M2C Unit 2 Lesson 5, 6, 7

The toxicity of CO is primarily attributed to its relatively high/low affinity for hemoglobin (Hb)

high

Cuases of CO poisoning

Accidental deaths peak in winter:

• Use of heating systems.

• Closed windows.

Fetal hemoglobin has a much greater/lower affinity for CO than adult hemoglobin.

greater

What also binds to other iron-containing proteins: • Myoglobin • Cytochrome • Neuroglobin

CO

Binding to myoglobin reduces __ available in the heart:

• Ischemia

• Dysrhythmias

• Cardiac dysfunction

O2

CO decreased myocardial ___ activity

CcOX

Causes of CO poisoning

• Increased enzyme destruction due to binding of CO to heme groups.

• Production of reactive oxygen species production, oxidative stress, and subsequent protein destruction.

Inhaled CO may interrupt myocardial oxidative phosphorylation by increasing/decreasing the activity of myocardial cytochrome oxidase (CcOX), the terminal oxidase in the electron transport chain.

decreasing

Exposure to CO gas initially causes what?

nonspecific neurologic features, such as headaches, confusion, fatigue, vertigo, paresthesia, and nausea.

Long-term neurologic effects of CO

may include amnesia, dementia, parkinsonism (from damage to dopamine neurons), and even psychosis.

The skin or lips may occasionally have a cherry-red color due to what?

CO

Cyanide effect on Oxygen dissociation curve

no effect

CO effect on Oxygen dissociation curve

shifts to the left in exposure

In CO poisoning and the resulting tissue hypoxia, anaerobic respiration occurs, leading to?

lactic acidosis

A COHb level of more than __ should make you suspect CO poisoning.

3%

However, results can be confusing if the patient is a heavy smoker, since the “normal” COHb levels for smokers can be elevated to about ___

10%

Management of Carbon Monoxide Poisoning

First step in treating any poisoning is separating the patient from the poisoning source.

• Initial treatment, use of 100% O2 for as long as it takes to normalize COHb levels. This can be done with a nonrebreather mask or using intubation with mechanical ventilation if the patient is unconscious.

Which is more toxic, CO or CN?

CN

Sources: • inhalation of HCN during house fires, of the products of combustion of plastics and rubber, • fumes given off by cigarette smoke or vehicle exhaust. • after intravenous (IV) administration of the vasodilator sodium nitroprusside

CN

Some patients may describe a “bitter almond” taste

CN

___ binding to the ferric iron (Fe3+) of cytochrome oxidase C in the mitochondria and preventing the cell’s uptake of O2 by blocking the mitochondrial transport chain

CN

Glycogenolysis

degradation of glycogen

Glycogen breakdown yields ___ which can be converted to G6P for metabolism via glycolysis and the citric acid cycle

G1P

Phosphorylase a (phosphorylated) of glycogen phosphorylase (GP)

active form

Phosphorylase b (dephosphorylated) of glycogen phosphorylase (GP)

less active form

Phosphoglucomutase catalyzes the conversion of G1P to

glucose 6-phosphate (G6P)

Insulin stimulates glycogen synthesis in the liver via the second messenger __

phosphatidylinositol 3,4,5-trisphosphate (PIP3)

Glycogen phosphorylase a is activated/inhibited by G6P

inhibited

Glycogen synthase b is activated/inhibited by G6P

activated

What Are Glycogen Storage Diseases?

Glycogen storage diseases are genetic defects in glycogen metabolism resulting in accumulation of glycogen.

What happens when macromolecules accumulate in cells?

Cell damage and dysfunction

Deficient enzyme in Type I, von Gierke disease

Glucose 6-phosphatase

Deficient enzyme in Type 2, Pompe disease

Lysosomal acid a-glucosidase (acid maltase)

Deficient enzyme in Type 3, Cori disease

Debranching enzyme (a-1,6-glucosidase)

Deficient enzyme in Type 5, McArdle disease

Muscle glycogen phosphoylase

How are Glycogen Storage Diseases detected?

Biopsies of liver or muscle will stain positive with periodic acid–Schiff (PAS), a stain that detects polysaccharides like glycogen

Andersen disease deficient enzyme

Branching enzyme deficiency.

Andersen disease effect

It leads to very long unbranched chains that are toxic to the liver and leads to liver failure.

Her disease deficient enzyme

liver glycogen phosphorylase deficiency

Her disease effect

Glycogen structure is normal, but the glycogen level in the liver is high. Since gluconeogenesis is intact in these patients, hypoglycemia is much milder than glucose-6-phosphatase deficiency (von Gierke disease).

What is glucose-6-phosphatase?

converts glucose-6- phosphate to glucose in the liver

A second subtype of von Dierke is caused by a deficiency in

glucose-6-phosphate translocase

What is glucose-6-phosphate translocase?

delivers glucose-6-phosphate from the cytosol into the endoplasmic reticulum.

Von Gierke Disease traits

• Liver can’t convert G6P into usable glucose, so it builds up inside liver cells.

• Patients have severely impaired gluconeogenesis and glycogenolysis.

• Generally, von Gierke disease spares the muscles, which are able to use the extra glucose6-phosphate for glycolysis.

Clinical aspects of von Gierke disease

• Present in infancy, usually after a few months of age.

• They have poor growth, relatively thin limbs, a typical “doll-like” face with fat cheeks, and a distended abdomen due to hepatomegaly.

• Can develop severe and life-threatening hypoglycemia after fasting, manifesting as seizures, coma, or even death. If untreated, recurrent hypoglycemic events can cause intellectual disability.

• Lactic acidosis results from an impaired Cori cycle, which normally converts lactate to glucose in the liver through the gluconeogenesis pathway. Because glucose-6-phosphatase doesn’t work, lactate also builds up in the bloodstream. Hypoglycemia and lactic acidosis contribute to early death in untreated von Gierke disease.

What glycogen storage disease has a typical “doll-like” face with fat cheeks, and a distended abdomen due to hepatomegaly?

von Gierke disease

von Gierke disease effect in body

• Elevated cholesterol and triglycerides due to impaired liver function, leading to increased risk of pancreatitis

• Kidney enlargement and kidney disease due to glycogen accumulation

• Elevated uric acid due to impaired renal clearance, leading to gout later in life

• Hepatic adenomas in the second or third decade of life, leading to increased risk of liver cancer

von Gierke Disease (Type 1): Diagnosis and Treatment

• DNA testing and blood tests

• dietary measures to prevent hypoglycemia.

• Patients eat uncooked corn starch throughout the day and night to maintain blood glucose levels. Avoid lactose, fructose, and sucrose because they worsen the accumulation of glucose-6- phosphate.

Medication for acidosis?

bicarbonate

medication for high triglyceride

fibrates

medication for kidney dysfunction inhibition

ACE (angiotensin-converting enzyme)

What is Pompe Disease?

Primarily affects muscles. Deficiency in acid α-glucosidase, also known as acid maltase,

• Also a lysosomal storage disease where the accumulated substrate is glycogen.

What is acid α-glucosidase aka acid maltase?

an enzyme that breaks down glycogen inside lysosomes

What is Pompe disease Glycogen accumulation causes damage to muscle fibers throughout the body

Classic form of Pompe Disease

• presents in infancy with macroglossia (enlarged tongue), weakness, hypotonia, and rapidly progressive hypertrophic cardiomyopathy.

• Although the liver functions properly (there’s no hypoglycemia or lactic acidosis), it is still often enlarged because of extra fluid from heart failure.

Pompe Disease (Type 2): Diagnosis and Treatment

• creatine kinase elevation, which indicates muscle damage

• Enzyme assays showing deficiency in acid α-glucosidase or DNA sequencing can confirm the diagnosis.

Fault of classic Pompe diseasae

has a very poor prognosis.

• Most kids die around 1 year of age from heart failure.

What is debranching enzyme (α-1,6 glucosidase)?

works in the beginning of glycogen metabolism to cleave α-1,6 bonds, or to debranch glycogen as its name suggests.

What is Cori disease?

A milder form of von Gierke.

• Patients of both diseases may have hepatomegaly, short stature, and lipid abnormalities.

Which diseaae has less severe hypoglycemia because gluconeogenesis is not affected (debranching enzyme is not relevant to gluconeogenesis)?

Cori disease

For which disease: The Cori cycle is intact in these patients, can use other fuels such as lactate to make glucose through gluconeogenesis. Therefore, no lactic acidosis.

Cori disease

Treatment for Cori disease is the same as?

von gierke disease treatment

• but there is no need to avoid sucrose, fructose, or lactose because gluconeogenesis is not affected.

What is glycogen phosphorylase (aka, myophosphorylase)?

normally removes glucose molecules from the outer branches of glycogen.

Unlike Pompe disease, McArdle disease primarily affects what?

skeletal muscle

Unique to glycogen storage diseases, McArdle disease typically presents in?

adolescence or young adulthood

In which disease do patients report muscle cramps and myoglobinuria (myoglobin breakdown causing urine to turn dark), especially after exercise?

McArdle Disease (Type 5)

In McArdle disease, when do patients feel the most fatigue, pain, and discomfort because glycogen cannot be broken down?

first 10 or so minutes of exercise when warming-up

Elevated _____ even at rest, is typical for McArdle disease.

creatine kinase

During this test, a blood pressure cuff is placed on a patient doing forearm exercises (opening and closing the fist) and blood is drawn. In someone with McArdle disease, there would be no increase in?

lactate