Carnitine Deficiency

Presented by: Group 3, MD I B Miranda, Sly Mawey Morales, Christina Anne Muldong, Frances Munoz, Rafael Francisco Nacpil, Ivy Naguiat, Anjelica Nipales, Warley Nogoy Princess May

Objectives:
By the end of the report, the students should be able to: 1. Define what carnitine is. 2. Determine the structure & function of carnitine. 3. Enumerate the dietary sources of carnitine. 4. Explain the synthesis of carnitine 5. Describe the absorption & metabolism of canitine in the body.

Objectives:
6. Explain its role in fatty acid metabolism. 7. Describe its physiologic effect on the body. 8. Explain the occurrence of carnitine deficiency. 9. Enumerate diseases associated with carnitine deficiency. 10. Determine treatments used for carnitine deficiency.

Case Report:
35 year old woman admitted to hospital with acute onset confusion and lethargy no history of alcohol or illicit substance use undergone several surgery and hemodialysis somnolent yet arousable; can follow simple commands asterixis present, with temporal wasting, hepatomegaly, diffuse muscle weakness and bilateral lower extremity edema with hypoglycemia, aspartate aminotransferase slightly elevated

Case Report .cont d:

serum ammonia level 276 ug/dL , continued to rise and peaked at 582 ug/dL (normal: 40-80 ug/dL) abdominal CT revealed fatty infiltration of liver Hepa A, B and C serologies are negative Serum total carnitine 22 mM (normal: 33.8-77.5 mM) Free carnitine 19 umol/L (normal: 25-55 umol/L) Acylcarnitine ester 3.0 umol/L (normal: 3.8-19 umol/L) Mgmt: Thiamine, Lactulose, Neomycin, Levocarnitine 330 mg TID

BRIEF REVIEW OF B-OXIDATION OF FATTY ACID

Fatty acids must first be activated in the outer mitochondrial membrane An enzyme AcylCoAsynthetase is responsible for the activation of fatty acids. Acyl- CoA.

BRIEF REVIEW OF B-OXIDATION OF FATTY ACID

BRIEF REVIEW OF B-OXIDATION OF FATTY ACID

Acetyl-CoA Acetyl-CoAcan then enter the Krebs cycle and lead to the production of ATP. Fatty acids -oxidation is a cycle composed of three consecutive reactions: 1. dehydrogenation, 2. hydration of the newly formed C=C double bond, 3. and oxidation of the alcohol to a ketone

BRIEF REVIEW OF B-OXIDATION OF FATTY ACID

Other important functions of fatty acids include: 1) serving as building blocks of phospholipids and glycolipids: 2) acting (as derivatives) as hormones and intracellular messengers: 3) modfying proteins through covalent attachment, and so affecting their cellular targeting and functioning.

BRIEF REVIEW OF B-OXIDATION OF FATTY ACID

Fatty acids contain a long hydrocarbon chain and a terminal
carboxylate group.

Fatty acid catabolism is initiated when triacylglycerol is

hydrolyzed by lipases.

levels of cAMP = protein kinase A =phosphorylate the lipase. This reaction yields 3 fatty acids and glycerol glycerol. fatty acids must attached to coenzyme A. A. This reaction is driven by ATP and is catalyzed by
acylCoAsynthase, in the cytosol.

BRIEF REVIEW OF B-OXIDATION OF FATTY ACID

Carnitine

hydrophilic amino acid derivative, produced endogenously in the kidneys and liver and biosynthesized primarily in the liver and kidneys from the aminoacids lysine (via trimethyllysi ne) or methionineand derived from meat and dairy products in the diet.

Carnitine
L-Carnitine is naturally occurring in all mammalian species and is found in almost all cells L-Carnitine was shown to be an essential nutrient for a meal worm (Tenebriomolitor) and was therefore called vitamin BT

Carnitine
the essential role of LCarnitine in the utilization of long chain fatty acids for energy was confirmed found that L-Carnitine can actually increase fatty acid oxidation in healthy adults

Functions of L-Carnitine
In Exercise: L-Carnitine supplementation may foster exercise performance. Both an increase in maximal oxygen consumption and a lowering of the respiratory quotient indicate that LCarnitine has the potential to stimulate lipid metabolism

Functions of L-Carnitine
Exercise:
high intensity exercise - significantly effective in assisting recovery. decrease in the production of free radicals, less tissue damage, reduced muscle soreness after exercise and better utilization of fat as an energy source during recovery.

Functions of L-Carnitine
Cardiovascular health:
L-Carnitine supplementation can positively support healthy heart muscle significantly increase heart muscle viability beneficial in supporting a healthy heartbeat have a favourable effect on blood lipid levels helpful for people with angina, arrhythmias and heart failure

Functions of L-Carnitine Infants:

an essential nutrient for infants unlike adults, infants are unable to synthesize sufficient L-Carnitine in their bodies to meet their requirements present in breast milk

Functions of L-Carnitine
Vegetarians (and people with reduced meat intake):
get very little L-Carnitine in their diet Since intake of dietary L-Carnitine is directly linked to meat intake & meat is the richest source of this nutrient

Functions of L-Carnitine
Vegetarians (and people with reduced meat intake):
also low in some of the nutrients that are essential for L-Carnitine biosynthesis in the body strict vegetarian diet over years = decreased plasma L-Carnitine concentrations and may benefit from supplementary L-Carnitine

Functions of L-Carnitine
Male Fertility:
High concentrations of L-Carnitine and its metabolite acetyl-L- Carnitine are found in sperm, and both have a crucial role to play in sperm energy metabolism The concentration of L-Carnitine in semen is closely linked to sperm quality

Functions of L-Carnitine
Healthy aging:
after supplementation with L-Carnitine = improved mental status and learning ability, improved immune function or an increase in muscle mass has beneficial effects in seniors for the maintenance of fitness and health

Importance of Carnitine
Is required for the transport of long-chain fatty longacids into the mitochondria, the site of betabetaoxidation of fatty acids. Plays a critical role in energy production. production. Essential for a variety of important physiological functions in energy metabolism. metabolism. It also transports the toxic compounds generated out of this cellular organelle to prevent their accumulation.

Other importance are:

Clears the bloodstream of ammonia and aids in creating glycogen, the form in which the body stores glucose. Carnitine is a key nutrient for helping to prevent muscle atrophy. Anyone suffering from a severe degenerative disease, such as cancer or AIDS, stands to gain from carnitine supplementation. Taking 2 grams of carnitine per day for four weeks, hospitalhospitalbased studies show, can cut the number of complications from heart attack in half. This amino acid protects the heart from damage when a heart attack or a spasm cuts off the oxygen supply.

Carnitine is considered indispensable for infants. Babies usually get carnitine through breast milk or fortified formulas. Low thyroid function indicates a need for carnitine to help overcome low energy levels and the tendency to gain weight. Kidney dialysis rinses away amino acids, causing a acids, weak, tired condition, which is threatened by high triglycerides. Carnitine may be of some value in treating diabetes, studies suggest, hypertension, liver disease, and immune problems.

Carnitine
exists in two stereoisomers:
Its biologically active form is L-carnitine, whereas its enantiomer, D-carnitine, is biologically inactive

Structure of L-Carnitine

Molecular Model

Sources of Carnitine
Dietary: 75% The highest concentrations of carnitine are found in red meat and breast milk, dairy products. Other natural sources of carnitine include nuts and seeds (e.g. pumpkin, sunflower, sesame) legumes or pulses (beans, peas, lentils, peanuts) vegetables (artichokes, asparagus, beet greens, broccoli, brussel sprouts, collard greens, garlic, mustard greens, okra, parsley) fruits (apricots, bananas, avocados) cereals (buckwheat, corn, millet, oatmeal, rice bran, rye, whole wheat, wheat bran, wheat germ) and other 'health' foods (bee pollen, brewer's yeast, carob, and kale)

Sources of L-Carnitine
Endogenous synthesis
The human body synthesizes about 20 mg of L-Carnitine every day (Liver & Kidneys)

Dietary sources
Daily L-Carnitine requirement is met by food intake. Animal products contain reasonable amounts of this nutrient whereas foods of plant origin contain only very little, if any, L-Carnitine

Table 1: L-Carnitine content in selected foods [mg/100g]

Food of animal origin (uncooked) Lamb Beef Pork Poultry Fish Egg L-Carnitine Food of L[mg/100g] plant origin Carnitine[ (uncooked) mg/100g] Mushroom 190 2.6 Carrot 143 0.4 Bread 25 0.4 Rice 13 0.3 Banana 3-10 0.1 Tomato 0.8 0.1

The pathway that Carnitine can be synthesize in our body Concentrated in tissues like skeletal and cardiac muscle that utilize fatty acids as a dietary fuel. Predominantly in the liver and kidney, via a biochemical pathway involving the amino acids L -lysine and methionine, vitamin C, and iron.

Drugs that contain Carnitine and its indications

Acetyl L-Carnitine
-is a dietary supplement used to improve memory, such as in Alzheimer's disease.

Carnitor
-For the acute and chronic treatment of patients with an inborn error of metabolism that results in secondary carnitine deficiency

Biosynthesis of L-Carnitine
Carnitine can be synthesized via an enzymatic pathway in the liver and kidney by utilizing the amino acids: Llysine and L-methionine L-lysine provides the four-carbon chain of carnitine (C3-C6), as well as provides the amino group from the (epsilon) amino group of lysine

Biosynthesis of L-Carnitine
The methyl groups in carnitine are provided by L-methionine. These residues are methylated as a posttranslational modification of peptidebound lysine residues, and are catalyzed by protein-lysine methyltransferase & methyl groups from S-adenosylmethionine, then removed from the protein via hydrolysis

Biosynthesis of L-Carnitine
The next step of formation of L-carnitine occurs when -N-Trimethyllysine is hydroxylated to -hydroxy-Ntrimethyllysine via the mitochondrial enzyme trimethyllysinedioxygenase. It is then cleaved in an aldolase-type reaction to trimethylaminobutyraldehyde and glycine.

Biosynthesis of L-Carnitine
Next, -trimethylaminobutyraldehyde is oxidized by trimethylaminobutyraldehydedehydroge nase into -butyrobetaine (also known as -trimethylammoniobutanoic acid). Finally, -butyrobetaine is transformed into L-carnitine via the enzyme butyrobetainedioxygenase.

Biosynthesis of L-Carnitine
The synthetic pathway of carnitine occurs ubiquitously in the human body. However the last step only occurs in the liver and kidney, as well as in the brain to a lesser extent, due to the presence of butyrobetainedioxygenase enzyme in only those organs. A number of transport systems then carry the produced carnitine to other tissues of the body

Metabolism of L-Carnitine
Carnitine transports long-chain acyl groups from fatty acids mitochondrial matrix broken down through -oxidation to Acetyl CoA to obtain usable energy via the citric acid cycle. Fungi - acetate is used in the glyoxylate cycle for gluconeogenesis and formation of carbohydrates.

Metabolism of L-Carnitine
Fatty acids must be activated before binding to the carnitine molecule to form acylcarnitine. The free fatty acid in the cytosol is attached with a thioester bond to coenzyme A (CoA). This reaction is catalyzed by the enzyme fatty acyl-CoA synthetase and driven to completion by inorganic pyrophosphatase.

Metabolism of L-Carnitine
The acyl group on CoA can now be transferred to carnitine and the resulting acylcarnitine transported into the mitochondrial matrix

This occurs via a series of steps:

1. Conjugation of AcylCoA to carnitine
carnitine acyltransferase I (palmitoyltransferase) located on the outer mitochondrial membrane

2. Shuttling of Acylcarnitine
carnitine-acylcarnitinetranslocase

3. Conversion of Acylcarnitine to acylCoA

carnitine acyltransferase II (palmitoyltransferase) located on the inner mitochondrial membrane. *The liberated carnitine returns to the cytosol.

Physiological effects of L-Carnitine

It helps increase lean body mass and maintains bone mass. It exhibits antioxidant effects and destroys free radicals in the body It protects against the risks of oxidative stress at the myocardial level and lipid peroxidation of phospholipid membranes.

Carnitine Deficiency
Biochemical Background Long chain fatty acids are the major source of metabolic energy in humans, in particular for the heart and skeletal muscles. Persons with carnitine or carnitinepalmitoyltransferase (CPT) deficiency are unable to metabolize long-chain fatty acids

Carnitine Deficiency
Biochemical Background Carnitine is an amino acid that is required for the transport of long-chain fatty acids into the mitochondria, the site of beta-oxidation of fatty acids. About 25 percent of the carnitine required by the body is produced by the liver and kidneys

Carnitine Deficiency
Biochemical Background While the rest is derived from dietary intake, primarily from red meat, poultry, fish, and dairy products. Most of the carnitine in the body is located in the voluntary and cardiac muscles.

Two Types of Carnitine Deficiency

Primary Secondary

Primary carnitine deficiency

A person with primary carnitine deficiency has very low levels of carnitine in the blood due to a faulty carnitine transporter which prevents carnitine from getting into the cells where it is needed.

Primary carnitine deficiency

systemic carnitine deficiency
affects many organ systems including the heart and the brain

muscle carnitine deficiency

restricted to voluntary muscles

Secondary carnitine deficiency

The secondary form of carntine deficiency can arise secondary to metalobic disorders in the mitochondria. Blockage of metabolic pathways in the mitochondria leads to a build-up of acyl compounds. These compounds then bind to carnitine and the bound complex is then excreted by the kidney, causing carnitine levels to drop.

Secondary carnitine deficiency

Some of these mitochondrial disorders include cytochrome c oxidase deficiency, mitochondrial ATPase deficiency, and fatty acyl-CoA dehydrogenase deficiencies.

Carnitine Deficiency: Pathophysiology

Causes/Risk Factors: Poor Intake (Fad diets, long-term IV feeding) Enzyme Deficiency (CPT-I, CPT-II) Carnitine Leak (Renal loss, inherited) Surgery or Medical Procedure (Hemodialysis) Medication (Valproate, Zidovudine) Prematurity among newborn Illness (2 , e.g., liver disease, ketosis, major burns, diuresis, severe diarrhea, intermittent claudication, angina and sepsis