8 - Gout Flashcards
What is purine metabolism?
The biochemical process involving the breakdown of purines to produce uric acid.
What is hyperuricemia?
A condition characterized by elevated levels of uric acid in the serum.
What are the two types of hyperuricemia?
- Primary hyperuricemia
- Secondary hyperuricemia
What are common risk factors that precipitate gout?
- High alcohol consumption
- Diet rich in purines (meat and seafood)
- Obesity
- Metabolic syndrome
What are potential clinical manifestations associated with hyperuricemia?
Excruciating joint pain, swollen joints, and inflammation.
What is the first step in diagnosing joint pain?
A comprehensive history and physical examination.
What is a monoarticular arthropathy?
Acute inflammatory change in a single joint.
What is the classic joint for a monoarticular presentation of gout?
The great toe.
What laboratory findings support a diagnosis of gout?
- Elevated serum uric acid level
- Attack of monoarticular arthritis with rapid onset
- Pain and erythema in the joint
- Culture negative upon aspiration
- Finding of a subcortical cyst without erosion on radiography
What is pseudogout?
Arthritis caused by calcium pyrophosphate crystals, often mimicking gout.
What are the key characteristics of gout?
Often monoarticular, severe pain, swelling, and typically involves lower extremities.
What lifestyle changes are recommended for managing chronic gout?
- Weight loss
- Smoking cessation
- Increased exercise
- Reduced intake of sugar-sweetened drinks and alcohol
- Diet rich in plant proteins and vegetables
What is the pKa of uric acid?
5.5.
What is the primary site of purine degradation?
The liver.
Fill in the blank: The end product of purine degradation is _______.
uric acid
True or False: Gout can be triggered by cool external environments.
True
What are the symptoms of reactive arthritis?
Associated with iritis and urethritis, often following a bacterial infection.
What are common organisms causing septic arthritis?
- Staphylococcus aureus
- Neisseria gonorrhoeae
What does the presence of monosodium urate (MSU) crystals in the joint indicate?
A diagnosis of gout.
What is the significance of a history of dietary indulgence in relation to gout?
Diet rich in purines and alcohol can precipitate gout attacks.
What are the common presentations of osteoarthritis?
Typically asymmetric, affecting larger joints such as knees and hips.
What is the relationship between hyperuricemia and metabolic syndrome?
Conditions like obesity, dyslipidemia, insulin resistance, and hypertension increase the risk of gout.
What type of crystals are found in gout?
Needlelike monosodium urate (MSU) crystals.
What is the role of temperature and pH in the formation of MSU crystals?
Temperature and pH affect the solubility and crystallization of uric acid.
What is the typical presentation of rheumatoid arthritis?
Symmetrical involvement of smaller joints, often with morning stiffness.
What does the acronym PRPP stand for?
5-Phosphoribosyl-1-pyrophosphate.
What is the typical age group affected by gout?
More common in males, often affecting those over 40.
What dietary components are associated with increased risk of gout?
- Alcohol
- Fructose
- Sugar-sweetened soft drinks
- Meat
- Seafood
What is the common characteristic of arthritis in systemic lupus erythematosus?
Typically not inflammatory and can present with a characteristic rash.
What is the impact of lifestyle changes on gout management?
Can significantly reduce the frequency of gout attacks.
What is the primary site of degradation of purines?
Liver
What are the end products of purine nucleoside metabolism in humans?
Uric acid
Which enzyme converts uric acid into allantoin in most mammals?
Uricase
What is the main intermediate in purine degradation?
Xanthine
How are adenosine and guanosine metabolized?
They are converted to xanthine
What is the role of adenosine deaminase (ADA) in the body?
Essential for immune function and regulating extracellular adenosine signaling
What is the final step in purine degradation?
Formation of uric acid by xanthine oxidase
What can dysregulation of purine metabolism lead to?
Hyperuricemia and gout
What are potential causes of primary hyperuricemia?
- Inborn error of metabolism
- Genetic defects
What is secondary hyperuricemia?
Hyperuricemia driven by an underlying disorder
What medication is commonly used to treat hyperuricemia in gout patients?
Allopurinol
What is the mechanism of action of allopurinol?
Inhibits xanthine oxidase
What dietary changes can help manage gout?
- Limit purine-rich foods
- Limit alcohol intake
What is the first-line treatment during an acute gout attack?
Corticosteroid treatment
What are common side effects of colchicine?
- Nausea
- Vomiting
- Diarrhea
What is required for chronic management of gout?
Xanthine oxidase inhibitors or uricosuric agents
What can chronic uric acid elevation lead to in joints?
Urate crystal formation and tissue damage
What is the appearance of MSU crystals under polarized light microscopy?
Strongly negatively birefringent and needle-shaped
How is uric acid processed in the kidneys?
Filtered by glomerulus and reabsorbed in the proximal tubule
What can lead to the formation of uric acid stones?
Low pH in urine and chronic urate nephropathy
What are high-yield concepts related to hyperuricemia and gout?
- Elevated serum urate may not cause gout
- Gout commonly affects the great toe
- Decreased uric acid excretion promotes hyperuricemia
- Increased purine-rich food enhances attack risk
- Normal serum urate can occur during gout attacks
What are the characteristics of choreoathetosis?
Involuntary writhing movements
What is dystonia?
A movement disorder characterized by involuntary muscle spasms
What is the purine salvage pathway?
A pathway for cells to recycle purine bases from nucleotide degradation
What could hyperuricemia and uric acid crystals in urine suggest in a pediatric patient?
Possible hematologic malignancy
What is choreoathetosis?
Involuntary writhing movements.
Define dystonia.
A movement disorder characterized by involuntary rapidly contractile muscle spasms.
What is the purine salvage pathway?
A pathway in which cells salvage and recycle purine bases that are released from nucleotide degradation.
What is a significant laboratory finding in the case presented?
Hyperuricemia and uric acid crystal in the urine.
What can hyperuricemia indicate in a child?
Possible hematologic malignancy due to high cellular turnover.
What diagnosis was ultimately made for the child?
Lesch-Nyhan syndrome due to a deficiency of hypoxanthine-guanine phosphoribosyltransferase (HGPRT).
What is the inheritance pattern of Lesch-Nyhan syndrome?
X-linked recessive trait.
What biochemical measurement supports the diagnosis of Lesch-Nyhan syndrome?
Measuring the level of HGPRT and confirmed with gene analysis.
What are common symptoms of Lesch-Nyhan syndrome?
Gout, renal calculi, loss of muscle control, dysarthria, and moderate psychomotor retardation.
What is the consequence of HGPRT deficiency?
Inability to salvage hypoxanthine or guanine.
What are the two major pathways for purine synthesis?
De novo and salvage pathways.
Which organ is the major site for de novo purine synthesis?
Liver.
What is PRPP?
5′-phosphoribosyl-1′-pyrophosphate.
What activates PRPP synthetase?
Inorganic phosphate.
What inhibits PRPP synthetase?
Purine-5′-ribonucleotides, particularly AMP and GMP.
What is the rate-limiting step in de novo purine nucleotide synthesis?
Formation of phosphoribosylamine (PRA) by glutamine PRPP-amidotransferase (GPAT).
What is the role of glutamine in purine synthesis?
It donates an amide group to form phosphoribosylamine (PRA).
What is the energy cost for producing one IMP molecule?
Five ATP.
What regulates the synthesis of AMP and GMP from IMP?
Reciprocal regulation; GTP favors AMP synthesis, ATP favors GMP synthesis.
How are purines synthesized via the salvage pathway?
Using purine bases obtained from the liver and degradation of RNA, which are converted to nucleotides by phosphoribosyltransferases.
What is the role of adenine phosphoribosyltransferase (APRT)?
Converts adenine to AMP.
What is the significance of HGPRT in purine synthesis?
Catalyzes the formation of GMP and IMP from guanine and hypoxanthine, respectively.
What are the neurological symptoms associated with Lesch-Nyhan syndrome?
Spasticity, mental retardation, aggression, and self-mutilation.
What medication is prescribed to control hyperuricemia in Lesch-Nyhan syndrome?
Allopurinol.
What are xanthomas?
Cholesterol-rich deposits in the skin and cutaneous manifestations of hyperlipidemia.
What is hematuria?
The presence of red blood cells in the urine.
What condition did the 7-year-old boy have?
Glycogen storage disease (GSD) type 1A or von Gierke disease.
What laboratory findings are associated with von Gierke disease?
Hypoglycemia, anemia, anion gap lactic acidosis, hyperuricemia, elevated cholesterol and triglycerides, abnormal liver function tests.
What are the presenting symptoms of von Gierke disease?
Profound hypoglycemia, lethargy, weakness, hepatomegaly.
What is the initial finding during the emergent evaluation of a child with glycogen storage disorder?
Hypoglycemia along with hepatomegaly
These findings prompt further investigation into insulin and glucose levels.
What does a low insulin level in the face of hypoglycemia suggest?
Excludes an insulin-secreting tumor or other causes for elevated insulin levels
This is crucial in diagnosing glycogen storage disorders.
What are the physical findings typical of glycogen storage disorder (GSD)?
Dysmorphic features of growth retardation and a doll-like facies
These features are due to fat deposition in the cheeks.
What is the cardinal manifestation of von Gierke disease?
Massive hepatomegaly along with nephromegaly
What laboratory findings are consistent with von Gierke disease?
Hypoglycemia, lactic acidosis, hyperuricemia, hypercholesterolemia, and hypertriglyceridemia
What is the role of glycogen in energy metabolism?
Provides a rapid source of glucose for energy
Essential for brain and red blood cells which constantly draw upon glucose.
How does the liver maintain blood glucose levels during fasting?
By glycogenolysis and gluconeogenesis
What enzyme is crucial for converting glucose 6-phosphate to glucose?
Glucose-6-phosphatase
What is glycogen?
An enormous branched chain of glucose molecules linked by glycosidic bonds
What enzyme controls glycogen synthesis?
Glycogen synthase
What is the process of glycogen degradation called?
Glycogenolysis
What enzyme catalyzes the rate-determining step of glycogenolysis?
Glycogen phosphorylase
Why is glycogen stored as a branched polymer?
To provide a rapid source of glucose and increase solubility
Why do muscles store glycogen?
For rapid energy during high-demand situations like sprinting
Does cardiac muscle store significant amounts of glycogen?
No, cardiac muscle stores very little glycogen
How is glycogen metabolism regulated hormonally?
Through glucagon and epinephrine in fasting/exercise and insulin in the fed state
What happens to glycogen synthase during fasting?
It is inactivated by phosphorylation
What transporter does skeletal muscle use for glucose uptake?
GLUT-4
What is the role of insulin in glycogen metabolism?
Activates glycogen synthase and inactivates glycogen phosphorylase
What type of glucose transporter does the liver use?
GLUT-2
What is the significance of the branching in glycogen structure?
Increases the speed of glucose incorporation and release
What can result from a defect in the enzyme that forms branches in glycogen?
Glycogen storage disease type IV (Andersen disease) leading to severe complications
What are negative regulators of glycogenolysis in the liver and muscle?
Glucose 6-phosphate and ATP
Excess ATP indicates energy abundance, while glucose 6-phosphate indicates sufficient substrate for glycolysis.
What stimulates glycogen synthesis in the liver and muscle?
Abundance of glucose 6-phosphate
This signals that there is available substrate for the production of glycogen.
What inhibits glycogenolysis in the liver?
Glucose
Glucose acts as a negative regulator of glycogen breakdown.
What stimulates glycogenolysis in muscle?
Increased Ca+2 and AMP
These are markers of energy depletion due to muscle contraction.
What are glycogen storage diseases (GSD)?
Inherited diseases caused by defective glycogen synthesis, glycogen breakdown, or glycolysis
Pathological presentations may involve liver, muscle, or both tissues.
What is the most common muscle-specific GSD?
McArdle disease
It results from a defect in muscle glycogen phosphorylase.
What are the biochemical markers indicative of exercise intolerance in muscle glycogen disorders?
Lactate, myoglobin, and creatinine
Strenuous exercise uses glycogenolysis, leading to increased lactate production.
What are the three key questions to decipher glycogen storage diseases?
- Which enzyme is affected?
- Is the amount or structure of glycogen altered?
- Which tissues are affected?
What is the defect in von Gierke disease (type 1 GSD)?
Mutation in the G6PC gene leading to glucose-6-phosphatase deficiency
This enzyme is responsible for converting glucose 6-phosphate into glucose and inorganic phosphate.
What causes hypoglycemia in von Gierke disease?
Defect in glucose-6-phosphatase blocks glucose release from the liver
This results in severe fasting hypoglycemia.
What treatment is used to manage hypoglycemia in von Gierke disease?
Frequent small servings of carbohydrates and uncooked cornstarch
Cornstarch is absorbed slowly, providing a continuous release of glucose.
What causes hepatomegaly in von Gierke disease?
Massive buildup of glycogen due to high levels of glucose 6-phosphate
Glucose 6-phosphate acts as a positive allosteric regulator of glycogen synthesis.
What leads to lactic acidosis in von Gierke disease?
Acc accumulation of glucose 6-phosphate leads to lactate production
The liver becomes a lactate producer instead of a consumer.
What contributes to hyperuricemia in von Gierke disease?
Increased lactate and ketone body secretion leading to uric acid reabsorption
Also, increased purine synthesis from glucose 6-phosphate contributes to uric acid production.
What is Pompe disease also known as?
Acid maltase deficiency or glycogenosis type 2
The defective enzyme is located in lysosomes and affects multiple tissues.
What are the cardinal signs of classic infantile Pompe disease?
Hypertrophic cardiomyopathy, hypotonia, muscle weakness, respiratory insufficiency
These signs differ from other GSDs.
What is Tarui disease caused by?
Mutation in the gene encoding muscle and erythrocyte phosphofructokinase 1 (PFK1)
This results in exercise-induced muscular pain and myoglobinuria.
How does glucose supplementation affect McArdle disease compared to Tarui disease?
Effective in McArdle disease but ineffective in Tarui disease
Tarui disease has a defect downstream of glucose in glycolysis.
What is the management focus for a child with von Gierke disease?
Maintenance of blood glucose by frequent feeding and carbohydrate intake
Minimize galactose and fructose in the diet to avoid complications.
What are the clinical manifestations of GSD type 1?
Hepatomegaly, hypoglycemia, lactic acidosis, hyperalaninemia, hyperlipidemia, hyperuricemia
These manifestations arise from the defect in glucose-6-phosphatase.
What is the role of glucose-6-phosphatase?
Converts glucose 6-phosphate into glucose and inorganic phosphate
It is a membrane-bound protein in the endoplasmic reticulum.
What is the relationship between fatty acids and glucose in energy production?
Fatty acids cannot meet the energy needs of the brain or red blood cells
These tissues depend exclusively on glucose for energy.
What are the initial symptoms observed in the infant after advancing to soft solids?
Listless and flaccid behavior, responds to stimuli but returns to a somnolent state
These changes occurred following the introduction of soft solids into the infant’s diet.
What are the vital signs of the infant during the physical examination?
Pulse: 105/min, Respiratory rate: 26/min, Temperature: 98.0 °F
These vital signs indicate a state of distress and potential metabolic disturbance.
What notable findings were revealed in the infant’s urinalysis?
pH 8.5, 3+ protein, positive for amino acids, normal microscopic examination
These findings suggest renal involvement and possible metabolic issues.
What is Fanconi syndrome?
A result of injury to the proximal renal tubule
This syndrome leads to the loss of multiple substances in urine including glucose and amino acids.
What symptoms are typical of fructose intolerance?
Gas, bloating, abdominal pain, and diarrhea
Symptoms are similar to those of lactase deficiency and irritable bowel syndrome.
What is tachypnea?
Abnormally rapid breathing
Tachypnea can indicate respiratory distress or metabolic issues.
What metabolic disturbances are indicated by the infant’s clinical presentation?
Hypoglycemia, lactic acidosis, elevated uric acid, and triglycerides
These disturbances suggest multiorgan system involvement and a serious metabolic disorder.
What are the key causes of Fanconi syndrome?
Inborn errors of metabolism, cystinosis, Wilson disease, hereditary fructose intolerance, medications
Various factors can lead to this syndrome, including genetic and environmental causes.
What is the most common cause of hereditary Fanconi syndrome in children?
Cystinosis
Cystinosis typically presents soon after birth, thus can help in differential diagnosis.
What dietary changes can unmask symptoms in hereditary fructose intolerance?
Introduction of fruits and vegetables or formulas containing sucrose
Fructose, present in these foods, exacerbates symptoms in affected individuals.
How is dietary fructose metabolized in the body?
Involves phosphorylation to fructose 1-phosphate and hydrolysis by aldolase B
This process is crucial for fructose utilization in glycolysis and gluconeogenesis.
What happens to glycolysis in patients with hereditary fructose intolerance (HFI)?
Residual activity of defective aldolase B allows glycolysis to continue
Compensatory mechanisms may help maintain glycolytic function despite the deficiency.
What are the two autosomal recessive disorders of fructose metabolism?
Essential fructosuria and hereditary fructose intolerance (HFI)
Essential fructosuria is usually benign, while HFI can lead to severe symptoms.
What are the clinical presentations of hereditary fructose intolerance?
Hypoglycemia, nausea, vomiting after exposure to fructose
These symptoms arise due to metabolic derangements from fructose accumulation.
What dietary restrictions are recommended for patients with hereditary fructose intolerance?
Elimination of fructose, sucrose, and sorbitol-containing foods
This is critical to avoid life-threatening complications.
What is the consequence of aldolase B deficiency?
Accumulation of fructose 1-phosphate leading to metabolic disturbances
This condition can result in hypoglycemia, hyperuricemia, and lactic acidemia.
What is the role of aldolase B in fructose metabolism?
Rate-limiting enzyme that cleaves fructose 1-phosphate into dihydroxyacetone phosphate and glyceraldehyde
Its deficiency is central to the pathophysiology of hereditary fructose intolerance.
What is plumbism?
Lead poisoning
This condition can lead to various systemic symptoms including neurological deficits.
What are the key symptoms of the 56-year-old man presented in Case 8.5?
Foot drop, numbness in feet, memory impairment, abdominal pain, chronic constipation
These symptoms suggest possible neuropathy or systemic illness.
What laboratory findings were notable in the 56-year-old man?
Microcytic hypochromic anemia with basophilic stippling, hyperuricemia, alkaline urine
These findings are indicative of lead poisoning and possible renal tubular acidosis.
What is the significance of anion gap in serum?
Useful marker for diagnosing acid-base disorders
Helps in identifying metabolic acidosis or other disturbances.
What findings suggest possible renal tubular acidosis in the 56-year-old man?
Alkaline urine in the face of metabolic acidosis
This suggests an inability of the renal tubules to properly acidify the urine.
What is the connection between heavy metal poisoning and gout?
Saturnine gout occurs as a result of lead toxicity
Lead can interfere with normal purine metabolism, leading to hyperuricemia.
What is the patient’s clinical presentation?
The patient presents with acute and chronic complaints involving multiple organ systems.
What laboratory findings are noted in the patient?
Laboratory findings include microcytic anemia with basophilic stippling and nonanion gap hyperchloremic acidosis.
What does nonanion gap hyperchloremic acidosis indicate?
It indicates acidosis without an increase in the anion gap, typically due to a decrease in bicarbonate concentration.
What are the possible causes of nonanion gap hyperchloremic acidosis with alkaline urine?
- Fanconi syndrome
- Medication (e.g., acetazolamide, ifosfamide, valproic acid, tenofovir)
- Toxic exposure (e.g., heavy metals like lead)
What occupation might expose the patient to lead?
The patient has worked for a firm that manufactures ammunition and has made his own lead bullets.
What additional history should be sought with this patient?
Inquire about occupational exposure, hobbies, and home remodeling activities that might involve lead.
What findings suggest lead poisoning in this patient?
Elevated serum lead levels at 88 μg/dL and the presence of Burton’s line in the gingiva.
What are common sources of lead exposure?
- Lead-based paint (homes built before 1970)
- Contaminated soil or water
- Lead plumbing
- Imported products (cosmetics, jewelry, toys)
How does lead exposure affect the body?
Lead accumulates in tissues, primarily in bones, leading to various health effects including neurotoxicity and renal impairment.
What are the symptoms of lead poisoning?
- Lethargy
- Anorexia
- Abdominal discomfort
- Joint pain
- Anemia
- Peripheral neuropathy
What laboratory findings are associated with lead poisoning?
- Microcytic hypochromic anemia
- Basophilic stippling in blood smear
- Ringed sideroblasts in bone marrow
What are the mechanisms through which lead causes microcytic hypochromic anemia?
Lead inhibits ALA dehydratase and ferrochelatase, preventing iron incorporation into protoporphyrin IX.
What is the treatment for lead poisoning?
Chelation therapy using metal chelators such as desferrioxamine, sodium calcium edetate, and penicillamine.
What is the significance of the lead line seen in radiographs?
It indicates lead accumulation in bone, commonly seen in children due to disrupted bone remodeling.
How does lead exposure lead to gout?
Lead-induced nephropathy results in underexcretion of urate, causing hyperuricemia and potential gout.
What diagnostic tests are used for lead poisoning?
Blood lead level (BLL) test is the most reliable, while erythrocyte protoporphyrin (EP) and hemoglobin screenings were previously used.
What is the outcome of chelation therapy in this patient?
Lead levels decreased to <5 μg/dL, with improvement in clinical symptoms and renal function.
What are high-yield concepts related to lead toxicity?
- Most common exposure is occupational or from old lead plumbing
- Lead enters the body via gastrointestinal tract, lungs, and skin
- Accumulates in bones and affects growth in children
- Symptoms include abdominal pain and renal tubular acidosis
- Treatment involves chelation therapy
What is hyperuricemia?
An elevated level of uric acid in the blood
Hyperuricemia can lead to gout and is often associated with various metabolic disorders.
What is the most likely diagnosis for a patient with hypoglycemia, hyperuricemia, and normal blood counts?
Lesch-Nyhan disease
This condition is characterized by self-mutilating behavior and neurological impairment.
What is the most appropriate next step in evaluating a 7-month-old with recurrent vomiting and mild liver enlargement?
Order complete metabolic panel
This helps assess metabolic disorders, including hereditary fructose intolerance.
What is the first step in managing a 44-year-old woman with acute knee swelling and tenderness?
Perform arthrocentesis
This helps analyze joint fluid for infection or crystals.
What is the most likely enzyme deficiency in a patient with hypoglycemia, lactic acidemia, hyperuricemia, and hyperlipidemia?
Glucose-6-phosphatase
This deficiency is associated with von Gierke disease.
What is the most likely explanation for hyperuricemia in a patient with glucose-6-phosphatase deficiency?
Stimulation of AMP deaminase by decreased inorganic phosphate
This leads to increased uric acid production.
What is the most likely mechanism of Lesch-Nyhan disease?
Decreased salvage of purines
This results from hypoxanthine-guanine phosphoribosyltransferase (HGPRT) deficiency.
What is the most appropriate treatment for urate-lowering therapy in Lesch-Nyhan syndrome?
Allopurinol
Allopurinol inhibits xanthine oxidase, reducing uric acid levels.
Fill in the blank: The most likely enzyme deficiency in a child with self-mutilating behavior and hyperuricemia is _______.
Hypoxanthine-guanine phosphoribosyltransferase
This deficiency is linked to Lesch-Nyhan syndrome.
True or False: Aldolase B deficiency presents with symptoms similar to glycogen storage disorders.
True
Symptoms can include hypoglycemia and hepatomegaly.
What dietary changes should be made for a patient with hereditary fructose intolerance?
Eliminate sources of fructose, sorbitol, and sucrose
This diet helps manage the condition effectively.
What is the expected laboratory finding in a patient with glucose-6-phosphatase deficiency?
Hypoglycemia, lactic acidemia, hyperuricemia, and hyperlipidemia
These findings are characteristic of von Gierke disease.
What is the primary cause of hyperuricemia in patients with gout?
Increased reabsorption of uric acid in the kidney
This is often due to the use of thiazide diuretics.
What are common symptoms of Lesch-Nyhan syndrome?
- Self-mutilation
- Delayed motor skills
- Severe mental retardation
- Hyperuricemia
These symptoms arise from HGPRT deficiency.
What is the most appropriate next step for a child with unexplained abdominal pain and developmental delay?
Dietary history
This helps identify any potential nutritional deficiencies or exposures.
What is a common consequence of thiazide diuretics related to uric acid?
Increased uric acid reabsorption
This can predispose patients to gout.
What is a common presentation of glycogen storage disorders?
Hypoglycemia and hepatomegaly
These are hallmark signs of various glycogen storage diseases.
