Clinical Correlations Unit 4

Name the Disorder

Causes: Dried secretion block pancreatic duct → Loss of digestive proteases

Symptoms: Recurrent infections, malabsorption, protein malnutrition, low serum albumin, poor child growth

Treatment: Pancreatic enzyme supplements

Cystic Fibrosis

Name the Disorder

Causes: Loss of enzyme secreting pancreatic cells → Loss of digestive proteases

Symptoms: Malabsorption, protein malnutrition, low serum albumin, poor child growth

Treatment: Pancreatic enzyme supplements

Chronic Pancreatitis

Amino acid absorption diseases can be detected by …

elevated levels of amino acids in the urine

Name the Disorder

• Autosomal recessive defect in neutral/hydrophobic amino acid transport

• Causes: Lack of tryptophan (precursor for niacin/NAD+) + poor diet

• Symptoms: Pellagra-like (photosensitivity, ataxia, tremors, nystagmus), elevated neutral amino acids in urine, MOSTLY normal clinically

• Treatment: Niacin-rich diet, high protein diet (to increases amount of dipeptides that can be taken up)

Hartnup Disease

Name the Disorder

• Deficient brush border transport of the basic amino acids COAL (cystine, ornithine, arginine, lysine)

• Symptoms: Hyperaminoaciduria, Cystiene stones in kidney/ureter/bladder

• Treatment: High fluid intake, Medications that elevate urine pH

Cystinuria

Name the type of medication

• Approved to treat multiple myeloma (a plasma cell leukemia)

• Prevents degradation of proteins that promote cell death

• EX: Bortezomib

Proteasome inhibitors

Name the Disorder

Defective E3 subunit (UBE3A) in brain neurons prevents the degradation of certain proteins in hippocampus and cerebellum

Symptoms: Proteins in neurons will be higher than homeostatic range, neurodevelopmental disease (delayed development, intellectual disability, unusual happy demeanor, frequent laughing, speech impairment, movement/balance disorder, seizures)

Angelman Syndrome

Name the Disorder

Defective E3 subunit (VHL) prevents degradation of hypoxia inducible factor subunits (HIF1α and HIF2α) that promote hypoxic responses such as blood vessel formation

Symptoms: Level of HIFs will be high even under normoxic conditions, tumor/cancer formation (vascular tumors in brain/spinal cord/retina, kidney carcinoma, adrenal gland tumors, inner ear tumors)

Von Hippel-Lindau (VHL) Syndrome

Glutamine usage in Acidosis

Kidney uses more glutamine for ammonia production → more HCO3- to releases back into circulation to balance blood pH

Amino Acid utilization in Sepsis

Muscle proteolysis provides amino acids to blood pool → Hepatocytes rapidly synthesize acute phase proteins & Leukocytes consume large amounts of glutamine for rapid proliferation to fight infections

States associated w/ Positive Nitrogen Balance (N intake > excretion)

Growth, pregnancy, recovery from illness/malnutrition

States associated w/ Negative Nitrogen Balance (N intake < excretion)

Severe illness, starvation, malnutrition

Name the Enzyme(s)

• Autosomal recessive

• Causes Type I hyperammonemia when deficient

• Normally catalyzes synthesis of carbamoyl phosphate

Carbamoyl phosphate synthetase I (CPSI) or

N-acetylglutamate (NAG) synthase (since it regulates CPSI)

Name the Enzyme

• X-linked recessive

• Causes Type II hyperammonemia, high levels of urine orotate when deficient

• Normally catalyzes synthesis of citrulline

Ornithine transcarbamoylase (OTC)

Name the Enzyme

• Causes Hyperornithinemia, Hyperammonemia, Homocitrullinuria (HHH Syndrome) when deficient

• Normally transports ornithine into the mitochondria from the cytosol

Ornithine translocase

Name the Enzyme

• Autosomal recessive

• Causes Type I Citrullinemia when deficient

• Normally catalyzes argininosuccinate synthesis

• Deficiency treated w/ citrulline t o capture aspartate

Argininosuccinate synthetase

Name the transporter

• Causes Type II Citrullinemia when deficient

• Deficiency treated w/ citrulline to capture aspartate

Citrin (mitochondrial glutamate/aspartate transporter)

Name the Enzyme

• Autosomal recessive

• Causes Arginonsuccinyl Acidemia, high blood citrulline when deficient

• Normally catalyzes arginine synthesis

• Deficiency treated w/ arginine to generate more ornithine and NAG

Argininosuccinate lyase

Name the Enzyme

• Causes Argininemia when deficient

• Noramlly catalyzes cleavage of arginine into urea and ornithine

Arginase

Name the Deficient Pathway

Causes hyperammonemia, hepatic encephalopathy, cerebral edema, seizures, nausea, vomiting, lethargy, coma, and death if untreated

Urea Cycle

What is defective in PRIMARY hyperammonemias?

**NOT the same as TYPE 1 hyperammonemia

Urea cycle enzymes

What is defective in SECONDARY hyperammonemias?

**NOT the same as TYPE 2 hyperammonemia

Hepatocytes (hepatic failure like cirrhosis, hepatitis, or hepatotoxins)

**Genetic defects in enzymes NOT related to the urea cycle is another cause

3 Treatments for reducing Nitrogen Load on the Urea Cycle

• Low protein, avoid fasting, scavenger drugs (conjugate AAs and target them for excretion)

• Lactulose laxative (decrease pH in gut so ammonia cannot be reabsorbed)

• Urease inhibitors

Name the Enzyme

• Causes Histidinemia when deficient

• Normally catalyzes histidine to urocanic acid

Histidase

What is measured to monitor folic acid deficiency?

FIGlu excretion

Deficiency of what will increase amounts of FIGlu in the urine?

Folic acid

Name the Enzyme

• Causes Tyrosinemia Type I when deficient

  • Accumulation of fumarylacetoacetate and succinyl-acetone in the urine

  • Cabbage-like odor occurs

  • Liver failure and renal tubular acidosis

• Normally catalyzes histidine to urocanic acid

• Treatment: Dietary restriction of phenylalanine & tyrosine

Fumarylacetoacetate hydrolase

Name the Enzyme

• Causes Oculocutaneous Albinism Type I when deficient

  • White skin, white hair, pink eyes

  • Eye and skin sensitive to sunlight

  • Nystagmus, far or near sightedness

• Normally catalyzes histidine to urocanic acid

• Treatment: Dietary restriction of phenylalanine & tyrosine

Tyrosinase

Name the Enzyme & Deficient Pathway

• Causes Alkaptonuria when deficient

  • Homogentisic acid accumulates in urine and tissues; in cartilage in causes crippling arthritis

  • Bluish-black pigmentation in sclera of eye & ear

• Normally catalyzes histidine to urocanic acid

• Treatment: Dietary restriction of phenylalanine & tyrosine

Homogentisic acid oxidase & Tyrosine degradation pathway

Name the Enzyme

• Causes Phenylketonuria (PKU) when mutated

  • Elevated phenylalanine / phenylactate / phenylacetate in blood and urine (musty odor)

  • Neurological problems (mental retardation, seizures, tremors, microcephaly) due to reduced production of catecholamines

  • Hypopigmentation (light skin, hair, blue eyes) due to reduced melanin production

• Neonatal screening is mandatory in US

• Treatment: Phe-restriction, Tyr-supplement, avoid aspartame, artificial sweetener

• Normally catalyzes Phenylalanine to tyrosine

Phenylalanine hydroxylase

Other than an enzyme, insufficiency of what causes SEVERE PKU?

Tetrahydrobiopterin (BH4) insufficiency

Name the Enzyme

• Causes methylmalonic acidemia, metabolic acidosis, and developmental problems

  • Can lead to secondary hyperammonemia

• Normally catalyzes succinyl CoA to methylmalonyl CoA

Methylmalonyl CoA mutase

Name the Enzyme

• Causes propionic acidemia and metabolic acidosis

  • Can lead to secondary hyperammonemia

• Normally catalyzes propionyl CoA to methylmalonyl CoA

Propionyl CoA carboxylase

Name the Enzyme

• Causes Homocystinuria when deficient

  • Accumulation of homocysteine in the urine

  • Accumulation of methionine in the blood

  • Mental retardation, osteoporosis, myocardial infarction, dislocation of the lens

  • Treatment: Restrict methionine, supplement cysteine

• Normally catalyzes L-Homocysteine to Cystathionine

Cystathionine synthase

Name the Enzyme

• Causes Cystathionuria when deficient

  • Accumulation of cystathionine

  • No clinical symptoms present

  • Treatment: Restrict methionine, supplement cysteine

• Normally catalyzes Cystathionine to L-Cysteine

Cystathionase

Name the Disorder

Symptoms

• Elevated BCAAs (especially leucine) in blood

• Elevated BCKA in blood/urine

  • Cause maple syrup odor in urine (5-7 days after birth) and earwax (12-24 hrs after birth)

• Encephalopathy (lethargy, poor feeding, apnea, opisthotonus, coma)

Treatment

• BCAA restricted high calorie diet (leucine is the most restricted)

Maple Syrup Urine Disease (MSUD)

• I Love Vermont Maple Syrup (Isoleucine, Valine, Leucine)

Lack of tryptophan & niacin (vitamin B3) causes?

Pellagra (dermatitis, diarrhea, dementia, death)

Deficiency of PLP/vitamin B6 reduces what pathway and causes what main symptom? Why?

Heme synthesis & sideroblastic anemia

• ALAS requires it to catalyze glycine to δ-ALA

Name the Enzyme

• “Housekeeping”, Chromosome 3

• Negatively regulated by heme

  • High levels of heme result in the formation of this enzyme & heme complex that cannot be translocated into mitochondria resulting in reduced heme synthesis

• Infusion of hematin can abort porphyria attacks in patients with an inborn error of heme synthesis by inhibiting this enzyme

• No diseases associated w/ this enzyme’s gene mutations

• Normally catalyzes condensation of glycine and succinyl-CoA

δ-ALA Synthase 1 (ALAS1)

Name the Enzyme

• Erythroid, Chromosome X

• Controlled by iron-binding element to prevent excess formation of porphyrin

• Loss of function causes X-linked sideroblastic anemia

  • Treated w/ PLP/B6

• Gain of function causes X-linked dominant protoporphyria

• Normally catalyzes condensation of glycine and succinyl-CoA

δ-ALA Synthase 2 (ALAS2)

Drugs metabolized by what molecule enhances hepatic ALAS activity and stimulates heme synthesis?

Cyt P450

In a fasting state (↑ glucagon), what is the effect on PGC-1α (a coactivator of ALAS1)?

It is induced → increases synthesis of enzymes in FA oxidation, gluconeogenesis, & heme synthesis

In a fed state (↑ glucose/insulin), what is the effect on PGC-1α (a coactivator of ALAS1)?

Its synthesis is inhibited → decreasing ALAS1 expression

Name the Enzyme & the 3 disorders associated with it

• Normally catalyzes the condensation of 2 δ-ALA to a pyrrole ring

• Causes elevated levels of δ-ALA when deficient

δ-ALA Dehydratase (ALAD)

• ALAD porphyria

• Hepatorenal tyrosinemia

• Lead poisoning

Name the Deficient Enzyme & Describe the Disorder: ALAD Porphyria

• δ-ALA Dehydratase

• Caused by mutation in ALAD gene (recessive)

Name the Deficient Enzyme & Describe the Disorder: Hepatorenal tyrosinemia

• δ-ALA Dehydratase

• Accumulation of succinylacetone (a competitive inhibitor of ALAD)

Name the Deficient Enzyme & Describe the Disorder: Lead poisoning

• δ-ALA Dehydratase

• Leads to anemia and accumulation of δ-ALA

• Inhibits ALAD activity by displacing zinc atoms

Elevated levels of δ-ALA can have what type of effect?

Neurotoxic

• Affects CNS & PNS

• Results in memory loss and confusion

Name the Enzyme

• Normally catalyzes the introduction of Fe2+ into protoporphyrin IX

• Inhibited by lead

• Deactivating mutations of this enzyme can lead to erythropoetic protoporphyria

Ferrochelatase

Defects in proteins regulating iron absorption may lead to what disorder?

Iron overload / Hereditary hemochromatosis

Name the 6 causes of Iron Deficiency

• Inadequate dietary iron intake

• Inhibitors of iron absorption (EX: polyphenol compound)

• Hookworm infestation

• Blood loss via menses & NSAID use

• High fertility rate in women

• Low iron stores in newborns

Foods containing what can facilitate iron absorption? Why?

(found in citrus fruits, broccoli, dark green vegetables)

Ascorbic acid

• Reduces iron from ferric to ferrous form to be absorbed by the deodenum

INCREASED saturation of Fe3+ on transferrin is indicative of what?

Iron overload

DECREASED saturation of Fe3+ on transferring is indicative of what?

Iron deficiency

INCREASED levels of transferrin is indicative of what?

Iron deficiency

DECREASED levels of transferrin is indicative of what?

Iron overload

INCREASED plasma levels of ferritin is indicative of what?

Iron overload

DECREASED plasma levels of ferritin is indicative of what?

Anemia

Name the Enzyme

• Causes Congenital Erythropoetic porphyria (CEP) when deficient

  • Autosomal recessive

  • Most rare porphyria

  • Extreme photosensitivity

  • Erythrodontia (red teeth)

  • Hemolytic anemia

  • Treated w/ sun avoidance, bone marrow transplant

Uroporphyrinogen III Synthase (UROS)

Name the Enzyme

• Causes Acute Intermittent Porphyria when deficient

  • Autosomal dominant

  • Most common acute porphyria

  • Results in elevated levels of PBG and δ-ALA

    • PBG in urine is oxidized to bright red colored prophobilin

  • NO light sensitivity symptoms

Porphobilinogen deaminase (PBGD)

Name the Enzyme

• Causes Porphyria Cutanea Tarda (PCT) when deficient

  • Autosomal dominant

  • Photosensitivity (blisters/erosions)

  • Cutaneous sensitivity (porphyrin accumulation under the skin that are phototoxic)

  • Red colored urine

  • Treated w/ avoidance of alcohol consumption, iron supplements, excess exposure to sunlight

Uroporphyrinogen decarboxylase (UROD)

Name the 7 Precipitating Factors of Porphyrias

• Harmful drugs (Barbiturates, Sulfa antibiotics, Antiepileptics, Progestogens, Synthetic estrogens)

• Excessive alcohol consumption

• Heavy exercise

• Infections

• Reproductive hormones

• Smoking

• Severe calorie restriction

Name the Enzyme

• Causes Hereditary coproporphyria when deficient

  • Autosomal dominant

  • Photosensitivity

  • Nausea / Vomiting

Coproprophyrinogen oxidase

Name the 2 causes of Jaundice

• Excessive hemolysis due to trauma/infection

• Failure of liver to transport, store or conjugate bilirubin

Name the type of jaundice

• Results from excessive hemolysis due to autoimmune disease, hemolytic disease of newborn, or structurally abnormal RBCs (sickle cell)

• HIGH plasma concentrations of unconjugated bilirubin

Prehaptic jaundice

Name the type of jaundice

• Caused by impaired uptake, conjugation, or secretion of bilirubin or viruses, toxins, or genetic errors

• Generalized liver dysfunction

• Hyperbilirubinemia accompanied by liver function abnormalities

Intrahepatic Jaundice

Name the type of jaundice

• Caused by obstruction of biliary tree (gallstones or tumors)

• Leads to increased levels of plasma bilirubin and bile acids

• Characterized by pale-colored stools and dark urine

• Urobilin is absent in urine if complete obstruction

Posthepatic jaundice

Name the type of hyperbilirubinemia

• Severe

• Caused by insufficient conjugation due to enzyme deficiency or excessive hemolysis due to trauma, infection or autoimmune disease

Unconjugated

Name the type of hyperbilirubinemia

• Less severe

• Caused by liver disease, infection, or inherited disorders of bilirubin transport to bile

Conjugated

Name the Deficient Enzyme & Disorder

• Mild genetic disorder

  • Mutations in promoter region result in autsomal recessive inheritance

  • Missense mutation in UGT1A1 gene result in autosomal dominant inheritance

• Characterized by period of elevated levels of bilirubin in blood and nonhemolytic jaundice

• Episodes caused by dehydration, fasting, or illness

• Usually recognized in adolescence

Glucuronyltransferase, Gilbert Syndrome

Name the Deficient Enzyme & Disorder

• Autosomal recessive

  • Extremely rare

• Caused by mutation in BOTH UGT1A1 genes

• Characterized by complete absence/marked reduction in bilirubin conjugation

• Those affected are at high risk for kernicterus (damage to brain centers of infants)

• Treated w/ phototherapy or liver transplant by age 5

Glucuronyltransferase, Cringer-Najjar Syndrome

Name the Disorder

• Autosomal recessive

• Caused by mutation in ABCC2 gene coding for bile canalicular multispecific organic anion transporter

• Characterized by impaired biliary secretion of conjugated bilirubin

• Lysosomal accumulation causes liver to turn black

Dubin-Johnson Syndrome

Name the Disorder

• Autosomal recessive

• Caused by mutation in SLCO1B1/B3 genes that result in deficiency of anion transporter in hepatocytes

• Characterized by impaired biliary secretion of conjugated bilirubin

• Leads to jaundice and accumulation of bilirubin in blood

Rotor Syndrome

Name the Protein

• Most important inhibitor of elastase

• Unchecked elastase activity can lead to destruction of CT in lungs and liver

• Causes liver disease when deficient

  • It accumulates in the ER of hepatocytes

  • Characterized by elevated plasma levels of conjugated/unconjugated bilirubin

  • Exacerbated by unhealthy diet and alcohol

Alpha-1 Antitrypsin (AAT)

Why are high levels of unconjugated bilirubin toxic to newborns? (Neonatal jaundice)

It can cross the blood-brain barrier due to not being fully developed, damaging the brain

Deficiency of what compromises synthesis of inosine monophosphate (IMP), resulting in megaloblastic anemia? Why?

Vitamin B12 (cobalamin); It traps B9 (folate) which impairs cell division and is required for N10-formyl-FH4 (carbon donor for IMP synthesis)

Name the Enzyme

• Normally catalyzes the reversible phosphorolysis of purine nucleosides into free purine bases and (deoxy)ribose-1-phosphate

• Causes immunodeficiency disease when deficient

  • Autosomal recessive

  • T-cell toxicity and death

  • Individuals are more sensitive to opportunistic infections

Purine nucleoside phosphorylase (PNP)

Name the Enzyme

• Normally catalyzes formation of IMP from hypoxanthine / GMP from guanine

• Causes Lesch-Nyhan syndrome when deficient

  • X-linked recessive

  • Purine bases cannot be reused, resulting in excessive amounts of uric acid due to increased degradation

  • Mental retardation

  • Self-mutilation

  • Gout

  • Treated w/ xanthine oxidase (allopurinol)

HGPRT

Name the Enzyme

• Normally catalyzes adenosine to inosine

• Causes severe combined immunodeficiency (SCID) when deficient

  • Accumulation of dATP

    • Inhibits diphosphate reducatse

    • Reduced generation of deoxyribonucleotides

    • Impairs proliferation of lymphocytes

  • Loss of immune cells (lack of T and B cells)

Adenosine deaminase (ADA1)

Name the Enzyme

• Normally catalyzes AMP to IMP

• Causes muscle fatigue during exercise when deficient

AMP deaminase

Name the Enzyme

• Normally catalyzes orotic acid to UMP

• Causes hereditary orotic aciduria when deficient

  • Blocks pyrimidine synthesis

  • Growth retardation

  • Megaloblastic anemia

  • Treated w/ uridine to bypass metabolic block

UMP Synthase

Name the Enzyme

• Normally catalyzes carbamoyl phosphate into orotic acid

• Leads to accumulation of carbamoyl phosphate in mitochondria when deficient

  • Carbamoyl phosphate leaks to cytoplasm

  • Orotic aciduria

Aspartate transcarbamoylase

What anticancer drug inhibits thymidylate synthase? How?

5-fluorouracil (5-FU), no dTMP synthesis which arrests cell division

What anticancer drug inhibits dihydrofolate reductase? How?

Methotrexate, antifolate drug

***Also used to treat autoimmune diseases

Name the Disorder

• Congenital disorder of uric acid metabolism

  • Caused by underexcretion or too much production of uric acid

  • Also caused by overproduction of purines via PRPP synthetase and G6Pase deficiency

• Treated w/ NSAIDs or glucocorticoid injections in joints

• Prevented via xanthine oxidase (allopurinol), limited alcohol consumption, uricosuric drugs

Gout/Metabolic Arthritis

Name the Enzyme and Cofactor

• Causes xanthinuria when their genes are mutated

  • Rare hereditary disorder

  • Catabolism of purine stops at xanthine and hypoxanthine

  • Low blood uric acid

  • Formation of renal xanthine stones

  • Reduced excretion of urinary uric acid

Xanthine dehydrogenase, Molybdenum

Name the Disorder

Pain from viscera that is misinterpreted as being somatic in origin and felt in a dermatome

Referred Pain

Name the dermatome and innervation: Referred pain from heart and visceral pericardium

• Thoracic dermatome T1-4

• Cutaneous branches of intercostal nerves T1-4

Name the dermatome and innervation: Referred pain from fibrous and parietal pericardium

• Shoulder dermatome C3-4

• Supraclavicular nerves

Penetrating wounds to the neck or poor technique in attempting to access what vein can result in a collapsed lung?

Subclavian vein

What structure is a loose CT layer that provides a natural cleavage plane for surgery?

Endothoracic fascia

Name the Disorder

• Accumulation of excess fluid in the pleural cavity

  • Hydrothorax, hemothorax, chylothorax

• Requires thoracentesis or thoracostomy to remove fluid

Pleural effusion