other non-pathologic forms of ketosis are found under
conditions of:
• High fat feeding.
• After severe exercise in the post-absorptive state.
5. Injection of anterior pituitary extracts.

65. Medical Importance
•Usually the utilization of ketone bodies by peripheral tissues is proportional
to their formation.
•Normal blood ketone bodies level is 1mg/100ml.
•Under certain metabolic conditions, the rate of ketone body formation
exceeds the rate of their utilization by peripheral tissues.
•This results in accumulation of ketone bodies in blood (hyper ketonemia)
and their excretion in urine (ketonuria).

66. Ketosis
•Hyper ketonemia and ketonuria gives rise to ketosis.
•Main clinical symptoms of ketosis are headache, nausae, vomiting and finally
coma.
•It occurs in starvation, uncontrolled diabetes mellitus, high fat diet, von
Geirke’sdisease, fevers, severe muscular exercise and congenital propinyl-
CoA carboxylase deficiency.
•Ketosis also occurs in ruminants.
•In cattle, it occurs during lactation.

67. Ketoacidosis
•Under normal conditions, ketone bodies, acetoacetate and β-hydroxybutyrate
are neutralized by blood bicarbonate to maintain constant blood pH.
•Their formation in large quantities in starvation and diabetes causes depletion
of blood bicarbonate.
•As a result blood pH decrease and leads to condition known as acidosis.
•Since acidosis is due to over production of ketone bodies it is also called as
ketoacidosis.
•Thus, over production of ketone bodies causes ketoacidosis.
Hypoketonemia
Ketone body formation is impaired in some disease like carnitine deficiency and
hepatic CAT-I (Carnitine acetyl transferase) deficiency.
Carnitine-Function-is the transfer of long-chain fatty acids to mitochondria from subsequent
beta oxidation.