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http://www.jaypeebrothers.com/pgDetails.aspx?cat=s&book_id=9789352501434

Book  of Spotting

This book is based on reviewing clinical correlations of Biochemical processes. To generate curiosity, the facts have been presented as clinical problems. The discussions are extremely instructive and very interesting. The textual matter is perfectly distributed into segments. The readers can use the information any time from any of the divisions. The beginning part is about the orientation of the readers to the tools of Biochemistry laboratory. The Second division is all about clinical discussions. The learning rule is different, but the main accent in each chapter is to establish a conceptual background ground. Visual, graphic and laboratory interpretations keep the readers engaged to explore the biochemical deviations. The spot questions, revise the entire course of Biochemistry. The third section of self-assessment represents an extract of the whole book. The readers shall use the skills gained through this book to solve the problems and appreciate the process of stress free learning.

I am sure this pattern of active learning would be most welcomed by the students and faculty all over the world.

 

 

 

 

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Introduction

  • The most abundant heteropolysaccharides in the body.
  • Highly negatively charged molecules,with extended conformation that imparts high viscosity to the solution.
  • GAGs are located primarily on the surface of cells or in the extracellular matrix (ECM).
  • Along with the high viscosity of GAGs comes low compressibility, which makes these molecules ideal for a lubricating fluid in the joints.
  • Their rigidity provides structural integrity to cells and provides passageways between cells, allowing for cell migration.

GAGs of physiological significance

The specific GAGs of physiological significance are:

  • Hyaluronic acid,
  • Dermatan sulfate
  • Chondroitin sulfate
  • Heparin
  • Heparan sulfate, and
  • Keratan sulfate.

Chemistry

  • These molecules are long unbranched polysaccharides containing a repeating disaccharide unit. [acidic sugar-amino sugar]n
  • Although each of these GAGs has a predominant disaccharide component, heterogeneity does exist in the sugars present in the make-up of any given class of GAG.

Nature of amino sugars (figure-1)

The disaccharide units contain either of two modified amino sugars,

  • N-acetyl galactosamine (GalNAc) or
  • N-acetylglucosamine (GlcNAc),

Amino sugars

Figure-1- Amino sugars- β-D Glucosamine and β-D Galactosamine

The amino sugar may also be sulfated on carbon 4 or 6 or on non acetylated nitrogen.

Nature of acid sugar

Uronic acid represents acid sugar in the form of:

  • Glucuronate or
  • Iduronate

The acidic sugars contain carboxyl groups that are negatively charged at physiological pH, (figure-2) and together with the sulfate groups, give glycosaminoglycans their strongly negative nature.

Acid sugars

Figure-2- The acid sugars present in Glycosaminoglycans are D- Glucuronate and L- Iduronate.

Structure- function relationship

Because of their large number of negative charges, these heteropolysaccharides chains tend to be extended in solution. They repel each other and are surrounded by a shell of water molecules. When brought together they “slip” past each other. This produces the slippery consistency of mucous secretions and synovial fluid. When a solution of GAG is compressed, the water is squeezed out and GAGs are forced to occupy a smaller volume. When the compression is released the GAGs get back to their original, hydrated volume because of the repulsion of the negative charges. This property contributes to resilience of synovial fluid and vitreous humor of eye.

THE SPECIFIC GAGs OF PHYSIOLOGICAL SIGNIFICANCE ARE:

1) Hyaluronic acid – The repeating disaccharide unit is:

Glucuronic acid and N Acetylglucosamine (figure-3)

(D-Glucuronate + GlcNAc) n

Hyaluronic acid

Figure-3- structure of Hyaluronic acid

Occurrence:  Hyaluronic acid is found in –

  • Synovial fluid,
  • ECM of loose connective tissue, umbilical cord and vitreous humor of the eye.

Function

  • It serves as a lubricant and shock absorber.
  • It is the only GAG that is not limited to animal tissue but is also found in bacteria.
  • Hyaluronic acid is unique among the GAGs because it does not contain any sulfate and is not found covalently attached to proteins.
  • It forms non-covalently linked complexes with Proteoglycans in the ECM.
  • Hyaluronic acid polymers are very large (100 – 10,000 k Da) and can displace a large volume of water.

2) Dermatan sulfate- The repeating disaccharide unit is L-Iduronic acid and N-Acetyl Galactosamine with variable amount of Glucuronic acids (figure-4).

(L-Iduronate + GalNAc sulfate) n

 Dermatan sulfate

Figure-4- structure of Dermatan Sulfate

Occurrence:  It is found in skin, blood vessels and heart valves

3) Chondroitin sulfate- The repeating disaccharide unit is Glucuronic acid and N-Acetyl galactosamine with sulfate on either C-4 or C-6. Based on presence of sulfate group, it may be labeled as Chondroitin-4-Sulfate or Chondroitin-6-Sulfate (figure-5).

(D-Glucuronate + GalNAc sulfate) n

Chondroitin sulfate

Figure-5-Structure of Chondroitin Sulfate

Occurrence:  It is found in cartilages, tendons, ligaments, heart valves and aorta.

Function

It is the most abundant GAG. In cartilages it binds collagen and holds fibers in a tight, strong network.

4) Heparin sulfate – The repeating disaccharide unit is:

L-Iduronic acid and D- Glucosamine with variable amounts of Glucuronic acid. Most glucosamine residues are bound in Sulfamide linkages (figure-6). Sulfate is also found on C-3 or C-6 of Glucosamine and C-2 of uronic acid (An average of 2.5 Sulfate per disaccharide unit)

(D-Glucuronate sulfate +N-Sulfo-D-glucosamine) n

Heparin sulfate

Figure-6- structure of Heparin Sulfate

Occurrence: Heparin is a component of intracellular granules of mast cells lining the arteries of the lungs, liver and skin (contrary to other GAGs that are extra cellular compounds, it is intracellular).

Function– It serves as an anticoagulant.

5) Heparan sulfate: Heparans have less sulfate groups than heparins. The repeating disaccharide unit is same as Heparin. Some Glucosamines are acetylated

Occurrence- It is an extracellular GAG found in basement membrane and as a ubiquitous component of cell surfaces

6) Keratan sulfate –The repeating disaccharide unit is galactose and N-Acetyl glucosamine (No uronic acid). The sulfate content is variable and may be present on C-6 of either sugar (figure-7).

(Gal + GlcNAc sulfate) n

Keratan sulfate

Figure-7- Structure of Keratan sulfate

Occurrence:  cornea, bone, cartilage; Keratan sulfates are often aggregated with Chondroitin sulfates.

Proteoglycans (mucoproteins) 

Proteoglycans are formed of glycosaminoglycans (GAGs) covalently attached to the core proteins. They are found in all connective tissues, extracellular matrix (ECM) and on the surfaces of many cell types. Proteoglycans are remarkable for their diversity (different cores, different numbers of GAGs with various lengths and compositions).

Structure of Proteoglycans

All of the GAGs, except Hyaluronic acid are found covalently attached to protein forming proteoglycan monomers.

Structure of Proteoglycan monomer

A Proteoglycan monomer found in cartilage consists of a core protein to which the linear GAG chains are covalently linked. These chains which each may be composed of more than 100 monosaccharides extend out from the core protein and remain separated from each other because of charge repulsion. The resulting structure resembles a ‘Bottle brush’ (figure-8). In cartilage proteoglycans, the species of glycosaminoglycans include Chondroitin sulfate and Keratan sulfate.

 

Proteoglycan polymer

Figure-8- structure of Proteoglycan monomer (Bottle Brush)

 Linkage between the carbohydrate chain and the protein

The linkage of GAGs such as (heparan sulfates and Chondroitin sulfates) to the protein core involves a specific trisaccharide linker (Galactose-galactose-Xylose). The protein cores of Proteoglycans are rich in Serine and Threonine residues which allow multiple GAG attachments.

An O-Glycosidic bond is formed between the Xylose and the hydroxyl group of Serine. Some forms of Keratan sulfates are linked to the protein core through an N-asparaginyl bond (N-Glycosidic linkage)

Proteoglycan Aggregates- The proteoglycan monomers associate with a molecule of Hyaluronic acid to form Proteoglycan aggregates (figure-9). The association is not covalent, but occurs primarily through ionic interactions between the core protein and Hyaluronic acid. The association is stabilized by additional small proteins called Link proteins.

Proteoglycan aggregate

Figure-9- structure of proteoglycan aggregate

Functions of Proteoglycans

They perform numerous vital functions within the body.

GAG dependent functions can be divided into two classes: the biophysical and the biochemical.

1) The biophysical functions depend on the unique properties of GAGs: the ability to fill the space, bind and organize water molecules and repel negatively charged molecules. Because of high viscosity and low compressibility they are ideal for a lubricating fluid in the joints. On the other hand their rigidity provides structural integrity to the cells and allows the cell migration due to providing the passageways between cells.

2) The other, more biochemical functions of GAGs are mediated by specific binding of GAGs to other macromolecules, mostly proteins. Proteoglycans participate in cell and tissue development and physiology.

3) Heparin acts as an anticoagulant and is used in the clinical practice.

 

 

 

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A 56-year-old man with longstanding poorly controlled diabetes mellitus visits his primary care physician for a follow-up after a recent hospitalization. The patient experienced an episode of acute renal failure while in the hospital, and his creatinine level rose to 3.4 mg/dl (normal, 0.7-1.5 mg/dl).

Creatinine a marker of kidney function, is produced from which of the following precursors?

A. Glutamine, Aspartic acid and CO2

B. Glutamine, Cysteine and Glycine

C. Serine and Palmitoyl Co A

D. Glycine and Succinyl Co A

E. Glycine, Arginine and S-Adenosyl Methionine.

The correct answer is E- Glycine, Arginine and S-Adenosyl Methionine

Creatinine is an anhydrous product of creatine.

Creatine also called, “Methyl guanidoacetic acid”, is produced from Glycine, Arginine and Methionine in the human body primarily in the kidney and liver (figure-1).

 

Synthesis-of-creatine

Figure-1- In the first step Glycine and Arginine react to form Guanido acetic acid; this reaction takes place in the kidney. In the second step, (in the liver), methylation of guanido acetic acid takes place to form Methyl guanido acetic acid (creatine). Creatine is reversibly phosphorylated to creatine-P by creatine kinase. Creatine phosphate is a high energy compound. Creatinine is produced by the loss of water from creatine.

 

Creatine is transported in the blood for use by muscles. Approximately 95% of the total creatine is located in skeletal muscle. It is also present in liver, testes and brain. It can occur in free form or phosphorylated form. The phosphorylated form is called ‘Creatine-Phosphate’, ‘Phosphocreatine’ or ‘phosphagen’.

In the skeletal muscle creatine is reversibly phosphorylated, The reaction is catalyzed by Creatine kinase, also called Creatine phospho kinase (CPK). The physiological role of creatine phosphate is to form a rapidly available reserve of energy-rich phosphate groups.

There are 3 main isoenzymes of CPK, which are present in brain (CPK-BB), myocardium (CPK-MB) and skeletal muscle (CPK-MM). High CPK-MB in plasma is an early marker of Acute myocardial infarction, whereas high CPK-MM is a marker of muscle injury or muscular disorder.

Creatine is excreted in the form of Creatinine, which is formed by removal of one molecule of water from creatine.

Creatine————–> Creatinine + H20

The reaction is non- enzymatic and irreversible. About 2 % of the total Creatine is converted daily to creatinine so that the amount of creatinine produced is related to the total muscle mass and remains approximately the same in plasma and urine from day-to-day unless the muscle mass changes.

Creatinine is mostly eliminated through kidney by glomerular filtration. Normal excretion ranges between 1-2 g/day.  Estimation of serum and urinary creatinine is undertaken to assess the renal functions. Creatinine clearance estimation is undertaken to determine Glomerular filtration rate (GFR). The normal serum creatinine ranges as follows :

1) < 12 Years-0.25-0.85 mg/dL

2) Adult male 0.7-1.5 mg/dL

3) Adult female 0.4 -1.2 mg/dL

It is higher in males because of the muscle mass.

As regards other options

A. Glutamine, Aspartic acid and CO2- these three along with ATP are needed for the synthesis of pyrimidine nucleotides.

B. Glutamine, Cysteine and Glycine- there is no peptide or compound formed from these amino acids. Glutamic acid, cysteine and glycine are required for the formation of Glutathione.

C. Serine and Palmitoyl Co A condense to form Sphingol, which is required for the synthesis of sphingolipids.

D. Glycine and Succinyl Co A are required for the heme biosynthesis.

 

 

 

 

 

 

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In a 39-year-old woman who just gave birth, chorionic villus sampling was performed, and a battery of genetic panels was assessed on the new born. One marker indicated a defective Cystathionine -β- Synthase. Which of the following compounds you most likely expect to be elevated in the blood of the infant at birth if the mother was not treated properly?

A) Valine

B) Methionine

C) Threonine

D) Glutamine

E) Cysteine

The correct answer is- B) – Methionine.

This seems to be a case of” Classical homocystinuria”, that occurs due to defective Cystathionine-β- Synthase activity.

Homocystinuria is a disorder of methionine metabolism, leading to an abnormal accumulation of homocysteine and its metabolites (homocystine, homocysteine-cysteine complex, and others) in blood and urine. Normally, these metabolites are not found in appreciable quantities in blood or urine.

Basic Concept-

Most homocysteine, an intermediate compound of Methionine degradation, is normally remethylated to Methionine. This Methionine-sparing reaction is catalyzed by the enzyme Methionine Synthase, which requires a metabolite of folic acid (5-methyltetrahydrofolate) as a methyl donor and a metabolite of vitamin B12 (Methylcobalamin) as a cofactor .Only 20–30% of total homocysteine (and its dimer homocystine) is in free form in the plasma of normal individuals. The rest is bound to protein.

The accumulation of homocysteine and its metabolites is caused by disruption of any of the 3 interrelated pathways of methionine metabolism—

1) Deficiency in the Cystathionine β-synthase (CBS) enzyme (Type I/Classical Homocystinuria)

2) Defective methyl cobalamin synthesis -Type II

3) Abnormality in Methylene tetrahydrofolate reductase (MTHFR) – Type III

Three different cofactors/vitamins—pyridoxal 5-phosphate, methylcobalamin, and folate—are necessary for the 3 different metabolic paths.

The pathway, starting at methionine, progressing through homocysteine, and onward to cysteine, is termed the trans- sulfuration pathway. Conversion of homocysteine back to methionine, catalyzed by MTHFR and methylcobalamin, is termed the remethylation pathway. (Figure-1).

 methionine metab

 

Figure-1- Remethylation and Transsulfuration pathway of methionine metabolism

Defective Cystathionine beta Synthase

 (Classical Homocystinuria)

Inheritance

Homocystinuria is inherited in families as an autosomal recessive trait.

Clinical Manifestations

Infants with this disorder are normal at birth.

  • Clinical manifestations during infancy are nonspecific and may include failure to thrive and developmental delay.
  • The diagnosis is usually made after 3 yr of age, when subluxation of the ocular lens (ectopia lentis) occurs (figure-2). This causes severe myopia and iridodonesis (quivering of the iris), astigmatism, glaucoma, cataract, retinal detachment, and optic atrophy may develop later in life.

Dislocated lens

Figure-2- Dislocated lens

  • Progressive mental retardation is common. Normal intelligence, however, has been reported.
  • Affected individuals with homocystinuria manifest skeletal abnormalities resembling those of Marfan syndrome; they are usually tall and thin with elongated limbs and arachnodactyly (figure-3), scoliosis (figure-4), pectus excavatum, genu valgum, pes cavus, high arched palate, and crowding of the teeth are common.

Arachynodactyly

Figure-3- Arachnodactyly

scoliosis

Figure-4- Scoliosis

  • Patients usually have fair complexions, blue eyes, and a peculiar malar flush.
  • Thromboembolic episodes involving both large and small vessels, especially those of the brain, are common and may occur at any age.

Laboratory findings

  • Amino acid screen of blood and urine – Elevations of both Methionine and homocystine in body fluids are the diagnostic laboratory findings, as in the given case.
  • Total plasma homocysteine is extremely elevated (usually >100μ M).
  • Cystine is low or absent in plasma.
  • The urine screening test for sulfur-containing amino acids, called the cyanide nitroprusside test, can be undertaken;
  • Liver biopsy and enzyme assay are diagnostic
  • Skeletal x-ray reveals generalized osteoporotic changes
  • Skin biopsy with a fibroblast culture (The diagnosis may be established by assay of the enzyme in liver biopsy specimens, cultured fibroblasts)
  • Standard ophthalmic examination is diagnostic for various eye changes
  • Genetic testing can be helpful.

Treatment

  • A high dose of vitamin B6 causes dramatic improvement in patients who are responsive to this therapy.
  • The cysteine deficiency must be made up from dietary sources.
  • Supplementation with pyridoxine, folic acid, B12 or trimethyl glycine (Betaine) reduces the concentration of homocysteine considerably in the bloodstream.
  • A low Methionine diet is also recommended.
  • Existing mental retardation can be improved by symptomatic treatment

As regards other options,

The amino acids such as

Valine, Threonine, Glutamine, or Cysteine are not found in high concentration in blood in conditions of defective Cystathionine-β-synthase activity. Cysteine concentration is rather decreased in such defect.

 

 

 

 

 

 

 

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Laboratory results for a patient with uncontrolled Type I diabetes mellitus reveal hyperglycemia (456 mg/dL) and hypertriglyceridemia (395 mg/dL). The most likely cause of the hypertriglyceridemia in this patient is which of the following?

A. Deficiency in apoprotein C-II

B. Increased hepatic triglyceride synthesis

C. Decreased lipoprotein lipase activity

D. Deficiency in LDL receptors

E. Absence of hormone-sensitive lipase.

 

The correct answer is-C- Decreased Lipoprotein lipase activity.

Circulating lipoproteins are just as dependent on insulin as is the plasma glucose, it is because, the lipoprotein lipase that catalyzes the degradation of circulating lipoproteins is activated by insulin.

Lipoprotein lipase

Occurrence

Lipoprotein lipase is located on the walls of blood capillaries, anchored to the endothelium by negatively charged proteoglycan chains of Heparan sulfate. It has been found in heart, adipose tissue, spleen, lung, renal medulla, aorta, diaphragm, and lactating mammary gland, although it is not active in adult liver.

Lp L

Figure-1- Action of lipoprotein lipase (LpL).

It is not normally found in blood; however, following injection of heparin, lipoprotein lipase is released from its heparan sulfate binding into the circulation.  Due to this reason ‘heparin’ is called a “clearing factor”, as it causes release of lipoprotein lipase that promotes utilization and clearance of lipoproteins from the plasma.

Activators and inhibitors of lipoprotein lipase

Both phospholipids and apo C-II are required as cofactors for lipoprotein lipase activity (figure-1), while apo A-II and apo C-III act as inhibitors. Hydrolysis takes place while the lipoproteins are attached to the enzyme on the endothelium.

Hypertriglyceridemia in Type 1 Diabetes Mellitus

Dyslipidemia is a common metabolic abnormality in uncontrolled diabetes mellitus. Dyslipidemia includes; hypercholesterolemia, hypertriglyceridemia, raised LDLc and LDLc, but low levels of HDLc.

Biochemical basis of dyslipidemia in uncontrolled DM

One major role of insulin is to stimulate the storage of food energy following the consumption of a meal.This energy storage is in the form of glycogen in hepatocytes and skeletal muscle. Additionally, insulin stimulates synthesis of triglycerides in hepatocytes and promotes their storage in adipose tissue. In opposition to increased adipocyte storage of triglycerides is insulin-mediated inhibition of lipolysis (insulin inhibits adipolysis because the enzyme hormone- sensitive lipase, that catalyzes adipolysis is stimulated by Glucagon and inhibited by Insulin).

Lipolysis and its implications in Type 1 DM

In uncontrolled IDDM since the lipolysis is promoted, thus  there is a rapid mobilization of triglycerides leading to increased levels of plasma free fatty acids. The free fatty acids are taken up by numerous tissues (however, not the brain) and metabolized to provide energy. Free fatty acids are also taken up by the liver.

Increased fatty acid oxidation

Normally, the levels of malonyl-CoA are high in the presence of insulin. These high levels of malonyl-CoA inhibits carnitine acyl Transferase I, the enzyme required for the transport of fatty acyl-CoA’s into the mitochondria where they are subject to oxidation for energy production. Thus, in the absence of insulin, malonyl-CoA levels fall and transport of fatty acyl-CoA’s into the mitochondria increases. Mitochondrial oxidation of fatty acids generates acetyl-CoA which can be further oxidized in the TCA cycle.

Suppressed TCA cycle and its implications

a) Ketosis

In hepatocytes the majority of the acetyl-CoA is not oxidized by the TCA cycle but is metabolized into the ketone bodies, Acetoacetate and β-hydroxybutyrate.These ketone bodies leave the liver and are used for energy production by the brain, heart and skeletal muscle. In IDDM, the increased availability of free fatty acids and ketone bodies exacerbates the reduced utilization of glucose furthering the ensuing hyperglycemia. Production of ketone bodies, in excess of the body’s ability to utilize them leads to ketoacidosis. In diabetics, this can be easily diagnosed by smelling the breath. A spontaneous breakdown product of acetoacetate is acetone which is volatilized by the lungs producing a distinctive odor.

b) Hypercholesterolemia

The unutilized Acetyl Co A, due to suppressed TCA cycle, is also channeled towards the pathway of cholesterol biosynthesis resulting in hypercholesterolemia.

Basis of hypertriglyceridemia

Normally, plasma triglycerides are acted upon by lipoprotein lipase (LPL). In particular, LPL activity allows released fatty acids to be taken from circulating triglycerides for storage in adipocytes. The activity of LPL requires insulin and in its absence a hypertriglyceridemia results (figure-2).

Clinical pearls

In type 1 diabetes, moderately deficient control of hyperglycemia is associated with only a slight elevation of LDL cholesterol and serum triglycerides and little if any change in HDL cholesterol. Once the hyperglycemia is corrected, lipoprotein levels are generally normal. However, in obese patients with type 2 diabetes, a distinct “diabetic dyslipidemia” is characteristic of the insulin resistance syndrome. Its features are a high serum triglyceride level (300–400 mg/dL), a low HDL cholesterol (less than 30 mg/dL), and a qualitative change in LDL particles, producing a smaller dense particle whose membrane carries supranormal amounts of free cholesterol. These smaller dense LDL particles are more susceptible to oxidation, which renders them more atherogenic. Since low HDL cholesterol is a major feature predisposing to macro vascular disease, the term “dyslipidemia” has preempted the term “hyperlipidemia,” which mainly denoted the elevated triglycerides. Measures designed to correct the obesity and hyperglycemia, such as exercise, diet, and hypoglycemic therapy, are the treatment of choice for diabetic dyslipidemia, and in occasional patients in whom normal weight was achieved, all features of the lipoprotein abnormalities cleared.

As regards other options

Deficiency in apoprotein C-II

Apo CII is an activator of lipoprotein lipase, but its concentration is not decreased in diabetes mellitus.

Increased hepatic triglyceride synthesis

The Acetyl Co A carboxylase, the key regulatory enzyme of fatty acid biosynthetic pathway, is activated by insulin, thus, de novo fatty acid synthesis is decreased in insulin deficiency. However, the fatty acids mobilized from adipose tissue are used for esterification to form triglycerides which are transported from liver as VLDL. The excess flux of fatty acids that cannot be transported out as VLDL results in fatty liver. The hypertriglyceridemia in uncontrolled DM can be because of excess hepatic triglyceride synthesis, but mainly it is due to non degradation of circulating chylomicrons (carriers of dietary lipids) and VLDL (carriers of endogenous triglycerides) by the inactive lipoprotein lipase (figure-2).

Deficiency in LDL receptors

LDL receptors internalize LDL, their deficiency cannot cause hypertriglyceridemia, and otherwise also, they are not deficient in diabetes mellitus.

Absence of hormone-sensitive lipase

Hormone- sensitive lipase catalyzes the breakdown of triglycerides in adipose cells. It is activated by glucagon and catecholamines; inhibited by insulin. It is not absent; instead it is overactive in uncontrolled type 1 diabetes mellitus.

Hyper tgs 

 

Figure-2- Diabetic dyslipidemia. In normal health, VLDL released from liver, carrying endogenous triglycerides and Chylomicrons released from intestinal cells carrying dietary lipids, are acted upon by lipoprotein lipase (LPL), and the resultant fatty acids are taken up by peripheral cells, whereas the lipoprotein remnants are taken up by liver. VLDL is converted to LDL, through intermediate formation of IDL (intermediate density lipoprotein). In diabetes mellitus, in the absence of active LPL, the lipoprotein metabolism is disturbed resulting in hypertriglyceridemia, hypercholesterolemia, small dense LDL, low HDL and  a fatty liver.

 

 

 

 

 

 

 

 

 

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A 10-month-old infant was admitted to the hospital in a state of coma. Examination revealed a high body temperature, rapid pulse rate, abnormal electroencephalogram and hepatomegaly. Analysis of his urine showed abnormally high amounts of glutamine and uracil, which suggested a high blood ammonium ion concentration. Considering the data, which enzyme might be defective in this patient?

A. Arginase

B. Carbamoyl phosphate synthetase I

C. Glutamate dehydrogenase

D. Glutaminase

E. Ornithine transcarbamoylase

The correct answer is- E- Ornithine Transcarbamoylase.

High amounts of glutamine in blood, urine or CSF indicate underlying hyperammonemia.

Glutamine is produced during the course of detoxification of ammonia.

Hyperammonemia and Glutamine levels

Ammonia is produced as a result of various metabolic activities. It has to be detoxified immediately else can prove toxic to the brain cells and other tissues.

Mechanism of Ammonia detoxification

1) The first line of defense- Glutamate condenses with ammonia to produce Glutamine. The reaction catalyzed can be represented as follows (figure-1):

Glutamine synthetase

Figure-1- Glutamate to Glutamine conversion is catalyzed by Glutamine synthetase. It is an energy requiring process, ATP acts as a source of energy.

Glutamine is transported to liver.The nitrogen of glutamine can be converted to urea in the liver (Figure -2).

Glutaminase

Figure-2- Hydrolytic release of the amide nitrogen of glutamine as ammonia,is catalyzed by glutaminase in liver. Ammonia thus released is detoxified producing urea.

2) Second line of defense

In conditions of excess ammonia release the second line of defense involves the formation of Glutamate from Alpha keto glutarate (intermediate of TCA cycle) that can be subsequently used for Glutamine synthesis (as explained above and also shown below). The reactions can be represented as:

Detoxification of ammonia

Figure-3-Steps of detoxification of ammonia. In the first step the reaction is catalyzed by Glutamate dehydrogenase, a unique enzyme that can use any of NAD+ or NADP+ as a coenzyme. The reaction is although reversible, but in the liver the reaction is directed towards Alpha keto glutarate formation and the released ammonia is used for the urea formation. In conditions of hyperammonemia, the reaction is favored towards glutamate formation. Glutamate to Glutamine is an energy requiring irreversible reaction catalyzed by Glutamine synthetase.

 

Thus, Glutamine is the end product of detoxification of ammonia; therefore the glutamine levels are directly proportional to the ammonia levels.

Overview of causes of hyperammonemia

There can be congenital or acquired causes of hyperammonemia. Urea cycle disorders are responsible for congenital hyperammonemia, whereas the cirrhosis of liver or other conditions causing liver failure are responsible for Acquired hyperammonemia.

The symptoms of ammonia intoxication include- Slurring of speech, blurring of vision, tremors, convulsions, coma and death. The symptoms are due to energy depletion (TCA cycle suppression due to depletion of alpha ketoglutarate) and hyperexcitation caused as a result of excess serotonin (excitatory)  but decreased GABA (gamma amino butyric acid- inhibitory neurotransmitter) formation.

Hyperammonemia and urea cycle disorders

The deficiencies of urea cycle enzymes cause hyperammonemia and corresponding increase in glutamine levels.

In the given case the clinical manifestations are indicative of hyperammonemia due to a defect in the urea cycle, and the simultaneous rise of uracil in urine indicates excess pyrimidine biosynthesis, that might be due to divergence of unutilized Carbamoyl-P towards the pathway of pyrimidine biosynthesis. The Carbamoyl-phosphate accumulates only if there is deficiency of Ornithine transcarbamoylase. The mitochondrial Carbamoyl-P leaks into the cytoplasm so as to be channeled towards pathway of pyrimidine biosynthesis (figure-4).

OTC-deficiency

Figure-4- Urea cycle disorder causing orotic aciduria. Ornithine transcarbamoylase deficiency leaves excess of Carbamoyl -P that acts as a substrate for pyrimidine biosynthesis.

As regards other options

A. Arginase- Catalyzes the conversion of Arginine to urea and ornithine (figure-4)

B. Carbamoyl phosphate synthetase I- catalyzes the first step of urea cycle. It is a rate limiting enzyme. There is a cytoplasmic Carbamoyl-P synthetase-II, which is the first enzyme of pathway of pyrimidine pathway. Thus Carbamoyl P is produced both in the urea cycle as well in the pyrimidine biosynthetic pathway by different enzymes. The mitochondrial Carbamoyl P, as in this case, can leak to cytoplasm to be subsequently utilized for pyrimidine biosynthesis if there is a block at the level of its utilization forming Citrulline in urea cycle.

C. Glutamate dehydrogenase- The reaction catalyzed by Glutamate dehydrogenase has been shown above (figure-3)

D. Glutaminase- Catalyzes the hydrolysis of Glutamine to glutamate (figure-2).

Thus ornithine transcarbamoylase deficiency is the most appropriate answer. Hyperammonemia and rise in glutamine levels can be observed in other urea cycle disorders as well but the simultaneous rise of orotic acid or uracil nucleotide in urine occurs only in ornithine transcarbamoylase deficiency.

 

 

 

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What is the basis of this statement “fats burn in the flame of carbohydrates”?

A)   Fats are hydrolyzed in the presence of carbohydrates

B)   Fatty acids and glucose are simultaneously oxidized

C)   Acetyl co A is the common product of fatty acid and glucose oxidation

D)   Acetyl co A is oxidized completely in the presence of oxaloacetate in TCA cycle

 

The correct answer is D) – Acetyl co A is oxidized completely in the presence of oxaloacetate in TCA cycle.

Fats burn in the flame of carbohydrates means fats can only be oxidized in the presence of carbohydrates.

Oxidation of fats

Fats includes triglycerides, cholesterol (free or esterified), free fatty acids and their derivatives such as phospholipids and other complex lipids. The end product of metabolism of almost all these fats is Acetyl co A. Hence, Acetyl co A can be considered a fat derivative. There are many other sources (figure-1), but fatty acid oxidation is the major source of Acetyl co A.

Sources of Acetyl Co A

Figure-1- Sources of Acetyl co A:  The major contribution of Acetyl Co A is from fatty acid oxidation, the pathways of fatty acid oxidation (minor and major), end up forming Acetyl Co A. Pyruvate, ketogenic amino acids and acetylcholine also contribute to Acetyl co A pool. The ketone bodies are synthesized from and are metabolized to Acetyl Co A.

Fate of Acetyl Co A

Acetyl Co A can be metabolized in many ways (figure-2); It is a precursor of fatty acids, cholesterol, steroids, ketone bodies, and Acetylcholine. It is also required for the detoxification of xenobiotics, but the major fate involves complete oxidation in the TCA cycle to provide energy.

Fate of Acetyl Co A

Figure-2- Central role of Acetyl co A: Acetyl Co A can be utilized in multiple ways depending upon the cell type and under different cellular conditions. Under low energy states, Acetyl co A is completely oxidized in the TCA cycle to provide energy.

Oxidation of Acetyl Co A in TCA cycle

The citric acid cycle is the central metabolic hub of the cell. It is the final common pathway for the oxidation of fuel molecule such as amino acids, fatty acids, and carbohydrates. It is the gateway to the aerobic metabolism of any molecule that can be transformed into an acetyl group or dicarboxylic acid. The citric acid cycle (Krebs cycle, tricarboxylic acid cycle) includes a series of oxidation-reduction reactions in mitochondria that result in the oxidation of an acetyl group to two molecules of carbon dioxide and reduce the coenzymes that are reoxidized through the electron transport chain, linked to the formation of ATP.

A four- carbon compound (oxaloacetate) condenses with a two-carbon acetyl unit to yield a six-carbon tricarboxylic acid (citrate). An isomer of citrate is then oxidatively decarboxylated. The resulting five-carbon compound (α-ketoglutarate) also is oxidatively decarboxylated to yield a four carbon compound (succinate) (Figure-3).

Overview of TCA

Figure-3- An overview of TCA cycle

Oxaloacetate is then regenerated from succinate. Two carbon atoms enter the cycle as an acetyl unit and two carbon atoms leave the cycle in the form of two molecules of carbon dioxide. This is considered as the complete oxidation of Acetyl co A having two carbon atoms in its structure.1 acetate unit generates approximately 12 molecules of ATP.

The four-carbon molecule, oxaloacetate that initiates the first step in the citric acid cycle is regenerated at the end of one passage through the cycle. The oxaloacetate acts catalytically: it participates in the oxidation of the acetyl group but is itself regenerated. Thus, one molecule of oxaloacetate is capable of participating in the oxidation of many acetyl molecules.

Sources and Fate of Oxaloacetate

Oxaloacetate can be synthesized from or metabolized to Aspartate (figure-4) in reversible transamination reaction. Aspartate can be used for the synthesis of purines and pyrimidines; it is also used in urea cycle. The major source of Oxaloacetate is pyruvate in a reaction catalyzed by Pyruvate carboxylase.

Pyruvate is mainly used up for Anaplerotic reactions to compensate for oxaloacetate concentration.  Thus without carbohydrates (Pyruvate), there would be no Anaplerotic reactions to replenish the TCA-cycle components. With a diet of fats only, the acetyl CoA from fatty acid degradation would not get oxidized and build up due to non- functioning of TCA cycle. Thus fats can burn only in the flame of carbohydrates -Figure-5

 Role of oxaloacetate

Figure-4- Role of Oxaloacetate in TCA cycle. Oxaloacetate acts as a catalyst of TCA cycle; it starts the cycle and is regenerated at the end of the cycle.

Conclusion

It can now be well concluded that the complete oxidation of Acetyl Co A, a derivative of fats cannot take place without the availability the derivative of carbohydrates, that is oxaloacetate,. Hence the statement “fats burn in the flame of carbohydrates”, is absolutely correct.

 Fats and carbs

Figure-5- Significance of oxaloacetate in TCA cycle operation.

As regards other options

A)   Fats are hydrolyzed in the presence of carbohydrates -is incorrect. Fats are not hydrolyzed in the presence of carbohydrates.

B)   Fatty acids and glucose are simultaneously oxidized- It is also not true. The location, enzymes, the nutritional states, the regulatory hormones are different for these oxidative processes. Fatty acid oxidation mainly takes place during period of starvation, in the presence of glucagon or catecholamines whereas glycolysis takes place in the well fed state in the presence of insulin as the regulatory hormone.

C)   Acetyl co A is the common product of fatty acid and glucose oxidation- The end product undoubtedly is Acetyl Co A but without oxaloacetate, Acetyl co A cannot be oxidized.

Therefore, D)   Acetyl co A is oxidized completely in the presence of oxaloacetate in TCA cycle, is the correct option.

 

 

 

 

 

 

 

 

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1) – A 47-year-old female is brought to the emergency department with complaints of malaise, nausea, vomiting, and fatigue. The patient reveals a long history of alcohol abuse for the last 10 years requiring drinks daily especially in the morning as an “eye opener.” She has been to rehab on several occasions for alcoholism but has not been able to stop drinking. She is currently homeless and jobless. She denies cough, fever, chills, upper respiratory symptoms, sick contacts, recent travel, hematemesis, or abdominal pain. She reports feeling hungry and has not eaten very well in a long time. She appears malnourished but in no distress. Her physical exam is normal. Her blood count reveals a normal white blood cell count but does show an anemia with large red blood cells. Her amylase, lipase, and liver function tests were normal. Which of the following nutrients might help to relieve her symptoms?

A. Iron and folic acid

B. High protein diet

C. Ketogenic diet

D. Supplementation with carnitine

E. Folic acid and B12

2) – A 50-year-old homeless man was brought to the emergency room in a stuporous state. Below are his lab results, Bicarbonate 10mEq/L (22-28), pH 7.2 (7.35-7.45), PCO2 25mmHg (35-45), Alcohol 40mmol/L (0), Osmolality 370mOsm/L (280-295), Glucose 50mg/dl (65-110) BUN 40mg/dl (8-25). What is the acid-base status?

A. Metabolic acidosis and metabolic alkalosis

B. Metabolic acidosis with partial respiratory compensation

C. Respiratory acidosis and partial metabolic compensation

D. Respiratory acidosis

E. Metabolic alkalosis.

3) – A 3-year-old girl was brought into the Emergency Room. She was cold and clammy and was breathing rapidly. She was obviously confused and lethargic. Her mother indicated that she had accidentally ingested automobile antifreeze while playing in the garage. Following gastrointestinal lavage and activated charcoal administration, a nasogastric tube for ethanol was administered. How will ethanol help in relieving the symptoms?

A. Conjugate with ethylene glycol to form a soluble compound

B. Inhibit the activity of alcohol dehydrogenase

C. Inhibit the binding of ethylene glycol to alcohol dehydrogenase

D. Promote the excretion of metabolite of ethylene glycol

E. Stimulate the activity of acetaldehyde dehydrogenase.

4) – After excessive drinking over an extended period of time while eating poorly, a middle-aged man is admitted to the hospital with “high output” heart failure. Which of the following enzymes is most likely inhibited?

A. Aconitase

B. Citrate synthase

C. Isocitrate dehydrogenase

D. α-Ketoglutarate dehydrogenase

E. Succinate thiokinase

5)- Asians and Native Americans may flush and feel ill after drinking a small amount of ethanol in alcoholic beverages. This reaction is due to genetic variation in an enzyme that metabolizes the liver metabolite of alcohol, which is-

A. Methanol

B. Acetone

C. Acetaldehyde

D. Glycerol  

E. Propionate    

6) – A 25-year-old man is brought to the emergency room after a motor vehicle accident. He has a dislocated hip, rib fractures and a facial laceration. Toxicology screen shows a high level of ethanol in his blood. Oxidation of ethanol produces acetaldehyde and NADH. A high level of NADH relative to NAD + promotes the conversion of which of the following reactions?

A. Dihydroxyacetone phosphate to glycerol-3-P

B. Citrate to Isocitrate

C. Pyruvate to Acetyl co A

D. Malate to oxaloacetate

E. Succinate to Fumarate

7) – A 57-year-old alcoholic is transported to the emergency room after sustaining an injury in a motor vehicle accident. A comprehensive metabolic panel and a serum γ- glutamyl transferase (GGT) level are ordered. The GGT is shown to be dramatically elevated. Apart from its role as a marker of alcoholism, this enzyme is also important for which of the following digestive processes?

A. Recycling of bile salts

B. Absorption of carbohydrates

C. Digestion of triglycerides

D. Absorption of amino acids

E. Digestion of carbohydrates

8) – A 55-year-old chronic alcoholic was brought to emergency by his friends. During their night-time gathering in the local bar he fell unconscious and they had been unable to revive him. The attending physician ordered for I/V Glucose and an injection of Thiamine. The patient was well oriented and alert next morning, his vital signs were stable, blood glucose was normal and he was discharged from the hospital. Which of the following enzymes is thiamine dependent and vital for glucose oxidation in brain?

A. Glucokinase

B. Transaldolase

C. Lactate dehydrogenase

D. Pyruvate dehydrogenase complex

E. Citrate synthase.

9) A 42-year-old executive complained of fatigue and some recent alterations in mental status, such as forgetting appointments. He traveled outside the United States 2 months ago on a business meeting. He had vague right upper quadrant pain on deep palpation and borderline enlargement of the liver.  Lab findings include-Serum AST = 120 U/L, ALT = 80 U/L, ALP = 68 U/L , GGT = 170U/L, Total bilirubin = 0.8mg/dL, Blood glucose = 60 mg/dL, Serum uric acid = 9.8 mg/dL, CBC and urinalysis results are normal. The patient is suffering from alcohol related liver disease. Which of the enzyme estimations is most diagnostic for alcohol related liver disease?

A. AST

B. ALT

C. ALP

D. GGT

E. LDH

10) A 45 -year-old male was brought to the emergency department after a family member found him extremely confused and disoriented. He had an unsteady gait and strange irregular eye movements. The patient had been a known heavy drinker from the past 6 years. 

There was no history of any known medical problem and he denied any other drug usage. On examination, he was afebrile with a pulse of 90 beats per minute and a normal blood pressure of 110/80 mmHg. Chest and abdominal examination were normal. He was extremely disoriented and agitated. Horizontal rapid eye movements on lateral gaze were noted bilaterally. His gait was very unsteady. The remainder of his examination was normal. The urine drug screen was negative and he had a positive blood alcohol level. Blood pyruvate and lactate levels were high. Which of the following nutrients might help in relieving the symptoms of this patient?

A. High carbohydrate diet

B. Ketogenic diet

C. Supplementation with Thiamine

D. Both A and B

E. Both B and C.

Key to answers

1) – E- Folic acid and B12

Most probably the patient is suffering from megaloblastic anemia due to cobalamine deficiency. The cause for this anemia is dietary deficiency which is very common in chronic alcoholics. Abstinence from alcohol and supplementation with B12 and folate.

2) – B- Metabolic acidosis with partial respiratory compensation.

Low pH and low bicarbonate are indicative of metabolic acidosis, which is usually compensated by hyperventilation to maintain the bicarbonate to carbonic acid ratio. The pCO2 is not very low in this patient, signifying partial compensation. The patient is alcoholic and has hypoglycemia, thus the underlying cause for metabolic acidosis is apparently lactic acidosis and ketoacidosis.

3) – C. Inhibit the binding of ethylene glycol to alcohol dehydrogenase.

Ethylene glycol is metabolized by the same enzyme system as ethanol to form toxic products that can cause severe acidosis and renal damage. Ethanol with least km is a true substrate for alcohol dehydrogenase and hence given as an antidote, it inhibit the binding of ethylene glycol to enzyme. The metabolism of ethylene glycol is thus inhibited.

4) – D. α-Ketoglutarate dehydrogenase.

The patient is most probably suffering from cardiac beriberi. The above said patient is a known alcoholic, mal nourished, and has heart failure .The probable diagnosis is Thiamine deficiency, which can be confirmed by Erythrocyte transketolase activity.  In the given list of enzymes, α-Ketoglutarate dehydrogenase is the only enzyme which is Thiamine dependent. It is a multienzyme complex, requiring thiamine, lipoic acid, pantothenic acid, riboflavin and niacin as coenzymes.

5) – C. Acetaldehyde.

In some Asian populations and Native Americans, alcohol consumption results in increased adverse reactions to acetaldehyde owing to a genetic defect of mitochondrial aldehyde dehydrogenase. The acetaldehyde formed from alcohol is oxidized in the liver in a reaction catalyzed by mitochondrial NAD-dependent aldehyde dehydrogenase (ALDH).

6) – A. – Dihydroxyacetone-P to Glycerol-3-P

Alcohol is metabolized  in two steps by two  NAD + requiring enzymes. Chronic alcohol consumption leads to build up of NADH, that changes the redox state of the hepatocytes. As a result the equilibrium of many reactions is shifted towards regeneration of NAD +. Out of the given list, its only the conversion of dihydroxyacetone-P which is likely to be effective.

7) – D. Absorption of amino acids

8) D- Pyruvate dehydrogenase complex

9)-A- AST

10) – E- Both B and C- Ketogenic diet and thiamine supplementation

 

 

 

 

 

 

 

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http://www.slideshare.net/namarta28/alcohol-induced-metabolic-alterations-a-case-based-discussion

 

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A 22- year-old diabetic comes to the Accident and Emergency department. She gives a 2-day history of vomiting and abdominal pain. She is drowsy and her breathing is deep and rapid. There is distinctive smell from her breath. She has been diagnosed with Diabetic ketoacidosis. Diabetic ketoacidosis is a complication of uncontrolled diabetes mellitus.

The TCA cycle in diabetes mellitus is suppressed and the excess Acetyl co A, resulting from fatty acid oxidation is channeled towards the pathway of ketogenesis.

Which of the following intermediates of TCA cycle is depleted in Type 1 Diabetes mellitus to suppress TCA cycle?

A) Succinate

B) Malate

C) α-Keto glutarate

D) Oxaloacetate

E) Pyruvate.

The correct answer is- D) – Oxaloacetate.

Two facts demand attention here-

1) TCA cycle suppression and

2) Basis of ketogenesis

In Diabetes mellitus, TCA cycle is in a state of suppression due to diminished availability of oxaloacetate which is channeled towards the pathway of gluconeogenesis.

The hyperglycemia in Insulin deficiency results from decreased utilization and excess pouring in of glucose. The processes of glucose utilization such as- Glycolysis, TCA cycle, HMP and glycogenesis occur at a diminished rate, whereas rates of gluconeogenesis and glycogen degradation are increased due to disturbed Insulin to Glucagon ratio in diabetes mellitus. Oxaloacetate is a common intermediate of  TCA cycle and gluconeogenesis. The utilization of oxaloacetate in the pathway of gluconeogenesis depletes the amount which is required for TCA cycle (Oxaloacetate acts as a catalyst; an optimum amount of oxaloacetate is required for the functioning of TCA cycle), therefore it undergoes in a state of suppression.

As glucose utilization is decreased in Diabetes mellitus, alternatively fatty acids are oxidized to compensate for the energy needs. Excess fatty acid oxidation results in:

i) Accumulation of NADH which further suppresses TCA cycle ( Excess of NADH decreases the catalytic activities of three NAD+ requiring enzymes of TCA cycle- Isocitrate dehydrogenase, Alpha ketoglutarate dehydrogenase and Malate dehydrogenase), and

Regulation of TCA cycle

Figure-1- Regulation of TCA cycle. Accumulation of NADH inhibits the activities of NAD + enzymes of TCA cycle, isocitrate dehydrogenase, Alpha keto glutarate dehydrogenase and Malate dehydrogenase. The activity of PDH complex is also decreased.

ii) Accumulation of Acetyl co A- The end product of fatty acid oxidation cannot be oxidized in TCA cycle at the same rate as that of its production, as a result , Acetyl co A is channeled either towards pathways of ketogenesis, or of cholesterol synthesis (figure-2).

TCA suppression

Figure-2- a) The rate of lipolysis is increased, fatty acids are oxidized to produce Acetyl CoA.

b) Due to non availability of oxaloacetate, which is diverted towards pathway of gluconeogenesis, TCA cycle is suppressed.

c) Acetyl co A is diverted towards pathway of ketogenesis. Acetone, acetoacetate and beta hydroxy butyrate are the three ketone bodies

d) Accumulated ketone bodies, (being acidic in nature and also as they deplete the alkali reserve) cause acidosis.

In Type 1 Diabetes mellitus, the onset of the disease is abrupt, which is why the body switches abruptly from glucose utilization to fatty acid oxidation for energy needs.  Acetyl co A resulting from excess fatty acid oxidation saturates TCA cycle and the other alternative pathways resulting in ketogenesis. This is the reason ketoacidosis is far more commonly found in type 1diabetes mellitus than type 2 diabetes.

The similar situation is observed in prolonged fasting or starvation. Diabetes mellitus and starvation depict a similar metabolic state, in both the conditions, the cells are deprived of glucose and switch to alternative fuels for their energy needs. The basis of ketosis is thus the same in both conditions.

As regards other options:

A) Succinate-Succinate is an intermediate of TCA cycle, but it is not depleted in Diabetes mellitus.

B) Malate- Similarly malate and C) α-Keto glutarate are also not depleted in Diabetes mellitus.

E) Pyruvate depletion does not directly affect the functioning of TCA cycle, of course pyruvate is also diverted towards glucose production, but there are other sources available, in any case TCA cycle activity is not affected.

Thus the most logical option is Oxaloacetate which is the most important regulator of TCA cycle, depletion of which suppresses TCA cycle.

 

 

 

 

 

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A 50-year-old, alcoholic male presents with a swollen face, distended abdomen, and an enlarged fatty liver. Fatty acids react with glycerol-3-P to form triglycerides, which accumulate to cause fatty liver. The liver has glycerol kinase, while adipose tissue lacks glycerol kinase. As a result, in adipose tissue, which of the following occurs?

A) Glucose cannot be converted to DHAP (dihydroxyacetone phosphate)

B) Glycerol cannot be converted to Glycerol-3-P

C) DHAP cannot be converted to Glycerol-3-P

D) Diacylglycerol cannot be converted to Triacylglycerol

E) Triacylglycerols cannot be stored.

The correct answer is- B) – Glycerol cannot be converted to Glycerol-3-P.

Glycerol kinase catalyzes the phosphorylation of glycerol to glycerol-3-p.

Glycerol released through adipolysis (breakdown of triglycerides) cannot be reutilized, as it has to be in the phosphorylated form, and glycerol kinase deficiency in adipose tissue makes glycerol a waste product (figure).

Therefore Glycerol is transported to liver, where upon conversion to dihydroxy acetone phosphate, (figure), it is either converted to glucose (through pathway of gluconeogenesis), or is completely oxidized through glycolytic pathway. The fate of glycerol is decided by the cellular requirements.

1)  In the fasting state- Glycerol released from lipolysis of adipose tissue triacylglycerol is used solely as a substrate for gluconeogenesis in the liver and kidneys. The conversion of glycerol to glucose requires phosphorylation to glycerol-3-phosphate by glycerol kinase and dehydrogenation to Dihydroxyacetone phosphate (DHAP) by glyceraldehyde-3-phosphate dehydrogenase (G3PDH) (Figure). The G3PDH reaction is the same as that used in the transport of cytosolic reducing equivalents into the mitochondrion for use in oxidative phosphorylation. This transport pathway is called the glycerol-phosphate shuttle.

Fate of glycerol

Figure-Glucose-Glycerol cycle. Glycerol released from adipocyte is used in the liver either for energy production or is utilized as a substrate for gluconeogenesis. Glycerol is initially converted to glycerol-3-P, in a reaction catalyzed by glycerol kinase. Subsequently glycerol-3-P is converted to Dihydroxy acetone-P (DHAP) by glycerol-3-p dehydrogenase. It is a reversible reaction. DHAP can then enter the pathway of glucose production. Glucose produced is transported back to adipocyte to complete the cycle. The entry of glucose in the adipocyte is by GLUT4 receptors that are regulated by Insulin.

2) In the well fed state- Glycerol upon conversion to DHAP in liver (as described above), is oxidized completely through the pathway of glycolysis. Glycolytic pathway is involved both for the utilization and production of glycerol-3-P.

It is noteworthy that glycerol-3-P in adipose tissue is obtained through glycolytic pathway (figure), and not by direct phosphorylation of glycerol (glycerol kinase is absent in adipose tissue).  In fact adipocytes require a basal level of glycolysis in order to provide them with DHAP as an intermediate in the synthesis of triacylglycerols.

As regards other options

A) Glucose cannot be converted to DHAP (dihydroxy acetone phosphate) – This in incorrect, Glucose can be converted to DHAP through glycolytic pathway (figure).

C) DHAP cannot be converted to Glycerol-3-P- This is also incorrect, DHAP is converted to Glycerol-3-P, in a reaction catalyzed by Glycerol-3-P dehydrogenase.

D) Diacylglycerol cannot be converted to Triacylglycerol- Diacyl glycerol can be converted to triacylglycerol. This is also not a correct option.

E) Triacylglycerols cannot be stored- Incorrect again, Triacylglycerols can be stored in an unlimited amount in the adipose cells.

Thus the most appropriate option is B) – Glycerol cannot be converted to Glycerol-3-P due to deficiency of glycerol kinase.

 

 

 

 

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A 32-year-old body builder has decided to go on a diet consisting of egg whites to ensure only proteins for muscle growth. After a few weeks he experiences decreased energy and is found to be hypoglycemic. A nutritionist tells the patient that he most likely has the deficiency of vitamin Biotin. Which of the following enzymes is unable to catalyze its step in synthesizing glucose from pyruvate?

A) Pyruvate carboxylase

B) Phospho enol pyruvate carboxykinase

C) Glucose-6-phosphatase

D) Fructose 1, 6 bisphosphatase

E) Phosphoglycerate kinase.

The correct answer is- A) – Pyruvate carboxylase.

Biotin deficiency is very common in bodybuilders, who consume raw egg whites. The Raw egg whites contain Avidin, a glycoprotein that strongly binds with biotin and prevents its absorption. Once a biotin-Avidin complex forms, the bond is essentially irreversible; the biotin-Avidin complex is not broken during passage of the food bolus through the stomach and intestines. As a result, biotin is not liberated from food, and the biotin-Avidin complex is lost in the feces. Thus, the ingestion of large quantities of raw egg white over a long period can result in a biotin deficiency. Cooking egg white denatures Avidin, rendering it susceptible to digestion and therefore unable to prevent the absorption of dietary biotin.

Biotin functions to transfer carbon dioxide in a small number of carboxylation reactions. Biotin is attached at the active site of carboxylases.

Each Biotin dependent carboxylase catalyzes an essential metabolic reaction:

1) Pyruvate carboxylase

Pyruvate carboxylase is a critical enzyme in gluconeogenesis—the formation of glucose from sources other than carbohydrates, for example, amino acids. Oxaloacetate formed from pyruvate can be utilized in many other ways depending upon the need of the cell (Figure-3)

Reaction catalyzed by pyruvate carboxylase

Figure-1 -Carboxylation of pyruvate to Oxaloacetate, catalyzed by Pyruvate carboxylase, is the first step of gluconeogenesis.

The other examples where Biotin is required as a coenzyme are:

2) Acetyl-CoA carboxylase (ACC) catalyzes the binding of bicarbonate to acetyl-CoA to form malonyl-CoA (Figure-2). Malonyl-CoA is required for the synthesis of fatty acids.

Reaction-catalyzed-by-Acetyl-co-A-carboxylase

Figure-2 -The carboxylation of Acetyl co A to form Malonyl co A, catalyzed by Acetyl co A carboxylase is the first and the rate limiting step in fatty acid synthesis.

3) Propionyl-CoA carboxylase catalyzes essential steps in the metabolism of certain amino acids, cholesterol, and odd chain fatty acids (fatty acids with an odd number of carbon molecules).

Fate of propionyl co A

Figure- 3-showing the fate of Propionyl co A

Propionyl co A is converted first to D- Methyl malonyl co A and then to its L isomer, ultimately to succinyl co A for complete utilization in the TCA cycle (Figure-3).

Anaplerotic reactions catalyzed by biotin dependent pyruvate carboxylase (PC) and Propionyl-coenzyme A carboxylase (PCC) regenerate oxaloacetate for the citric acid cycle.

As regards other options

B) Phospho enol pyruvate carboxykinase- Catalyzes the conversion of Oxaloacetate to phosphoenol pyruvate, it is an enzyme of pathway of gluconeogenesis but it is not a biotin dependent enzyme

C) Glucose-6-phosphatase catalyzes the last step of conversion of glucose-6-Phosphate to free glucose, but it is also not biotin dependent enzyme.

D) Fructose 1, 6 bisphosphatase- catalyzes the conversion of fructose1, 6 bisphosphate to Fructose 6 Phosphate; it is also not a biotin dependent enzyme.

E) Phosphoglycerate kinase- is a common enzyme, both for the pathways of glycolysis and gluconeogenesis. It catalyzes the reversible conversion of 1, 3 bisphosphoglycerate to 3, phosphoglycerate, ATP is formed by substrate level phosphorylation in glycolysis. ATP is consumed in the reverse reaction, in the pathway of gluconeogenesis.

 

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Introduction

A colorimeter is a device used in colorimetry. The word generally refers to the device that measures the absorbance of particular wavelengths of light by a specific solution. This device is most commonly used to determine the concentration of a known solute in a given solution by the application of the Beer-Lambert law.

Principle of colorimetry

Colored solutions have the property of absorbing light of definite wave lengths. The amount of light absorbed or transmitted by a colored solution is in accordance with the Beer-Lambert law.

Beer’s law- The intensity of the color is directly proportional to the concentration of the colored particles in the solution.

Lambert’s law- The amount of light absorbed by a colored solution depends on the length of the column or the depth of the depth of the liquid through which the light passes.

Equations

When a monochromatic light with an original intensity ‘Io’, passes through a solution that can absorb radiant energy, Is will be less than the Io.

Some of the radiant energy is reflected back by the cell containing the solution, or absorbed by the cell wall or the solvent.

The amount of radiation absorbed may be measured in a number of ways:

  1. By measuring transmittance
  2. by measuring absorbance

1. By measuring transmittance-  The transmittance (T) is defined as-

T= Is/ Io

The ratio is expressed as percentage, thus

% T= 100 x Is/ Io

As the concentration of the compound increases, less light is transmitted.

%T varies inversely and logarithmically with the concentration.

 2) By measuring absorbance-  Absorbance measurement is convenient than transmittance.

Absorbance (A) or optical density is directly proportional to the concentration.

The relationship between absorbance and transmittance can be expressed as –

A = – log Is/ Io

   = – log T

   = log 1/T

To convert T to % T,

A = log 1/T x 100/100

   = log (100)/%T

   = log 100-log %T

    = 2-log %T

Thus,

A = 2-log %T

In other words, absorbance (Optical density) and Transmittance (T) are reciprocally related.

So, if all the light passes through a solution without any absorption, then absorbance is zero, and percent transmittance is 100%. If all the light is absorbed, then percent transmittance is zero, and absorption is infinite (Figure-1)

Absorbance versus Transmittance

Figure 1: Transmittance and absorbance are reciprocally related.

Lambert -Beer’s law

The mathematical expression at a given wavelength can be represented as follows-

OD = A = Ʃcl

Since,

OD = – log Is/ Io

(Absorption has no units, since it is a ratio)

Thus:

– log Is/ Io = cl

or Is/ Io = e Ʃcl

Where =Ʃ is a Constant- It is the molar extinction coefficient( Molar absorptivity) with units of L mol-1 cm-1

C = Concentration of the colored substance, expressed in mol L-1

l = is the path length of the sample – that is, the path length of the cuvette in which the sample is contained.

e- base of the natural logarithm.

Since Is/ Io is known as transmittance (T)

Thus,

T= e Ʃcl

Taking logarithm:

-log 10T =Ʃcl

As per equation:

-log T= A

Hence

A = OD = Ʃcl

Since the thickness of the layer of solution is constant in the instrument, optical density is proportional to the concentration.

When optical density is plotted against concentration “c”, a straight line passing through the origin should be obtained, because the absorbance is directly proportional to the concentration. (Figure-2)

Absorbance versus concentration

Figure 2: Relationship of absorbance and concentration of a solute in a solution

 

The concentration of an unknown solution can be readily determined by measurement of its absorbance and interpolation of its concentration from the graph of the standards.

When % T is plotted versus concentration, a curvilinear relationship is obtained.

The linear relationship between concentration and absorbance is both simple and straightforward, which is why it is preferred to express the Beer-Lambert law using absorbance as a measure of the absorption rather than %T.

Calculation of unknown concentration in the test sample

Since there is a linear relationship between absorbance and concentration, it is possible to calculate the unknown concentration of a substance in the test sample by simple proportional equation-

Absorbance of unknown         Concentration of unknown

———————————- = ————————————–

Absorbance of standard          Concentration of Standard

                                                            Absorption of unknown

Concentration of unknown = ————————————— x Concentration of Standard

                                                            Absorption of standard

Thus,

Concentration of Unknown (Test sample T)

                                                            OD of Test

                                                = ————————– x Concentration of Standard

                                                            OD of standard

Some of the incident energy may be reflected by the cell containing the solution or absorbed by the cell wall or the solvent. To eliminate these factors and to consider the absorption by the compound, a blank solution or a reference solution having everything but the compound to be measured is used.

Thus The concentration of unknown can be expressed as-

Concentration of Unknown (Test sample T)

                                                            OD of Test – OD of Blank

                                                = —————————————— x Concentration of Standard

                                                            OD of standard – OD of Blank

Deviations from Beer’s law are observed when a very large concentration of an unknown substance is measured or when the incident light is not mono chromatic light.

 

Components of a photo colorimeter

1) Light source

The light source is usually a tungsten lamp for wavelength in the visible range (320-700 nm) and a deuterium or hydrogen lamp for ultraviolet light (below 350 nm). Hydrogen lamp is usually preferred to UV range.

2) Monochromators

This is for the selection of sufficiently narrow wave band. The monochromator consists of an entrance slit to exclude unwanted, followed by absorption or interference filters, prisms or diffraction grating for wave length selection. (Figure-3)

Colorimeter

Figure 3: Components of a colorimeter.

 

The interference filters consist of thin layer of magnesium fluoride crystals with a semitransparent coating of silver on each side. The interference filters have a bandpass of 5-8 nm. The band pass is defined as the width of the spectrum that will be isolated by a monochromator. The choice of filter depends upon the final color of the  solution formed.

Wave length (nm) Filter used/Color absorbed Color of solution
350-430 Violet Yellow Blue
430-475 Blue Yellow
475- 495 Green blue Orange
495-505 Blue green Red
505-555 Green Purple
555-575 Yellow green Violet
575-600 Yellow Blue
600=650 Orange Green blue
650-700 Red Blue green

3) Lens

Instruments using filters as wavelength selectors require lenses to focus correctly the light from the source through the filter and cuvette to the detector. In the ultraviolet range, quartz or fused silica is essential because the glass does not transmit light efficiently at wave length shorter than 340 nm.

An exit slit at the end of monochromator allows only a narrow fraction of the spectrum of reach the sample cuvette.

4) Sample cuvette

For accurate and precise reading, cuvette must be transparent, clean, devoid of any scratches. The optical path of the cuvette is always 1 cm. Glass cuvettes are used for reading in the visible light range while quartz or fused silica cuvettes are used for UV range.

5) Photosensitive detectors

These detectors contain a light-sensitive surface that releases electrons in number proportional to the intensity of light on it, converting light energy into electrical energy. Different detectors used are-

a) Barrier layer cells

b) Photosensitive tubes

c) Photomultiplier tubes

d) Photoconductive cells

6) Read out devices– The detector response can be measured by any of the following read out devices-

a) Galvanometer

b) Ammeter

c) Recorder

d) Digital read out.

The signal may be transmitted to computer or print out device. Most modern instruments are of direct reading type where the amplified detector signal operates a galvanometer.

 

 

 

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A 14-year-old high school girl who is extremely conscious about her appearance has gone  near fasting for two days to fit in to a dress she intentionally brought a size smaller than her actual size for a dance party. Which of the following organs/tissues contributes to the glucose that is being synthesized through gluconeogenesis?

A) Spleen

B) Red blood cells

C) Skeletal muscle

D) Liver

E) Brain

The correct answer is- D) Liver.

Gluconeogenesis is the process of converting non-carbohydrate precursors to glucose or glycogen.

Gluconeogenesis meets the needs of the body for glucose when sufficient carbohydrate is not available from the diet or glycogen reserves. A supply of glucose is necessary especially for the nervous system and erythrocytes. Failure of gluconeogenesis is usually fatal.

Liver and kidney are the major gluconeogenic tissues.

Substrates of Gluconeogenesis

The major substrates are-

  1. The glucogenic amino acids,
  2. Lactate
  3. Glycerol, and
  4. Propionate.

These noncarbohydrate precursors of glucose are first converted into pyruvate or enter the pathway at later intermediates such as oxaloacetate and Dihydroxyacetone phosphate (figure-1).

Pathway of gluconeogensis

 

Figure-1- Reactions of gluconeogenesis. Three irreversible reactions of glycolysis are substituted by alternative reactions. Pyruvate carboxylase, Phospho enol pyruvate carboxy kinase, Fructose 1,6 bisphosphatase and glucose-6-Phosphatase enzymes are unique to pathway of gluconeogenesis. Lactate enters as pyruvate, glycerol as Dihydroxy acetone-phosphate, propionate as Succinyl co A, and the intermediates of TCA cycle distal to α-Keto glutarate are glucogenic. Acetyl co A  is not glucogenic but it is a positive modulator of pyruvate carboxylase enzyme.

Role of kidney

Although the liver has the critical role of maintaining blood glucose homeostasis and therefore, is the major site of gluconeogenesis, the kidney also plays an important role. During periods of severe hypoglycemia that occur under conditions of hepatic failure, the kidney can provide glucose to the blood via renal gluconeogenesis. In the renal cortex, glutamine is the preferred substance for gluconeogenesis.

Glutamine is produced in high amounts by skeletal muscle during periods of fasting as a means to export the waste nitrogen resulting from amino acid catabolism. The glutamine is then transported to the kidneys where the reverse reactions occur. Glutamate is first produced from hydrolysis of Glutamine by glutaminase, which is then further catabolized  liberating ammonia and producing α-ketoglutarate which can enter the TCA cycle and the carbon atoms diverted to gluconeogenesis via oxaloacetate.

Role of kidney in gluconeogenesis

Figure-2- Role of kidney in gluconeogenesis

This process serves two important functions. The ammonia (NH3) that is liberated spontaneously ionizes to ammonium ion (NH4+) and is excreted in the urine effectively buffering the acids in the urine. In addition, the glucose that is produced via gluconeogenesis can provide the brain with critically needed energy.

 

 

 

 

 

 

 

 

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Case detail

A 3-year-old girl was brought into the Emergency Room. She was cold and clammy and was breathing rapidly. She was obviously confused and lethargic. Her mother indicated that she had accidentally ingested automobile antifreeze (ethylene glycol) while playing in the garage. Following gastrointestinal lavage and activated charcoal administration, a nasogastric tube for ethanol was administered. How will ethanol help in relieving the symptoms?

A. Conjugate with ethylene glycol to form a soluble compound

B. Induce the alcohol dehydrogenase enzyme

C. Competitively inhibit the metabolism of ethylene glycol

D. Promote the excretion of metabolite of ethylene glycol

E. All of the above.

The correct answer is- C- Competitively inhibits the metabolism of ethylene glycol.

Ethylene glycol is the major ingredient of almost all radiator fluid products. It is used to increase the boiling point and decrease the freezing point of radiator fluid, which circulates through the automotive radiator. Ethylene glycol is added to prevent the radiator from overheating or freezing, depending on the season.

As with ethyl alcohol and methanol, ethylene glycol is metabolized by alcohol dehydrogenase to form glycoaldehyde. Through interaction with aldehyde dehydrogenase, ethylene glycol is then metabolized to glycolic acid (GA). A profound acidosis often ensues and is attributable to the glycolic acid in circulation. The patient may develop hyperventilation that results from acidemia. This glycolate is then transformed into glyoxylic acid. This glycolate is then transformed into glyoxylic acid. At this point, the molecule may be transformed into the highly toxic oxalate.

Reaction:

 Ethylele glycol

Figure- Metabolism of ethylene glycol

With the formation of oxalate crystals in the urine, calcium oxalate crystals form and accumulate in blood and other tissues. The precipitation of calcium oxalate in the renal cortex results in decreased glomerular filtration and renal insufficiency. Calcium is consumed in circulation, and hypocalcemia may occur.

The rate-dependent step of ethylene glycol metabolism is the alcohol dehydrogenase–catalyzed step. Ethyl alcohol binds much more easily to alcohol dehydrogenase than ethylene glycol or methanol does. Because ethanol is the preferential substrate for alcohol dehydrogenase, the presence of ethanol may essentially block metabolism of ethylene glycol.

Treatment of ethylene glycol poisoning

Emergency and Supportive Measures

For patients presenting within 30–60 minutes after ingestion, the stomach is emptied by gastric lavage. Charcoal is not very effective but should be administered if other poisons or drugs have also been ingested.

Specific Treatment

Patients with significant toxicity (manifested by severe metabolic acidosis, altered mental status, and markedly elevated osmolar gap) should undergo hemodialysis as soon as possible to remove the parent compound and the toxic metabolites. Treatment with folic acid, thiamine, and pyridoxine may enhance the breakdown of toxic metabolites.

Ethanol blocks metabolism of the parent compounds by competing for the enzyme alcohol dehydrogenase. The desired serum ethanol concentration is 100 mg/d. Fomepizole (4-methylpyrazole; Antizol), blocks alcohol dehydrogenase and can be used instead of ethanol.

As regards other options

Alcohol does not form any complex with ethylene glycol, it does not induce alcohol dehydrogenase enzyme and even it does not promote the excretion of metabolites of ethylene glycol.

 

 

 

 

 

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Case details

A 15 year-old boy had numbness and tingling around his mouth and in his finger tips. The problem was intermittent usually occurring during times of great stress. Aside from his problem, he had been in good health. His physical examination was normal, as were his laboratory values, especially his total calcium concentration was 2.5 mM/L, with ionized calcium of 1.2 mM/L(normal 2.1 to 2.6 mM/L and 1.14- 1.30 mM/L respectively). After breathing rapidly for about 3 minutes at 30 breaths per minute, he stated that it provoked the episode. At this time he had increased irritability of his seventh cranial nerve (Chovstek’s sign) and carpal spasm on oxygen deprivation of his hand (trousseau’s sign) both indicating clinical hypocalcemia. His plasma calcium concentration during an episode remained at 2.5 mM/L but his ionized calcium level fell to 0.8 mM/L.

What is the cause for all these symptoms?

A) Stress induced high catecholamine release

B) Stress induced low PTH release

C) Respiratory alkalosis

D) Respiratory acidosis

E) Vitamin D deficiency.

The correct answer is -C) Respiratory alkalosis.

Respiratory alkalosis is a primary decrease in PCO2 with or without compensatory decrease in HCO3 ; pH may be high or near normal.

Alveolar hyperventilation in respiratory alkalosis leads to a decreased partial pressure of carbon dioxide (PCO2). In turn, the decrease in PCO2 increases the ratio of bicarbonate concentration to PCO2 and increases the pH level. The decrease in PCO2 (hypocapnia) develops when a strong respiratory stimulus causes the lungs to remove more carbon dioxide than is produced metabolically in the tissues.

Respiratory alkalosis can be acute or chronic. In acute respiratory alkalosis, the PCO2 level is below the lower limit of normal and the serum pH is alkalemic. In chronic respiratory alkalosis, the PCO2 level is below the lower limit of normal, but the pH level is normal or near normal.

Acute respiratory alkalosis causes small changes in electrolyte balances. Minor intracellular shifts of sodium, potassium, and phosphate levels occur. A minor reduction in free calcium occurs due to an increased protein-bound fraction.

In the given clinical situation the symptoms of perioral and finger tip paresthesias etc are typical of Hypocalcaemia. When seen intermittently such as this, such symptoms are almost caused by hyperventilation.

In this patient the hyperventilation is related with anxiety.

Effect of hyperventilation on ionic calcium concentration

Normal total serum Calcium concentration ranges from 8.8 to 10.4 mg/dL (2.20 to 2.60 mmol/L). About 40% of the total blood Calcium is bound to plasma proteins, primarily albumin.The remaining 60% includes ionized Ca plus Ca complexed with phosphate (PO4) and citrate.

The circulating calcium binds to plasma proteins via anionic sites that are highly dependent on the pH of blood. Small increase in pH creates more anionic sites for the binding of calcium.

Hyperventilation due to any cause, can acutely raise the pH of blood.

The increased respiratory rate removes carbon dioxide from the lung alveoli and lowers blood CO2, forcing a shift in the indicated equilibrium towards left.

CO2 + H2O <——–> H2CO3 <——–> H+ + HCO3

Carbonic acid (H2CO3) can be ignored because negligible amounts are present at physiological pH, leaving the equilibrium

CO2 + H2O <——-> H+ + HCO3

The leftward shift to replenish exhaled CO2 decreases the hydrogen ion (H+) concentration and increases the pH to produce alkalosis.

The rise in pH promotes binding of ionic calcium to anionic sites on albumin dropping the ionized calcium by up to 30 % without altering the total plasma calcium conc. Since it can occur in just a few seconds, PTH (parathyroid hormone) is unable to compensate for the hypocalcaemia and the symptoms may occur.

PTH is secreted by the parathyroid glands. It has several actions, but perhaps the most important is to defend against hypocalcemia. Parathyroid cells sense decreases in serum Ca and, in response, release preformed PTH into the circulation. PTH increases serum Ca within minutes by increasing renal and intestinal absorption of Ca and by rapidly mobilizing Ca and PO4 from bone (bone resorption).

Since in this case the hyperventilation is due to anxiety the therapy should be directed at lowering the patient’s anxiety. Counseling may be necessary for this.

This respiratory alkalosis is best treated by diminishing the respiratory rate to elevate the blood [CO2], forcing the above equilibrium to the right, elevating the [H+], and decreasing the pH.

The patient can treat his symptoms by preventing the diminished CO2 that accompanies the hyperventilation. He can do this simply by breathing in to paper bag, thereby increasing the CO2 of the inspired air.

As regards other options

A) Stress induced high catecholamine release- Catecholamines have no role to play in calcium homeostasis

B) Stress induced low PTH release- This is also not true, there are no evidences of stress mediated PTH release.

D) Respiratory acidosis by decreasing pH promotes ionization of calcium. Hypocalcemia is not observed in respiratory acidosis.

E) Vitamin D deficiency does not affect only ionic calcium concentration. The total calcium concentration is lowered in vitamin D deficiency.

 

 

 

 

 

 

 

 

 

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