A defect in alpha oxidation (the lipolysis pathway that deals with branched-chain fatty acids in the peroxisome)

Childhood-onset neurological peroxisomal disorder.

The liver

Glycerol Kinase and Glycerol phosphate dehydrogenase convert Glycerol + ATP to DHAP →TCA

Mitochondrial matrix

So does oxidation of unsaturated and odd chain FAs.

A disorder charactarized by the virtual absence of peroxisomes/peroxisomal enzymes.

Patients are unable to carry out the oxidation of VLCFA or alpha oxidation.

Alpha oxidation (used to break down branched-chain FA) takes place int he peroxisomes.

Refsum's Disease is the name of a disease charactarized by a defect in alpha oxidation.

In the Endoplasmic Reticulum

Generates dicarboxilic acids and is an alternative pathway to beta oxidation, becomes key when beta oxidation is defective.

In the Cytosol

The Citrate Shuttle is vital to get the starting substance for FA synthesis (citrate) out of the IMM and into the cytosol where it can become the basis of building FAs.

The first step! Catalyzed by Acetyl CoA Carboxylase and assisted by the essential cofactor Biotin.

Acetyl CoA + ATP + CO2 → Malonyl CoA (a 2C donor)

This step is inhibited by Palmitoyl CoA (product) and induced by Citrate (a precursor)

In the ER

On an Elongase Complex

In the ER

By Desaturase an oxidase that converts

Palmitate → Palmitolate

Acetylates and perminatnly inactivates Cyclooxygenases (COX) the enzymes that convert Arachadonic acid→PGG2 (inhibit prostaglandin synthesis)

By inhibitng Prostaglandin synthesis you inhibit the aggregation of platelets that is carried out by some prostaglandins and thromboxanes (a downstream product of PGG2)

Activate when phosphorylated

Catalyzes the release of FA from TAG stores

Lysozomal Storage Disease/mucolipodosis caused by a devect in the enzyme beta-glucocerebrosidase (can't breakdown Glucocerebrosides)

Leads to a build up of glucocerebrosides in the lysozomes.

Causes neurological symptoms, hepatosplenomegly, anemia and yellow deposits in the sclera of the eyes.

AR Lysosomal Storage Disease

Caused by a defect in Hexosaminodase A which leads to an accumulation of GM2 ganglioside causing neurodegeneration, blindness, and seizures.

X-linked Lysosomal Storage Disease

Caused by a defect in alpha galactosidase A which leads to an accumulation of Globosides (glycolipids with Glc and Gly)

Causes cardiac and renal failure and a purple rash on the skin.

The first step! Catalyzed by HMG CoA Reductase

Acetyl CoA + 2 CoA-SH + 2 NADPH →→→ Mevalonic Acid

HMG CoA Reductase is the enzyme inhibited by Statins*

Its activity is ↑ by high [Insulin], [TH] and ↓ by high [free cholesterol], [HMG CoA] glucagon, and cortisol*

Caused by a deficiency in the cholesterol synthesis pathway (in the last step, 3 beta-hydroxysterol-delta-7-reductase)

Causes a build up in 7-dehydrocholesterol which causes ID and multiple congenital abnormalities.

Tested for on newborn screens.

Defects in steroid synthesis enzymes that results in failure to produce Aldosterone (Mineralocorticoids) and Cortisol (Glucocorticoids).

Causes excess ACTH secretion which causes hyperplasia of the adrenal glands and build up of steroid precursors that are shunted to the androgen pathway (leading to excess adrenal androgens).

In the ER membrane of hepatocytes and enterocytes.

MTP lipidates ApoB in the first step of lipoprotein assembly.

Large subunit has the lipid-transferase activity and the small subunit is a PDI (solubility and ER localization)

ApoAI activates LCAT

LCAT converts free cholesterol to cholesterol esters which can be clustered in the core of a lipoprotein.

GPAT

G3P Acetyltransferase

Regulated by negative feedback via GDP and ADP

Note that this is not the first irreversible step in the pathway but that the product of that reaction is used in many other reactions and therefore this step cannot be rate-limiting. (PRPS1 reaction, first in the pathway)

Phosphoribosyl pyrophosphate synthetase 1

Catalyzes the first step of de novo Purine biosynthesis

Ribose-5-Phophate + ATP→Phosphoribosyl pyrophosphate (PRPP)

This step, though irreversible, cannot be the rate-limiting step because PRPP is used in many other reactions*

Diseases associated with PRPS-1 there is a condition where this enzyme is no longer sensitive to negative feedback which leads to excessive formation of Purine (excessive Uric Acid formation = Gout)

I

Phosphoribosyl pyrophosphate

The product of the first step of Purine de novo biosynthesis.

Used in lots of places!

***Vital in the feed forward activation of Purine Biosynthesis. Whenever there is an excess of PRPP there is an ↑ in Pur biosynthesis (Gout)***

Activates GPAT

They are both branchpoints in Nucleotide biosynthesis pathways.

IMP is the branchpoint in Purine (A and G) metabolism

It is an important regulatory point as GMP and AMP both negatively feed back here.

Also, GMP synthesis requires ATP and AMP synthesis requires GTP (balances nucleotides).

UMP is the branchpoint/regulatory point in Pyrimidine Biosynthesis (building a Pyr from Carbamoyl Pi + Asp)

An enzyme that acts in the de novo Purine synthesis pathway at two seperate points!

With each reaction, a Fumarate is cleaved off (Asp acting as a Nitrogen donor).

Defects in ASDL→Succinylpurinemic Autism

Purine Nucleotide Phosphorylase

An enzyme that acts in the Purine Degredation pathway.

After a nucleosidase has removed the Pi to make the nucleotid a nucleoside, PNP comes in and cleaves/phosphorylates the ribose.

Adenosine Deaminase

An enzyme that acts in the Purine Degredation pathway.

Converts AMP to IMP or denosine which are then converted to Inosine.

Defects in ADA leads to SCID

No ADA=Build up of dATP (a vital allosteric regulator of the Ribonucleotide Reductase enzyme; converts all nucleotides→deoxynucleotides to make DNA)

dATP build up=no Ribuonucleotide Reductase=No DNA=

SCID

Note: not the same as ADA*

AMP Deaminase acts in muscle in the Purine Nucleotide Cycle which cycles AMP→ IMP (step cat by AMP deaminase) and then back to AMP giving off a Fumarate (a reaction that provides TCA intermediates in muscle).

Defective AMP Deaminase=Muscle Myopathy (inability to perpetuate the TCA in muscle)

Purines (A/G) are degraded to Uric acid (via hypoxanthine and Xanthine)

↑ Purines (usually via ↑ in PRPP) causes ↑ uric acid = Gout

Treatment with an Xanthine Oxidase inhibitor/hypoxanthine analog (Allopurinol) which prevents formation of uric acid and instead allows a build up of the more soluble Hypoxanthine/Xanthine.

Gout Drug (new version =Uloric)

Is a hypoxanthine analog that can be acted on in the first step by xanthine oxidase but in the second step cannot be acted on further (is a XO inhibitor)

Prevents formation of uric acid and instead allows a build up of the more soluble Hypoxanthine/Xanthine and thereby prevents gout (uric acid precipitation).

Purine Salvage Pathway enzymes

Hypoxanthine guanine phophoribosyl transferase (HGRPT) captures excess hypoxanthine or guanine and joins them with PPRPP to form IMP or GMP.

ARPT joins excess adenine bases with PRPP to form AMP.

Lesch Nyhan Sundrome is caused by a defects in HGPRT (inhibition of Purine Salvage leads to PRPP build up and gout)

Caused by a complete loss of HGPRT

Impaired salvage of hypoxanthine/guanine bases.

More importantly there is a failure to use PRPP to carry out this salvage pathway which leads to a build up of PRPP which acts in the feed-forward pathway of Purine synthesis leading to a build up of Pur and Gout.

Works on all nucleotides!

Converts nucleotides → deoxynucleotides (2'OH→H in a reaction that requires NADPH and has a free radical in its mechanism)

Active site has a critical Tyrosine residue where the free radical forms*

Has a specificity site to allow it to make all 4 dNTPs in equal amounts.

Has an allosteric regulatory site that binds dATP

When dATP is bound the ribonucleotide reductase enzyme is shut off**

This is how ADA causes SCID* Build up of dATP shuts off DNA synthesis*

Carbamoyl Phosphate Synthetase II

Located in the cytosol

The committed step in humans for the synthesis of Pyr**

Catalyzes the formation of Carbamoyl Phosphate (makes Pyr along with Asp)

Note that CPS I is a varient located in the mitochondria that is key in the Uric Acid Cycle.

An enzyme that is required to make Thymine and used only in this reaction.

Acts on dUMP and adds a methyl group to it using THF as a methyl donor.

THF →DHF and must be converted back to THF for the reaction to continue. THis is where DHFR comes in*

Thymidylate Synthase is targeted by 5'Flurouracil which blocks a key H+ removal and therefore blocks the synthesis of T and therefore DNA.

Used to suicide inhibit Thymidylate Synthase by blocking the removal of a hey H+ ion.

Used as a cancer treatment. Inhibits DNA synthesis (but not RNA).

Resistance is acquired at the step before it by a modification of the enzyme active site*

Dihydrofolate Reductase

In Thymidine Synthesis, thymidylate synthase acts on dUMP and adds a methyl group to it using THF as a methyl donor which THF →DHF

THF must be converted back to THF for the reaction to continue. This is what DHFR does*

DHFR is the target of the anti-cancer drug Methotrexate

A folate analog that inhibits Thymidine synthesis by inhibiting DHFR

If DHFR can't covert DHF back to THF, thymidylate synthase cannot continue its job and Thymidine bases cannot be made (halts DNA synthesis).

Are analogs/immitators of the Purine Xanthine

Include caffeine, theophylline (in tea) and Theobromine (in coca)

Act as stimulants by inhibiting cAMP phosphodiesterases and therefore ↑ [cAMP]

Azothymidine

A thymidine analog that is converted in the body to the tripohosphate form and acts in two ways.

Inhibits Reverse Transcriptase.

Also inhibits DNA syntheisis because at the 3' position instead of an OH it has an Azo group which means that a new base cannot be added there.

Glutamine Analogs that form covalent bonds at the active sites of enzymes that use glutamine (many!) and block these pathways.

Potentially Affected Enzymes

GPAT (Glu:PRPP AmidoTransferase, the committed step in de novo Pur synthesis)

GMP Synthase (catalyzes the conversion of Xyantylate →GMP, a Pur)

CPS II (Carbamoyl Pi Synthetase, Cat Glu or NH3→Carbamoyl Phosphate in Pyr Synthesis)

Ubiquinone-Proteosome Pathway targets PEST Regions: Regions rich in Pro, Glu, Ser, and Thr are targeted for Ubiquination and proteosomal degredation.

N-Terminal Residues=Phe, Leu, Asp, Lys or Arg=Unstable

Oxidative Damage

*Heme, muscle proteins, GI cell proteins and digestive enzymes use these signals as they must undergo frequent degredation/regeneration*

Arginine, Histadine, Isolucine, Thrionine, Leucine, Lysine, Methionine, Tryptophan, Phenylalanine, and Valine.

"Adolph Hitler Is The Least Likely Man To Pop Valium"

...he was too uptight to be on anything that mellowing.

Used to transport amino acids into the cells of the intestine and kidney.

Amino acids in the lumen bind gamma-glutamyl transpeptidase → gamma-glutamyl-aa which reacts with GSH and can bass through the cell membrane.

Inside the cell the amino acid is released and the GSH is reformed.

A wasting syndrome causes by the complete lack of any one of the 20 amino acids.

Causes muscle wasting, malnutrition, edema and a plump abdomen.

Treatment is with pancreatic proteases (helps with malnutrition due to inability to synthesize dietary/pancreatic enzymes)

AR

Neutral Aminoacidurea

Caused by a defect in the ability of intestinal cells to take up neutral or aromatic amino acids causing hyperaminoacidurea and malabsorption.

Leads to Trp deficiency which results in deficiencies in Naicin and NAD+/NADP+

Symptoms are Pellagra-like (the 3 Ds): Dermatitis, Diarrhea, and Dementia.

Treated with niacin supplements and a high protein diet.

AR

Caused by defective Cystine and dibasic (+ Arg, Lys, Ornithine) amino acids leading to their increased excretion.

Because they are nonessential, there are still normal levels of these amino acids in plasma.

The problem comes from the formation of Cys-S-S-Cys insuluble compounds leading to UTI and/or persistant Kidney/Cys Stones.

Treatment

Maintain a large urine volume at a neutral or alkaline pH to prevent the precipitation of Cys.

Penicillamine is a drug that reacts with Cys to form a soluble adduct and prevent precipitation.

Takes place in the cytosol and the mitochondrial matrix.

Uses numerous key enzymes

(Cabamoyl phosphatase, OTC, Glutamine dehydrogenase, and the transaminases [ALT and AST])

In the Cytosol: Removal of the N by converting the aa to a keto acid and transfering the nitrogen to oxygluterate to form glutamate.

NAD+→NADH allows the release of ammonia which enters the mitochondrial matrix.

In the Matrix:

Ornithine+NH3+Carbamoyl Pi → Citrulline 

Citrulline is exported to the cytosol.

Back in the cytosol: Citrulline is converted to arginosuccinate which is converted to arginine.

Arginine → Ornithine + Urea

Ornithine goes back to the matrix to perpetuate the reactions and Urea is excreted.

IS BAD! → Brain damage and death!

There is very little circulating NH3 as it can cross cell membranes and be excreted in the urine (where it binds excess H+ and ↑ urine pH)

NH3 → Glu which depletes the brains supply of alpha-KG →halts TCA→no ATP → tissue death.

Excess Glu→Gln which depletes Glu

Insufficent Glu to make GABA and neurotransmission suffers!

A way to transport ammonia between muscle and liver using the fact that alanine (Ala) and Glucose can be transported in the blood but that Pyruvate can't.

In the muscle: Pyruvate (from Glc breakdown) →Alanine → to the liver.

In the liver: Alanine→Pyruvate →→Glucose →Glc back to the muscle to perpetuate the process.

A variation on this is the Alanine Cycle

In the muscle: Glutamate (by transaminase)→Ala →transported to the liver.

In the liver: Ala →Pyruvate

A defect of the urea cycle, can be caused by a defect at any step in the cycle.

High NH4+ and Gln in the blood.

Usually presents at birth with ataxia, lethargy, vomiting though can arise in alcoholic adults due to liver damage.

Type I is the most severe.

Causes Type I Hyperammonemia

Caused by a failure to corm Carbamoyl phosphate, a key substrate for the conversion of ornithine to citrulline in the uric acid cycle in the IMM.

Can be caused by a defect in the Carbamoyl Pi Synthetase enzyme itself or in its essential activator N-acetyl Gultamate which is synthesized by NAGS)

Treatment

Benzoate soaks up the Gly

Phenylacetate soaks up the Gln

Together these force the cells to get rid of NH3

A defect in the Urea Cycle that causes Type I Hyperammonemia

Caused by a defect in the OTC catalyzes conversion of Ornithine → Citrulline

Leads to a build up upstream of carbamoyl Pi (↑ Pyr synthesis) + Ortic acid in the urine.

Treatment

Benzoate to get rid of excess Gly and Phenylacetate to get rid of excess Gln and make the body use up NH3.

A defect in the Urea Cycle that causes

Type II Hyperammonemia

Inability to convert arginosuccinate → Arg + Fumarate

Can be treated by administering Arg Rx to circumvent the block as excess arginosuccinate can be excreted.

Can be caused/exacerbated by bacteria which have Urease which cat:

Urea→Carbonic Acid + NH3

Excess NH3 increases the pH of the urine and can be precipitated out with Mg to form kidney stones.

Ketogenic Amino Acids are those whose carbon skeleton can be converted to acetylCoA or to Acetoacetate (KB)

Only 2!

Leucine and Lycine

Those whose carbon skeleton can be made into glucose and pass through being glucose during their synthesis.

All of them but Leu and Lys*

Ala, Cys, Gly, Ser, Thr, Arg, Gln, Glu, His, Pro, Met, Thr, Val, Asp, Asn (14 Total)

Are both ketogenic (can be made into acetylCoA/acetoacetate) AND/OR into Glucose.

4 Total:

Phenylalanine, Tyrosine, Isolucine, Tryptophan

TTIP

Glycine (a glucogenic aa) is made from Serine in a reaction that requires PLP, THF and FH4*

Glycine can be oxidized to glyxoylate which can make KB or oxalate (kidney stones)

Glyoxylate can be transaminated to reform Glycine.

Is a non-essential, guucogenic amino acid made from homocystine.

However, it gets its SH group from the essential amino acid Met so if you are nutritionally deficient in Met, Cys becomes essential.

Met→Aldo-Met→Homocystine

Homocystine + Serine (using cystathionine)→ Cystine

- FB regulation is by Cys on this enzyme.

Defect in the Cystine Biosynthesis pathway

Charactarized by excess cystathione in the urine and caused by a defect in the Cystathionease enzyme OR by a deficinecny in B6, B12 or THF (all essential cofactors)

A defect in Cystine Biosynthesis

Caused by improper metabolism of the Cys precursor homocystine leading to an accumulation of Homocystine and Met in the brain.

Dangerous because it can trap adenosine which ↓[Adenosine] and impairs cognitive function.

Can also cause osteoperosis, dislocation of the lens, heart disease etc...

Treatment by reducing homocys and Met in the blood, maintaining a low Met diet, and administering B6.

A deficiency of the Tyrosine Transaminase enzyme

Leads to lesions in the neurological tissues.

Treated with a Low Tyr/Phe diet.

AR

A defect in the degredation of Tyrosine

A deficiency in the enzyme homogentisate oxidase enzyme which leads to an accumulation of homogentisate.

Homogentisate oxidises in the urine and gives the urine a dark color.

A defect in the breakdown of Tyrosine.

Deficency in the enzyme fumarylacetoacetate hydroxylase.

Results in liver failure and death

(more severe than Type II)

Phenylketonuria

Caused by a deficiency in the Phenylalanine Hydroxylase enzyme (that synthesizies Tyr from Phe and requires oxygen and BH4)

Leads to a build up of Phe which causes delayed motor development, ID, seizures etc...

Detectible prenatially

Treatment

High Tyrosine, low Phenylalanine diet

Pyrodoxine = Vitamin B6*

Tyr can be broken down to make NAD+ in a reaction catalyzed by Pyrodoxine and requiring PLP*

Deficency in Pyrodoxine causes Pellagara-like symptoms

Allopecia, dermatitis, mental confusion and ataxia.

Caused by a defect in the degredation of branched-chain amino acids (Leucine, Valine, and Isolucine).

Causes branched-chain aminoaciduria

Severe neurological symptoms and high mortality if left untreated though even management is very difficult.

An enyzme that brain and muscle contain that allow them to use Creatine Phosphate (a storage form for high-energy Pi groups) for energy by cleaving the high energy Pi.

This enzyme is abundant in tissues that rapidly use lots of ATP* (hence muscle, brain and heart).

Isozymes of CPK are used to assay for Stroke (BB isozyme in the brain), muscle breakdown as in DMD (MM isozyme in muscle) and MI (the MB isozyme is found in the heart)

Glutamic acid

Is Glu (remember that glutamate is Gln)

Glutamic acid is an excitatory neurotransmitter that can be readily decarboxylated to form GABA (an inhibitory neurotransmitter linked to mood disorders).

Gives rise to Nitric Oxide

(NOS acts on Arg to generate NO)

NO is a key second messenger, vasodilator, neurotransmiiter and inhibitor of platelet aggretation and acts by increasing intracellular cGMP levels.

Is a precursor to pigments (melatonin), to thyroid hormones (T3/T4) and to the catecholamines.

Albinism is a defect in the ability of the tyrosinase enzyme to form melanin from Tyrosine.

A hypopigmentation disorder caused by defective tyrosinase, the enzyme that catalyzes the conversion of tyrosine to melanin.

Two types:

Oculocutaneous Albinism (I, II, III with ↓ severity, each caused by a different genetic mutation) has effects on the eyes and skin color.

Ocular Albinism: is X-linked* and only affects the eyes (not the pigmentation of the skin)

A tumor of the Chromaffin Cells of the adrenal medulla that synthesize and secrete catecholamines.

Leads to excess secretion of catecholamines with a variety of effects.

Diagnosis is often made based on high levels of VMA in the urine.

(Epi → VMA + Metanephrine)

Serotonin and Melatonin are both made from Trp*

Serotonin

Made in the GI and some neurons and is primarily stored in the platlets.

Controls anger, mood, temp, sleep, vomiting, sexuality, and appitite.

Low levels have been asociated with OCD, IBS, bipolar disorder, anxiety and SIDS.

Serotonin is broken down into Melatonin.

Melatonin

Produced by acetylation and methylation of serotonin in the Pineal Gland and released at night

Regulation of light/dark cycles

Colored, have conjugated double bonds and side chains.

Heme is a porphyrin*

Porphrinogens are colorless biosythetic intermediates in the syntheiss of porphyrins like heme (they are the reduced form of porphyrins and are readily oxidized to colored porphyrins in light)

Takes place in both the mitochondria and the cytosol.

Initial substrates are Succinyl CoA + Gly

ALA Synthase catalyzes the first step and is the rate-limiting enzyme.

Generating Urophyrinogen III (the precursor to heme) requires 2 enzymes: Uroporphyrinogen I Synthase and Uropphyrinogen III Cosynthase

Without cosythase the heme ring is not functional and a congenital erythropoetic porphyria occurs.

ALA Synthase and Ferrochetalase can both be inhbited by heavy metals causing anemia.

Catalyzes

Succinyl CoA + Gly → ALA

in the mitochondria

This is the COMMITTED STEP of Heme Synthesis*

ALA Synthase is regulated by heme in several ways:

-Has a short half life

-is allosterically FB inhibited by heme

-heme can suppress the transcription/translation of the ALA Synthase protein

-heme can regulate the translocation of pre-ALA Synthase (made in the cytosol) into the Mitochondria

ALA Synthase is Stimulated by:

Need for Cytochrome P450s: ↑ demand for CYPs upregulates ALA Synthase.

Barbituates and Steroids: these drugs ↑ synthesis of ALA synthase.

Deficency in Vitamin B6/PLP (active form of B6): slows down the activity of ALA Synthase which ↓ heme synthesis and causes Hypochromic Anemia, a condition charactarized by pale RBCs.

Heavy metals can inhibit heme synthesis at two key enzymes/steps (listed below) leading to ↓ ability to synthesize heme and anemia.

ALA Deydratase the cytoplasmic enzyme that converts

2 ALA→ a pyrole ring

and

Ferrochetalase the enzyme that catalyzes the final step in heme synthesis in the mitochondria.

Inherited (usually AD) defects in porphyrin/heme synthesis.

Erythropoietic Porphyrias are defects in porphyrin syntheiss in the blood producing tissues and Hepatic Porphyrias are defects in porphyrin production in the liver.

If the defect occurs before the generation of Porphyrinogen you will see an accumulation of ALA and BPG and a decrese in heme with accompanying heurological symptoms.

If the defect occurs after the generation of Porphyrinogen porphrinogens will be oxidized and deposited in the skin leading to photosensitivity.

Acute Intermittent Porphyria (AIP)

Caused by a deficiency in hepatic uroporphyrinogen I synthase an example of a block that occurs before the generation of porphrinogen and therefore reuslts in an accumulation of ALA and PBG along with decreased heme synthesis.

When heme synthesis is decreased there is reduced - FB on ALA Synthase whcih measn that even more precursors will be made.

Neurological symptoms inculding agitation but no photosensitivity due to the location of the block.

Barbituates exacerbate the condition by ↑ ALA synthase generation and thereby generating more precursors.

A heme precursor generated from 4 porphobilins.

Synthesis requires two enzymes:

Urophorphyrinogen I Synthase and Urophoyrinogen III Cosynthase.

A defect in the Synthase = Acute Intermittent Porphyria (AIP)

A defect in the Cosynthase=production of a not functional ring and Congenital Erythropoetic Porphyria.

An enzyme found in the macrophages of the reticuloendothelial system that carry out the breakdown of heme.

Heme oxidase catalyzes the first step of this pathway and opens the ring to release the Fe2+ (salvaged) and to generate Biliverdin (a linear tetrapyrole that will be reduced to form insoluble Biliruben in the cytosol of reticuloendothelial macrophages).

The secretion of conjugated (in the liver) Bilirubin Diglucuronide into the bile canaliculi*

From there it is sent to the intestines, deconjugated by intestinal bacterai and reduced to Urobilinogens which are either absorbed or excreted.

Urobilinogen =colorless product of bilirubin reduction. Formed in the intestines by bacterial action. Some is reabsorbed into the circulation and excreted by the kidney.

↑ amounts of bilirubin are formed in hemolysis, which generates ↑ urobilinogen in the gut. In liver disease (such as hepatitis), the intrahepatic urobilinogen cycle is inhibited = ↑ urobilinogen levels.

In these cases Urobilinogen → yellow pigmented urobilin apparent in urine.

The urobilinogen is reduced to stercobilinogen in the intestine and is then oxidized to brown stercobilin, which gives the feces their characteristic color.

Caused by an obstruction to the drainage of conjugated bilirubin from the liver into the bile ducts.

Can be due to gallstones, drugs, inflammation (common) or to cancer/biliary cirrosis.

Leads to conjugated hyperbilirubinemia when conjugated bilirubin from the liver backs up into the system because it can't get to the intestines.

Conjugated bilirubin in urine (not reduced)= Dark Urine

No Urobilinogen in the feces (can't be made bc bilirubin can't get to the intestine to be reduced)=light feces

Back up of conjugated BR causes liver damage and therefore elevated AST, ALP, and ALT levels.

Can be caused by Dubin Johnson Syndrome or Rotor's Syndrome which are both bile secretory defects.

Jaundice caused by defects in the uptke of free bilirubin, conjugation of bilirubin to form bilirubin diglucuronide, or release of bilirubin diglucuronide (conj BR).

Results in unconjugated hyperbilirubinemia

Examples include: Newborn Jaundice, Kernicterus, Gilbert's Syndrome, and hepatitis (discussed on seperate cards) as well as...

Cringler-Najjar Syndrome: a form of congenital non-hemolytic/intrahepatic jaundice.

Toxic hyperbilirubinemia caused by alcohol-induced liver damage or by Acetomenophin.

A form of Intrahepatic Juandice (unconjugated hyperbilirubinemia) that occurs in 50% of newborns.

The immature liver of the newborn is unable to properly conjugate BR which leads to elevation of circulating unconjugated BR and jaundice.

Treated easily with lights to reduce toxicity of BR.

If it occurs within the first 24h hemolysis is ruled out and if it persists beyond 10d it is no longer normal.

A form of intrahepatic jaundice

Occurs when serum BR exceeds 15 mg/dl resulting in the deposition of uncojugated BR on the basal ganglia→ brain damage.

Signs in the newborn ar lethargy, loss of the mororeflex and poor feeding.

Treatment with phototherapy and plasma exchange transfusion to try and reduce the toxic levels of BR in the blood.

5% of the population has this form of Intrahepatic Jaundice which is normally asymptomatic.

Caused by reduced activity of the UDP-Glucuronic Acid transferase which impairs conjugation of BR.

Causes Intrahepatic Jaundice

Hepatitis decreases BR conjugation which leads to elevated levels of unconjugated BR in the blood.

Dark Urine (lack of conjugated BR in the urine)

Pale Feces (decreased urobilinogen)

aka Hemolytic Jaundice

Occurs when BR synthesis (via heme breakdown) exceeds the capacity of the liver to conjugate it resluting in ↑ unconjugated BR and ↑ urinary and fecal urobilinogen.

Excess BR is typically due to hemolysis.

Fe2+ is the form of iron that is found in heme (+in Mb, Fe-S protiens etc...) and salvaged in heme breakdown. It is also the form that can be transfered across the plasma membrane.

Fe3+ is the storage form (Fe2+→Fe3+ by ferroxidase II)

Fe2+ is highly reactive and is always found bound to a carrier: Serum Transferrin, ferritin or hemosiderin.