BIOCHEMSTRY Flashcards
What are the main components of the TCA cycle?
Acetyl CoA
Citrate
Isocitrate
a-Ketoglutarate
Succinyl-CoA
Succinate
Fumarate
Malate
Oxaloacetate
What are the enzymes of the TCA cycle?
Citrate synthase
Aconitase
Isocitrate dehydrogenase
a-Ketoglutarate dehydrogenase
Succinyl-CoA Synthetase
Succinato dehydrogenase
Fumarase
Malate dehydrogenase
What are the products of one turn of the TCA cycle?
3 NADH
1 FADH2
1 GTP (or ATP)
2 CO2
What are the regulatory points of the TCA cycle?
The key regulatory points of the TCA cycle:
* Citrate synthase (Inhibited by ATP)
* Isocitrate dehydrogenase (Inhibited by NADH and ATP)
(Activated by ADP and CA)
* α-ketoglutarate dehydrogenase.
(Inhibited by NADH and Succinyl-CoA)
(Activated by CA)
What are the two major products of the TCA cycle that are used in the electron transport chain?
NADH
FADH2
What are the regulatory roles of citrate beyond TCA cycle?
Inhibit phosphofructokinase-1 (PFK-1) –> Glycolysis
Activate Acetyl-CoA carboxylase –> fatty acid synthesis
How does oxaloacetate function in the TCA cycle during the fasting state?
During fasting, the levels of oxaloacetate in the liver can be reduced due to increased gluconeogenesis, which uses oxaloacetate to produce glucose. This reduction can impact the TCA cycle’s efficiency, potentially leading to a shift in metabolism towards ketogenesis to provide energy.
Which enzyme Arsenic poisoning inhibit?
a-ketoglutarate dehydrogenase
What accumulates in the body due to the deficiency of homogentisate oxidase in alkaptonuria?
Homogentisic acid.
What enzyme is deficient in alkaptonuria?
Homogentisate oxidase
How does alkaptonuria affect the urine?
The urine turns dark upon standing due to the oxidation of homogentisic acid.
What is the inheritance pattern of alkaptonuria?
Autosomal recessive.
What is ochronosis?
A condition where homogentisic acid deposits in connective tissues, causing a blue-black discoloration of tissues, including cartilage and sclera.
What genetic mutation causes alkaptonuria?
Mutations in the HGD gene.
What joint problems are associated with alkaptonuria?
Arthritis, particularly in large joints.
What potential cardiac issue can occur in alkaptonuria?
Aortic stenosis (though less commonly emphasized).
How is alkaptonuria diagnosed?
By detecting elevated levels of homogentisic acid in the urine.
What are the primary management strategies for alkaptonuria?
Symptomatic treatment and potentially reducing intake of tyrosine and phenylalanine.
What is the name of the condition that causes urine to turn black upon standing in contact with air, and what is its underlying cause?
Alkaptonuria.
Deficiency: homogentisate oxidase
Accumulation: homogentisic acid, which darkens the urine when exposed to air.
A patient presents with a history of urine that darkens to a deep brown or black color after being left in a container for a few hours. Additionally, the patient reports persistent joint pain and has noted a bluish-black discoloration in their cartilage and sclera. Laboratory tests reveal elevated levels of homogentisic acid in the urine. Based on these findings, what is the most likely diagnosis?
Alkaptonuria
This test involves isolating a DNA sample and using a DNA polymerase enzyme along with specific primers . The process consists of repeated cycles of heating and cooling . What test is ? What is the purpose of this test?
Polymerase Chain Reaction (PCR)
Purporse: Amplify a target DNA sequence
DNA is first digested with restriction enzymes that cut it into fragments. These fragments are then separated by gel electrophoresis and transferred onto a membrane. A labeled probe that is complementary to a specific DNA sequence is used to bind to the target sequence on the membrane. The bound probe is detected, revealing the presence of the target sequence.
What test is ?
Southern Blotting
RNA is isolated and separated by gel electrophoresis. The separated RNA is then transferred to a membrane, and a labeled probe complementary to a specific RNA sequence is added. This probe binds to the target RNA, and the bound probe is detected, indicating the presence and size of the target RNA. What test is this?
Northern Blotting
Proteins are first separated by gel electrophoresis and then transferred to a membrane. The membrane is incubated with a primary antibody that specifically binds to the target protein. A secondary antibody, which is linked to an enzyme or fluorophore, is then added to bind to the primary antibody. The enzyme or fluorophore produces a detectable signal, indicating the presence of the protein.
Which test is this?
Western Blotting
Antigens or antibodies are immobilized on a microtiter plate. A sample containing the target antigen or antibody is added, and it binds to the immobilized counterpart. An enzyme-linked secondary antibody that binds to the target is then added. A substrate for the enzyme is used to produce a colorimetric or fluorescent signal, which is measured to determine the amount of target present. What test is this?
ELISA (Enzyme-Linked Immunosorbent Assay)
What is the primary mechanism of action of statins?
Statins inhibit HMG-CoA reductase, an enzyme involved in the biosynthesis of cholesterol. This leads to decreased cholesterol levels in the liver and increased uptake of LDL cholesterol from the bloodstream.
Which statin is most commonly used and has a high potency for lowering LDL cholesterol?
Atorvastatin (Lipitor).
What are some common side effects of statins?
Muscle-related issues (myalgia, myopathy, and rhabdomyolysis), liver enzyme elevation, and gastrointestinal symptoms.
What is a serious but rare side effect of statins that involves severe muscle damage?
Rhabdomyolysis, characterized by the breakdown of muscle tissue, which can lead to acute kidney injury.
How do statins affect cardiovascular risk?
Statins reduce the risk of cardiovascular events (such as heart attacks and strokes) by lowering LDL cholesterol levels and stabilizing atherosclerotic plaques.
Which statin is known for having the longest half-life, allowing for flexible dosing?
Rosuvastatin (Crestor).
What should be monitored periodically in patients on statins?
Liver function tests (LFTs) to monitor for liver enzyme elevations and creatine kinase (CK) levels to check for muscle-related side effects.
What drug interactions should be considered when prescribing statins?
Statins can interact with drugs that inhibit CYP3A4 (e.g., certain antibiotics and antifungals), which can increase statin levels and the risk of side effects. Examples include clarithromycin and ketoconazole.
Which statin is considered to have the lowest risk of drug interactions and is less affected by CYP3A4 inhibitors?
Pravastatin.
What lifestyle changes should be recommended in addition to statin therapy to manage hyperlipidemia?
- Diet modification (low saturated fat and cholesterol)
- Regular exercise
- Weight management
- Smoking cessation.
What is the key spirometric finding in COPD?
A reduced FEV1/FVC ratio, typically less than 0.70 (70%).
How does the post-bronchodilator response differ in COPD compared to asthma?
In COPD, the improvement in FEV1 post-bronchodilator is typically less than 12% and 200 mL from baseline.
Define Chronic Obstructive Pulmonary Disease (COPD).
Group of progressive lung diseases characterized by chronic airflow limitation, including chronic bronchitis and emphysema. It is primarily caused by long-term exposure to irritants, such as smoking.
What are the main pathophysiological changes in COPD?
COPD involves chronic inflammation, increased mucus production, and destruction of lung tissue (emphysema), leading to airflow limitation and impaired gas exchange.
Define Asthma.
Asthma is a chronic inflammatory disease of the airways characterized by reversible airflow obstruction, bronchial hyperreactivity, and increased mucus production, leading to wheezing, breathlessness, and cough.
What are the primary risk factors for developing COPD?
Smoking, occupational exposure to dust or chemicals, alpha-1 antitrypsin deficiency, and environmental pollutants.
What are common triggers for asthma exacerbations?
Allergens (e.g., pollen, dust mites), respiratory infections, exercise, cold air, and irritants such as smoke and pollution.
What spirometric changes are indicative of asthma?
A reversible decrease in FEV1/FVC ratio with significant improvement (≥12% and 200 mL increase) after bronchodilator administration.
What is the key spirometric finding in COPD?
A reduced FEV1/FVC ratio (<0.70) indicating persistent airflow limitation.
How is the severity of COPD classified based on FEV1?
Mild: FEV1 ≥ 80% of predicted
Moderate: FEV1 50-79% of predicted
Severe: FEV1 30-49% of predicted
Very Severe: FEV1 < 30% of predicted or FEV1 < 50% with respiratory failure
How is asthma typically diagnosed?
Diagnosis is based on clinical symptoms and spirometry:
* Reversible airflow obstruction (significant response to bronchodilators)
* Peak flow variability.
What are the cornerstone treatments for COPD?
- Corticoesteroid
- Oxygen (advanced cases)
- Pause smoking
- Dialator (Bronchodilators:beta-agonists, anticholinergics)
What are key treatments for managing asthma?
Inhaled corticosteroids
Beta-agonists for acute relief
Leukotriene receptor antagonists
Avoiding triggers.
What is the primary storage site for calcium within the cell?
The endoplasmic reticulum (ER) and mitochondria.
Which cellular mechanisms maintain low cytosolic calcium levels?
Calcium pumps (ATPases) actively transport calcium out of the cytosol into the ER, mitochondria, or extracellular space, and calcium channels regulate its flow across cell membranes.
Name two major causes of increased intracellular calcium.
Ischemia (reduced blood flow) or hypoxia (low oxygen levels) and cellular damage due to toxins or trauma.
What are the three main types of enzymes activated by increased intracellular calcium that cause cell damage?
Proteases, phospholipases, and endonucleases.
How does increased intracellular calcium lead to mitochondrial damage?
It causes the loss of mitochondrial membrane potential, disrupts ATP production, and leads to the release of cytochrome c, triggering apoptosis.
What role does calcium play in oxidative stress?
Elevated calcium can enhance the generation of reactive oxygen species (ROS), causing oxidative damage to lipids, proteins, and DNA.
What are the two main types of cell death caused by increased intracellular calcium?
Necrosis (unregulated cell death) and apoptosis (programmed cell death).
How does increased intracellular calcium contribute to reperfusion injury?
Sudden increases in calcium after restoring blood flow lead to ROS generation and enzyme activation, causing further cell damage.
Which clinical conditions often involve disrupted calcium homeostasis and subsequent cell damage?
Myocardial infarction, stroke, traumatic brain injury, and neurodegenerative diseases.
What is the difference between necrosis and apoptosis in terms of calcium’s role?
In necrosis, unregulated calcium influx causes cell swelling and membrane rupture; in apoptosis, calcium triggers mitochondrial damage and programmed cell death pathways.
What does affinity mean in the context of receptor-ligand interactions?
Affinity refers to the strength with which a ligand (such as a drug or agonist) binds to its receptor. Higher affinity means stronger binding and often lower concentrations needed to achieve an effect.
What is an agonist?
An agonist is a substance that binds to a receptor and activates it to produce a biological response.
What is a G-protein-coupled receptor (GPCR)?
A GPCR is a cell surface receptor that, when activated by an agonist, interacts with G-proteins to trigger intracellular signaling pathways.
How does activation of the 5-HT1B receptor lead to intracellular signaling?
Activation of the 5-HT1B receptor, a GPCR, triggers the exchange of GDP for GTP on the G-protein, initiating downstream signaling cascades.
What does the Km (Michaelis constant) represent in pharmacology?
Km represents the concentration of a ligand needed to achieve half of the maximum receptor activity. A lower Km indicates a higher affinity of the ligand for the receptor.
What is the significance of a lower Km for a drug’s action?
A lower Km means that the drug has a higher affinity for the receptor, requiring a lower concentration to achieve half-maximal activation.
What does Vmax (Maximum Reaction Rate) represent in the context of receptor-ligand interactions?
Vmax is the maximum rate of a reaction when the receptor is fully saturated with a ligand. It reflects the total receptor concentration and the intrinsic activity of the receptor-ligand complex.
Does a higher affinity agonist always result in a higher Vmax?
No, Vmax depends on the total number of receptors and their intrinsic activity, not directly on the ligand’s affinity.
How can understanding Km and Vmax help in clinical pharmacology?
Knowing Km and Vmax helps predict how drugs will behave in the body, determine dosing, understand therapeutic effects, and anticipate potential side effects.
What type of receptor is the 5-HT1B receptor, and what is its physiological role?
The 5-HT1B receptor is a serotonin GPCR involved in neurotransmission, affecting mood, vasoconstriction, and other physiological functions.
What are porphyrias?
Porphyrias are metabolic disorders caused by enzyme deficiencies in the heme biosynthesis pathway, leading to the accumulation of porphyrins or their precursors and resulting in clinical symptoms such as photosensitivity or neurovisceral symptoms.
What are the two main types of porphyrias?
The two main types are:
* Acute porphyrias (neurovisceral symptoms)
* Cutaneous porphyrias (photosensitivity and skin lesions).
What enzyme deficiency causes Acute Intermittent Porphyria (AIP)?
Porphobilinogen deaminase.
What are the clinical features of Acute Intermittent Porphyria (AIP)?
- Severe abdominal pain
- Neuropsychiatric disturbances (e.g., anxiety, depression, psychosis)
- Peripheral neuropathy.
(Patients do not have photosensitivity)
Which laboratory findings are characteristic of Acute Intermittent Porphyria (AIP)?
Increased levels of porphobilinogen and δ-aminolevulinic acid (ALA) in the urine.
What enzyme deficiency causes Porphyria Cutanea Tarda (PCT)?
Uroporphyrinogen decarboxylase.
What are the clinical features of Porphyria Cutanea Tarda (PCT)?
- Photosensitivity
- Blistering skin lesions on sun-exposed areas
- Hyperpigmentation
- Increased skin fragility.
P hotosensitivity
🌞 expousured blistering
R ise of skin fragility
P igmenttation
Which laboratory findings are characteristic of Porphyria Cutanea Tarda (PCT)?
Elevated levels of uroporphyrin in the urine.
What enzyme deficiency causes Hereditary Coproporphyria (HCP)?
Coproporphyrinogen oxidase.
What are common triggers for Porphyria Cutanea Tarda (PCT)?
- Alcohol consumption
- Hepatitis C infection
- Estrogen use
What are the clinical features of Hereditary Coproporphyria (HCP)?
- Neurovisceral symptoms (similar to AIP)
- Cutaneous photosensitivity.
Which laboratory findings are characteristic of Hereditary Coproporphyria (HCP)?
Increased levels of coproporphyrin in urine and feces
What enzyme deficiency causes Erythropoietic Protoporphyria (EPP)?
Ferrochelatase
What are the clinical features of Erythropoietic Protoporphyria (EPP)?
- Photosensitivity with non-blistering
- Painful erythema
- Swelling after sun exposure
Which laboratory findings are characteristic of Erythropoietic Protoporphyria (EPP)?
Elevated levels of protoporphyrin in erythrocytes, plasma, and feces.
How are cutaneous porphyrias managed?
- Avoiding sun exposure
- Using sunscreens
- Hydroxychloroquine or
- Phlebotomy to reduce porphyrin levels
How are acute porphyrias managed?
- Avoiding triggers (e.g., certain drugs, alcohol, fasting)
- Providing glucose to suppress heme synthesis
- Hemin infusions to inhibit ALA synthase.
What is the significance of urine color changes in diagnosing porphyrias?
- Pink/red urine (“tea colored”): PCT (⬆︎uroporphyrin)
- Dark urine (“Port-wine colored”): AIP (⬆︎porphobilinogen)
How does lead poisoning affect heme synthesis?
Inhibits:
* Ferrochelatase
* δ-aminolevulinic acid dehydratase (ALA dehydratase),
⬆︎ ALA and protoporphyrin
= Anemia and Neurological symptoms.
What is the purpose of hemin infusions in acute porphyrias?
Provides a negative feedback mechanism to inhibit ALA synthase.
⬇︎ production of toxic porphyrin precursors.
What distinguishes cutaneous porphyrias from acute porphyrias in terms of clinical presentation?
- Cutaneous porphyrias - photosensitivity and skin lesions.
- Acute porphyrias - neurovisceral symptoms (e.g., abdominal pain, psychiatric symptoms, and neuropathy).
What is the role of genetic testing in the diagnosis of porphyrias?
Genetic testing can confirm specific enzyme deficiencies and help identify asymptomatic carriers or individuals at risk for developing symptoms.
A 32-year-old woman presents to the emergency department with severe abdominal pain, confusion, and weakness in her extremities. Her symptoms started a few days after a crash diet and increased alcohol intake. Physical examination reveals mild tachycardia, but no skin lesions or rashes. Laboratory tests show increased levels of porphobilinogen in her urine. Which of the following enzymes is most likely deficient in this patient?
(A) Uroporphyrinogen decarboxylase
(B) Porphobilinogen deaminase
(C) Coproporphyrinogen oxidase
(D) Ferrochelatase
(E) δ-Aminolevulinic acid synthase
(B) Porphobilinogen deaminase
This deficiency causes Acute Intermittent Porphyria (AIP), characterized by severe abdominal pain, neurological symptoms, and increased porphobilinogen levels without photosensitivity.
A 45-year-old man with a history of hepatitis C infection presents with blistering lesions on his hands and forearms, which appear after sun exposure. He has noticed increased skin fragility and hyperpigmentation over the last several months. His urine is reddish in color and shows increased uroporphyrin levels on spectrophotometric analysis. Which of the following is the most likely diagnosis?
(A) Acute Intermittent Porphyria
(B) Hereditary Coproporphyria
(C) Porphyria Cutanea Tarda
(D) Erythropoietic Protoporphyria
(E) Lead poisoning
(C) Porphyria Cutanea Tarda
Porphyria Cutanea Tarda (PCT) is associated with photosensitivity, blistering skin lesions, and increased uroporphyrin in urine, often triggered by hepatitis C, alcohol, or estrogen.
A 5-year-old boy is brought to the pediatrician by his parents due to recurrent episodes of painful, burning erythema on his face and hands after brief sun exposure. He has no blisters, but his skin becomes red and swollen. Laboratory studies reveal increased protoporphyrin levels in erythrocytes. Which of the following is the most likely underlying enzyme deficiency?
(A) Porphobilinogen deaminase
(B) Uroporphyrinogen decarboxylase
(C) Coproporphyrinogen oxidase
(D) Ferrochelatase
(E) δ-Aminolevulinic acid dehydrase
(D) Ferrochelatase
Deficiency in ferrochelatase causes Erythropoietic Protoporphyria (EPP), presenting with painful erythema and swelling after sun exposure and increased protoporphyrin levels in erythrocytes.
A 28-year-old woman presents with recurrent episodes of severe abdominal pain, anxiety, and muscle weakness. Her symptoms worsen with stress and during her menstrual periods. Her urine darkens when left standing. Laboratory tests show elevated δ-aminolevulinic acid (ALA) and porphobilinogen. Which of the following triggers is most likely to precipitate her condition?
(A) Sun exposure
(B) Phlebotomy
(C) Carbohydrate loading
(D) Barbiturate use
(E) Hydroxychloroquine use
(D) Barbiturate use
Barbiturates can induce cytochrome P450 enzymes, increasing heme demand and triggering acute attacks in Acute Intermittent Porphyria (AIP) patients.
A 40-year-old male presents with fatigue, weight loss, and abdominal pain. Physical examination reveals a pale complexion and mild hepatomegaly. Blood tests show anemia, and his urine has an elevated level of coproporphyrin. A fecal porphyrin analysis also reveals elevated coproporphyrin levels. Which enzyme is most likely deficient in this patient?
(A) Uroporphyrinogen decarboxylase
(B) Porphobilinogen deaminase
(C) Ferrochelatase
(D) Coproporphyrinogen oxidase
(E) δ-Aminolevulinic acid synthase
(D) Coproporphyrinogen oxidase
Deficiency of coproporphyrinogen oxidase causes Hereditary Coproporphyria (HCP), which can present with both abdominal pain and increased levels of coproporphyrin in the urine and feces.
What enzyme converts glucose to sorbitol in the polyol pathway?
Aldose reductase converts glucose to sorbitol in the polyol pathway.
Why is sorbitol accumulation harmful in diabetic patients?
Sorbitol is osmotically active and poorly permeable to cell membranes, leading to
* osmotic stress
* oxidative damage
in tissues, such as the lens of the eye, nerves, and kidneys.
What diabetic complication is associated with sorbitol accumulation in the lens of the eye?
Cataracts are associated with sorbitol accumulation in the lens, leading to lens opacity and vision changes.
How does the polyol pathway contribute to oxidative stress in diabetes?
The polyol pathway depletes NADPH, which is necessary for regenerating reduced glutathione, an important antioxidant. This increases susceptibility to oxidative damage.
What is the role of aldose reductase inhibitors in diabetes management?
Aldose reductase inhibitors aim to reduce sorbitol accumulation and prevent complications like neuropathy and cataracts, but their clinical use is limited.
Which tissues are most affected by sorbitol accumulation due to hyperglycemia?
Tissues with insulin-independent glucose uptake:
* lens of the eye
* nerves
* kidneys
.
What are the four major mechanisms of tissue damage in diabetes?
The four major mechanisms are:
* Polyol pathway flux
* Advanced glycation end products (AGEs) formation
* Protein kinase C (PKC) activation
* Hexosamine pathway flux
What is the significance of protein kinase C (PKC) activation in diabetes?
- Increase vascular permeability
- Promote inflammation
- Enhance the production of extracellular matrix (ECM) proteins
- Reduce nitric oxide (NO) production
Leading to endothelial dysfunction.
Contributes to:
* Retinopathy
* Nephropathy
* Atherosclerosis
How does hyperglycemia affect the hexosamine pathway in diabetes?
- Production of UDP-N-acetylglucosamine (UDP-GlcNAc) that modify proteins involved to signaling, transcription and metabolism
- Impairming insulin signaling
- Altering gene expression involved in inflammation and fibrosis
- Insulin resistance
- Vascular and tissue damage leading to cardiovascular disease and nephropathy
What is the relationship between NADPH depletion and diabetic complications?
Polyol pathway deplet NADPH ⇢ ⬇︎availability of NADPH to regenerate reduced glutathione (GSH) (antioxidant) ⇢ ⬆︎oxidative stress, contributing to complications such as neuropathy and cataracts.
How does the polyol pathway specifically contribute to diabetic neuropathy?
Sorbitol accumulation in nerves:
* osmotic stress
* oxidative stress
Why is cataract formation more common in diabetic patients?
Diabetic patients have elevated blood glucose levels, which increases sorbitol production by aldose reductase in the lens, leading to osmotic stress and lens opacity (cataracts).
What is the role of hexokinase in normal glucose metabolism, and how is it different from aldose reductase?
Hexokinase converts glucose to glucose-6-phosphate in glycolysis; it has a low Km (high affinity for glucose) and functions efficiently at normal glucose levels, whereas aldose reductase is primarily active in hyperglycemic states.
Which pathway becomes more active in hyperglycemia and leads to the formation of fructose from glucose?
The polyol pathway becomes more active, converting glucose to sorbitol (via aldose reductase) and then to fructose (via sorbitol dehydrogenase).
A 58-year-old woman with a 15-year history of poorly controlled type 2 diabetes mellitus presents with blurry vision that has progressively worsened over the past year. She reports difficulty reading and increased glare while driving at night. Fundoscopic examination reveals lens opacities. Which of the following best explains the pathophysiological mechanism behind her symptoms?
(A) Increased production of advanced glycation end products (AGEs) in the lens
(B) Oxidative damage due to elevated sorbitol levels
(C) Retinal microaneurysms and hemorrhages due to microvascular damage
(D) Activation of protein kinase C leading to increased vascular permeability
(E) Increased hexosamine pathway activity causing glycosylation of lens proteins
Answer: (B) Oxidative damage due to elevated sorbitol levels
In diabetic cataracts, hyperglycemia leads to excess glucose conversion to sorbitol by aldose reductase. Sorbitol accumulation causes osmotic and oxidative stress, resulting in lens opacities.
A 46-year-old man with uncontrolled type 1 diabetes mellitus presents to the clinic with numbness and tingling in his feet, particularly noticeable at night. His symptoms have progressively worsened over the past six months. Physical examination reveals decreased sensation to light touch and pinprick in a stocking-glove distribution. Which enzyme’s activity is most directly responsible for this patient’s neurological symptoms?
(A) Sorbitol dehydrogenase
(B) Aldose reductase
(C) Hexokinase
(D) Protein kinase C
(E) Glucose-6-phosphatase
Answer: (B) Aldose reductase
Aldose reductase converts glucose to sorbitol in hyperglycemic states. Sorbitol accumulation in peripheral nerves causes osmotic stress and contributes to diabetic neuropathy, presenting with numbness and tingling.
A 50-year-old male with long-standing poorly controlled diabetes is found to have proteinuria and decreased renal function. His nephrologist suspects diabetic nephropathy. Which of the following mechanisms involving aldose reductase contributes to the development of this patient’s renal complication?
(A) Increased production of advanced glycation end products (AGEs)
(B) Sorbitol accumulation causing osmotic stress in renal cells
(C) Activation of protein kinase C leading to increased glomerular basement membrane thickness
(D) Increased diacylglycerol production stimulating mesangial cell proliferation
(E) Enhanced collagen cross-linking in the glomerulus
Answer: (B) Sorbitol accumulation causing osmotic stress in renal cells
Aldose reductase converts excess glucose to sorbitol in hyperglycemic conditions. Sorbitol accumulates in renal cells, causing osmotic damage and contributing to diabetic nephropathy.
A 65-year-old woman with type 2 diabetes mellitus reports worsening vision and recent cataract surgery in both eyes. She has been on metformin and insulin for several years, but her hemoglobin A1c remains elevated at 9.8%. Which of the following is a potential therapeutic target to prevent further vision complications in this patient?
(A) Inhibition of hexokinase
(B) Inhibition of aldose reductase
(C) Inhibition of insulin-like growth factor (IGF)
(D) Activation of sorbitol dehydrogenase
(E) Stimulation of protein kinase C
Answer: (B) Inhibition of aldose reductase
Aldose reductase inhibitors could prevent further sorbitol accumulation in the lens and reduce the risk of developing cataracts and other microvascular complications in diabetes.
A 72-year-old man with a history of type 2 diabetes presents with new-onset bilateral foot pain, described as burning and tingling. His blood glucose has been poorly controlled, with a recent HbA1c of 10.5%. Which of the following biochemical processes most likely contributes to his symptoms?
(A) Increased oxidative stress from sorbitol accumulation in Schwann cells
(B) Decreased glycolysis in peripheral nerves
(C) Enhanced production of advanced glycation end products in nerve axons
(D) Hyperglycemia-induced activation of hexokinase
(E) Reduced activation of sorbitol dehydrogenase in nerve cells
Answer: (A) Increased oxidative stress from sorbitol accumulation in Schwann cells
Sorbitol accumulation in Schwann cells due to aldose reductase activity causes osmotic and oxidative stress, leading to diabetic peripheral neuropathy.
What is the primary function of the p53 protein?
Transcription factor that regulates the expression of genes involved:
* Cell cycle arrest
* DNA repair
* Apoptosis
Prevent tumor development
Why is p53 often called the “guardian of the genome”?
Prevents the accumulation of mutations
by
* arresting the cell cycle
* promoting DNA repair
* inducing apoptosis
in response to cellular stress.
What type of mutation in the p53 gene is most commonly found in human cancers?
Acquired mutations that lead to loss of function of the p53 protein are the most common mutations in human cancers, occurring in more than 50% of all cases.
What is Li-Fraumeni syndrome?
Autosomal dominant familial cancer syndrome caused by a germline mutation in the p53 gene, resulting in a high risk of multiple cancers at a young age.
What cellular processes are activated by p53 in response to DNA damage?
- Cell cycle arrest (via p21)
- DNA repair (via GADD45)
- Apoptosis (via BAX, PUMA, NOXA)
How does p53 induce cell cycle arrest?
Upregulation of p21⇢ Inhibition of CDK ⇢ Inhibition of phosphorilation of Rb protein ⇢ inhibition of release of E2F
E2F is essential to entering into S phase
What role does MDM2 play in regulating p53?
Controlling p53 levels under normal condition:
MDM2 is an E3 ubiquitin ligase that binds to p53 and targets it for degradation via the ubiquitin-proteasome pathway
What are the consequences of a loss of function mutation in the p53 gene?
- Failure to regulate the cell cycle
- Impaired DNA repair
- Reduced apoptosis
Increased risk of tumor formation due to unchecked cell proliferation.
Which cellular stressors can activate p53?
- DNA damage (e.g., radiation, UV light)
- Oncogene activation (e.g., Ras, Myc)
- Hypoxia
- Telomere shortening
What is loss of heterozygosity (LOH) in the context of p53 mutations?
Loss of heterozygosity (LOH) occurs when one allele of the p53 gene is deleted and the other is mutated, resulting in a complete loss of p53 function in many tumors.
How does p53 contribute to apoptosis?
Upregulating pro-apoptotic genes like BAX, PUMA, and NOXA, which lead to mitochondrial membrane permeabilization and activation of the apoptotic cascade.
.
What is the clinical significance of p53 in cancer diagnosis and prognosis?
- Poor prognosis
- Guide therapeutic decisions, such as the use of specific chemotherapies or targeted therapies.
Which checkpoint does p53 primarily control in the cell cycle?
p53 primarily controls the G1/S checkpoint to prevent the replication of damaged DNA.
What is the role of p53 in preventing the formation of tumors?
p53 prevents tumor formation by ensuring that cells with damaged DNA do not proliferate, either by arresting the cell cycle for repair or by inducing apoptosis if the damage is irreparable.
A 35-year-old woman is diagnosed with breast cancer, and genetic testing reveals a germline mutation in the p53 gene. Her family history is significant for multiple cancers, including brain tumors, sarcomas, and adrenocortical carcinoma in first-degree relatives. Which of the following best explains the role of the p53 protein in preventing tumor formation?
(A) Activation of DNA repair enzymes that directly remove damaged bases
(B) Inhibition of BAX and PUMA to prevent apoptosis of damaged cells
(C) Induction of cell cycle arrest at the G1/S checkpoint to allow DNA repair
(D) Promotion of telomerase activity to prevent cellular senescence
(E) Inhibition of the retinoblastoma (Rb) protein to stop cell proliferation
Answer: (C) Induction of cell cycle arrest at the G1/S checkpoint to allow DNA repair
p53 induces cell cycle arrest at the G1/S checkpoint by upregulating p21, allowing time for DNA repair before replication proceeds. This mechanism prevents the proliferation of damaged cells, reducing the risk of tumor formation.
Question 2: A 45-year-old man is found to have a mutation in one allele of the p53 gene and a deletion in the other allele, leading to a complete loss of p53 function in his tumor cells. Which of the following cellular processes is most likely disrupted as a result of these genetic changes?
(A) Increased synthesis of cyclin D and progression through the G2/M checkpoint
(B) Impaired induction of p21, resulting in uncontrolled progression through the G1/S checkpoint
(C) Enhanced repair of DNA double-strand breaks by homologous recombination
(D) Suppression of MDM2-mediated degradation of p53 protein
(E) Activation of caspases leading to increased apoptosis
Answer: (B) Impaired induction of p21, resulting in uncontrolled progression through the G1/S checkpoint
Loss of p53 function leads to a failure to induce p21, which is critical for inhibiting CDKs and halting cell cycle progression at the G1/S checkpoint. Without p21, cells with damaged DNA continue to divide, contributing to tumorigenesis.
Question 3: A 50-year-old patient with a history of Li-Fraumeni syndrome presents with a new diagnosis of osteosarcoma. Analysis of the tumor cells shows upregulation of MDM2 protein expression. What is the most likely consequence of increased MDM2 levels in this patient’s tumor?
(A) Increased stabilization of p53 and enhanced tumor suppression
(B) Enhanced degradation of p53, leading to reduced transcription of pro-apoptotic genes
(C) Activation of the Bcl-2 pathway and inhibition of apoptosis
(D) Direct inhibition of p21, allowing unchecked cell cycle progression
(E) Increased repair of DNA damage and prevention of cell cycle arrest
Answer: (B) Enhanced degradation of p53, leading to reduced transcription of pro-apoptotic genes
MDM2 is a negative regulator of p53; increased MDM2 expression promotes ubiquitin-mediated degradation of p53, reducing its levels and impairing its ability to activate pro-apoptotic genes.
Question 4: A researcher studying a tumor sample from a patient with colon cancer discovers that one allele of the p53 gene has been deleted, while the other allele has a point mutation that prevents p53 from binding DNA. Which of the following gene products is most likely to be decreased as a direct consequence of this mutation?
(A) MDM2
(B) Bcl-2
(C) p21 (CDKN1A)
(D) Cyclin D1
(E) Cyclin E
Answer: (C) p21 (CDKN1A)
p21 is a direct target of p53 and is crucial for cell cycle arrest in response to DNA damage. A mutation in p53 that prevents it from binding DNA would result in decreased p21 expression.
Question 5: A 60-year-old woman with a history of smoking presents with a lung mass that is found to have a p53 mutation. This mutation prevents the activation of apoptosis in response to DNA damage. Which of the following best describes the mechanism by which p53 normally promotes apoptosis?
(A) Direct activation of caspases in the apoptotic pathway
(B) Upregulation of pro-apoptotic genes like BAX and PUMA, leading to mitochondrial membrane permeabilization
(C) Inhibition of the anti-apoptotic gene Bcl-2 through direct binding
(D) Recruitment of death receptors on the cell membrane to induce extrinsic apoptosis
(E) Activation of telomerase to promote cellular senescence and apoptosis
Answer: (B) Upregulation of pro-apoptotic genes like BAX and PUMA, leading to mitochondrial membrane permeabilization
p53 promotes apoptosis by upregulating pro-apoptotic genes such as BAX and PUMA, which increase mitochondrial membrane permeability, leading to the release of cytochrome c and activation of the intrinsic apoptotic pathway.
Which HLA subtype is associated with ankylosing spondylitis?
HLA-B27
Name the HLA subtypes associated with celiac disease.
HLA-DQ2
HLA-DQ8
What HLA subtype is linked to type 1 diabetes mellitus?
HLA-DR3
HLA-DR4
Which HLA subtype is associated with multiple sclerosis?
HLA-DR2
Which HLA subtype is linked to psoriatic arthritis?
HLA-B27
Which HLA subtype increases the risk for Graves’ disease and Hashimoto’s thyroiditis?
HLA-DR3
What HLA subtype is associated with rheumatoid arthritis?
HLA-DR4
Which HLA subtype is associated with Goodpasture syndrome?
HLA-DR2
What HLA subtype is linked to pernicious anemia?
HLA-DR5
Which HLA subtype is associated with abacavir hypersensitivity in HIV patients?
HLA-B57
Which HLA subtype is associated with hemochromatosis?
HLA-A3
Which HLA subtype is associated with systemic lupus erythematosus (SLE)?
HLA-DR2
HLA-DR3
Which HLA subtype is linked to reactive arthritis (Reiter syndrome)?
HLA-B27
What HLA subtype is associated with primary biliary cholangitis?
HLA-DR3
Which HLA subtype is associated with carbamazepine-induced Stevens-Johnson syndrome?
HLA-B15
Which HLA subtype is associated with allopurinol hypersensitivity?
HLA-B58
What HLA subtype is associated with myasthenia gravis?
HLA-DR3
What is the primary mechanism of vancomycin resistance in Enterococcus faecium?
Resistance is due to the modification of the peptidoglycan precursor from D-Ala-D-Ala to D-Ala-D-Lac or D-Ala-D-Ser, reducing vancomycin binding.
Which genes are responsible for vancomycin resistance in Enterococcus species?
The van genes (e.g., vanA, vanB) encode proteins that alter the terminal amino acids in the cell wall precursors.
What is the role of vancomycin in bacterial cell wall synthesis?
Vancomycin binds to the D-Ala-D-Ala terminus of peptidoglycan precursors, preventing their incorporation into the cell wall and inhibiting cell wall synthesis.
How do β-lactamases confer antibiotic resistance?
β-lactamases hydrolyze the β-lactam ring of penicillins, cephalosporins, and other β-lactam antibiotics, rendering them inactive.
What mechanism of resistance is associated with fluoroquinolones?
Mutations in DNA gyrase or topoisomerase IV, reducing drug binding to these enzymes.
How do efflux pumps contribute to antibiotic resistance?
Efflux pumps actively transport antibiotics out of bacterial cells, decreasing intracellular drug concentration and efficacy.
Which mechanism allows bacteria to resist macrolides like erythromycin?
Methylation of 23S rRNA at the ribosome binding site prevents macrolides from binding effectively to the bacterial ribosome.
How do mutations in penicillin-binding proteins (PBPs) cause resistance?
Reduce their affinity for β-lactam antibiotics, as seen in methicillin-resistant Staphylococcus aureus (MRSA).
What is a key treatment option for vancomycin-resistant Enterococcus (VRE) infections?
Linezolid
Daptomycin
Tigecycline
Quinupristin/dalfopristin.
What role does genetic material (plasmids and transposons) play in antibiotic resistance?
Plasmids and transposons often carry resistance genes (e.g., van genes) that can be transferred between bacteria, spreading resistance.
What clinical setting is associated with a high risk of VRE infections?
Hospitalized patients, especially those with prolonged antibiotic use, are at high risk for VRE infections.
What infection control measures help prevent the spread of VRE in healthcare settings?
- Hand hygiene
- Contact precautions
- Antibiotic stewardship
Why is porin mutation an important resistance mechanism for some Gram-negative bacteria?
Porin mutations decrease the permeability of the bacterial outer membrane, reducing antibiotic uptake.
What is the primary effect of vancomycin resistance on bacterial cell wall synthesis?
Vancomycin resistance leads to continued peptidoglycan synthesis despite the presence of the antibiotic, maintaining cell wall integrity.
Why is it important to understand different mechanisms of antibiotic resistance?
- Selecting appropriate antibiotics
- Managing resistant infections effectively.
Question 1: A 72-year-old woman is admitted to the intensive care unit with sepsis secondary to a urinary tract infection caused by Enterococcus faecium. She is started on vancomycin, but her condition does not improve. Further testing confirms that the isolate is vancomycin-resistant. Which genetic alteration is most likely responsible for this resistance?
(A) Point mutation in the bacterial DNA gyrase gene
(B) Substitution of D-alanine with D-lactate in the peptidoglycan precursor
(C) Overproduction of efflux pumps
(D) Methylation of 23S ribosomal RNA
(E) Mutations in the penicillin-binding protein (PBP) gene
Answer: (B) Substitution of D-alanine with D-lactate in the peptidoglycan precursor
Vancomycin-resistant Enterococcus (VRE) resists vancomycin by substituting D-alanine with D-lactate or D-serine in its peptidoglycan precursor, which prevents vancomycin from binding effectively to the target
Question 2: A 58-year-old man develops hospital-acquired pneumonia after a long stay in the intensive care unit. The causative agent is identified as methicillin-resistant Staphylococcus aureus (MRSA). Which of the following resistance mechanisms does MRSA primarily use to resist the action of β-lactam antibiotics?
(A) Production of β-lactamase enzymes
(B) Methylation of the 23S ribosomal RNA
(C) Alteration of porin channels in the bacterial outer membrane
(D) Overexpression of efflux pumps
(E) Mutation in penicillin-binding proteins (PBPs)
Answer: (E) Mutation in penicillin-binding proteins (PBPs)
MRSA resists β-lactam antibiotics primarily through a mutation in the penicillin-binding proteins (PBPs), particularly PBP2a, which has a low affinity for β-lactams.
Question 3: A 67-year-old patient has been receiving broad-spectrum antibiotics for a prolonged period due to recurrent infections. He now presents with a new urinary tract infection, and cultures grow Enterococcus faecium resistant to vancomycin. Which gene is most likely responsible for this resistance mechanism?
(A) mecA gene
(B) vanA gene
(C) blaZ gene
(D) tetM gene
(E) gyrA gene
Answer: (B) vanA gene
The vanA gene is responsible for vancomycin resistance in Enterococcus faecium by encoding enzymes that alter the terminal D-Ala-D-Ala to D-Ala-D-Lac.
Question 4: A 45-year-old woman presents with severe cellulitis, and a tissue biopsy reveals an infection with vancomycin-resistant Enterococcus faecium (VRE). She is started on daptomycin. Which of the following best explains why daptomycin is effective in treating VRE infections?
(A) Daptomycin inhibits DNA synthesis by binding to DNA gyrase.
(B) Daptomycin depolarizes the bacterial cell membrane, causing rapid cell death.
(C) Daptomycin prevents protein synthesis by binding to the 50S ribosomal subunit.
(D) Daptomycin binds to and inhibits bacterial RNA polymerase.
(E) Daptomycin disrupts folate synthesis by inhibiting dihydropteroate synthase.
Answer: (B) Daptomycin depolarizes the bacterial cell membrane, causing rapid cell death.
Daptomycin works by binding to bacterial cell membranes and causing depolarization, which leads to the loss of membrane potential and cell death.
Question 5: A 60-year-old man with a history of cirrhosis develops spontaneous bacterial peritonitis. Cultures from ascitic fluid grow Enterococcus faecium resistant to vancomycin. Which of the following changes in the bacterial cell wall is most likely responsible for this resistance?
(A) Substitution of D-alanine with D-glutamate
(B) Substitution of D-alanine with D-serine or D-lactate
(C) Methylation of peptidoglycan precursors
(D) Increased synthesis of N-acetylmuramic acid
(E) Cross-linking of glycine residues in peptidoglycan
Answer: (B) Substitution of D-alanine with D-serine or D-lactate
VRE achieves resistance to vancomycin by substituting the terminal D-alanine in its peptidoglycan precursors with either D-serine or D-lactate, reducing vancomycin binding affinity.
What is Kartagener Syndrome?
A subtype of Primary Ciliary Dyskinesia (PCD) characterized by the triad of recurrent sinusitis, bronchiectasis, and situs inversus (e.g., dextrocardia).
What is the main cause of Primary Ciliary Dyskinesia (PCD)?
Genetic mutations that result in defective ciliary structure or function, leading to impaired mucociliary clearance.
Which genes are commonly mutated in PCD?
DNAI1 and DNAH5, which encode proteins crucial for ciliary function.
What are the classic clinical features of Kartagener Syndrome?
The triad of recurrent sinusitis, bronchiectasis, and situs inversus totalis (mirror image reversal of thoracic and abdominal organs).
Why does Kartagener Syndrome cause infertility?
Infertility in males is due to immotile or dysfunctional sperm (defective flagella). In females, impaired ciliary function in the fallopian tubes can reduce fertility or cause ectopic pregnancies.
What diagnostic tests are used to confirm Primary Ciliary Dyskinesia (PCD)?
- Nasal nitric oxide test (low levels)
- High-speed video microscopy (abnormal ciliary beat)
- Genetic testing
- Electron microscopy (revealing ciliary defects).
How does situs inversus manifest in Kartagener Syndrome?
Situs inversus refers to the mirror-image reversal of internal organs, such as the heart on the right side (dextrocardia) and abdominal organs reversed.
What is the main treatment strategy for Kartagener Syndrome?
- Airway clearance techniques (e.g., chest physiotherapy)
- Antibiotics for infections
- Supportive care (e.g., bronchodilators, management of hearing loss).
What are potential complications of Kartagener Syndrome?
- Chronic respiratory issues such as bronchiectasis
- Hearing loss from recurrent otitis media
- Potential fertility problems.
What is the role of cilia in the body, and how is it affected in PCD?
Cilia are hair-like structures that move mucus and fluids; in PCD, ciliary dysfunction leads to poor mucus clearance and recurrent infections.
Why do patients with PCD often have recurrent respiratory infections?
Defective ciliary function impairs mucociliary clearance, leading to mucus stasis and recurrent infections like sinusitis and bronchitis.
A 5-year-old boy presents with chronic cough, recurrent episodes of pneumonia, and otitis media. Physical examination reveals decreased breath sounds in the right lower lung field and crackles on auscultation. Imaging shows bronchiectasis, and an abdominal ultrasound reveals situs inversus. Which of the following is the most likely underlying cause of this patient’s condition?
(A) Defective chloride transport in epithelial cells
(B) Ciliary dysfunction due to dynein arm defects
(C) IgA deficiency
(D) Deficiency of the CFTR gene product
(E) Alpha-1 antitrypsin deficiency
Answer: (B) Ciliary dysfunction due to dynein arm defects
The patient’s symptoms (chronic cough, recurrent pneumonia, otitis media, bronchiectasis, and situs inversus) suggest Kartagener Syndrome, a subtype of Primary Ciliary Dyskinesia (PCD) caused by dynein arm defects.
A 25-year-old man with a history of recurrent sinusitis, chronic productive cough, and situs inversus totalis presents to the fertility clinic due to difficulty conceiving with his partner. A semen analysis shows a significantly reduced sperm motility. Which of the following is the most likely explanation for his findings?
(A) Genetic mutations leading to defective sperm head formation
(B) Defective chloride transport resulting in thickened secretions
(C) Absent or dysfunctional dynein arms in the sperm flagella
(D) Autoimmune destruction of spermatogenic cells
(E) Decreased testosterone production by Leydig cells
Answer: (C) Absent or dysfunctional dynein arms in the sperm flagella
Infertility in males with Kartagener Syndrome is due to defective ciliary function in the sperm flagella, leading to reduced sperm motility
A 12-year-old girl with recurrent upper respiratory tract infections, chronic sinusitis, and frequent episodes of otitis media is suspected of having primary ciliary dyskinesia (PCD). Which of the following diagnostic tests is most likely to confirm the diagnosis?
(A) Sweat chloride test
(B) Measurement of nasal nitric oxide levels
(C) Spirometry to assess lung function
(D) Serum immunoglobulin levels
(E) Erythrocyte sedimentation rate (ESR)
Answer: (B) Measurement of nasal nitric oxide levels
Low nasal nitric oxide levels are characteristic of PCD and are used as a diagnostic test to support the diagnosis.
A 4-year-old boy is brought to the clinic for evaluation of recurrent bronchitis and sinusitis since birth. Physical examination reveals dextrocardia. Given the suspected diagnosis, which of the following findings would most likely also be present?
(A) Elevated sweat chloride levels
(B) Presence of Kartagener Syndrome triad
(C) Elevated IgE levels and eosinophilia
(D) Positive tuberculin skin test
(E) Absence of beta-lactamase production
Answer: (B) Presence of Kartagener Syndrome triad
The patient’s presentation suggests Kartagener Syndrome, which includes the triad of recurrent sinusitis, bronchiectasis, and situs inversus.
A 30-year-old woman presents with a history of chronic cough, recurrent pneumonia, and difficulty becoming pregnant. Physical examination reveals crackles in the lung bases and situs inversus. What is the most likely underlying cause of her infertility?
(A) Blockage of fallopian tubes due to thick mucus secretions
(B) Defective ciliary motility in the fallopian tubes
(C) Autoimmune oophoritis leading to ovarian failure
(D) Polycystic ovarian syndrome with anovulation
(E) Cervical stenosis due to chronic infections
Answer: (B) Defective ciliary motility in the fallopian tubes
Infertility in females with Kartagener Syndrome is typically due to defective ciliary motility in the fallopian tubes, which affects the transport of the ovum.
What is the most common urea cycle disorder?
Ornithine Transcarbamylase (OTC) Deficiency.
How is OTC deficiency inherited?
X-linked recessive.
What enzyme is deficient in OTC deficiency, and what reaction does it catalyze?
Ornithine Transcarbamylase (OTC) catalyzes the conversion of carbamoyl phosphate and ornithine to citrulline in the urea cycle.
What are the characteristic laboratory findings in OTC deficiency?
- Elevated plasma ammonia
- Low blood urea nitrogen (BUN)
- Elevated orotic acid in urine
- Low or absent plasma citrulline.
Why is orotic acid elevated in OTC deficiency?
Due to excess carbamoyl phosphate being diverted into the pyrimidine synthesis pathway, leading to increased orotic acid production.
What are the main clinical features of OTC deficiency in neonates?
- Poor feeding
- Vomiting
- Lethargy
- Hypotonia (decreased muscle tone)
- Seizures
- Hyperammonemic encephalopathy.
What is the primary acute management strategy for hyperammonemia in OTC deficiency?
- Hemodialysis to rapidly reduce ammonia levels
- Ammonia scavenger drugs (e.g., sodium phenylacetate, sodium benzoate)
- Intravenous glucose and lipids to prevent catabolism.
What are the key components of long-term management in OTC deficiency?
- Low-protein diet
- Ammonia scavenger medications (e.g., sodium phenylbutyrate)
- Essential amino acid supplementation
- Consideration of liver transplantation in severe cases.
Which laboratory test differentiates OTC deficiency from other urea cycle disorders?
- Elevated orotic acid in urine
- Low or absent citrulline in plasma
Why is blood urea nitrogen (BUN) low in OTC deficiency?
Because urea synthesis is impaired due to the enzyme defect in the urea cycle.
What triggers the symptoms of late-onset OTC deficiency?
- High protein intake
- Illness
- Fasting
What is a mnemonic to remember the key features of OTC deficiency?
“OTC: Out of The Citrulline”
O: Orotic aciduria (elevated orotic acid in urine)
T: Toxic Ammonia (hyperammonemia)
C: Citrulline Low (low or absent plasma citrulline)
What is the role of L-arginine in managing OTC deficiency?
L-arginine provides substrates to enhance residual urea cycle function and helps promote the excretion of nitrogen.
Why is OTC deficiency more common in males?
Because it is an X-linked recessive disorder, and males have only one X chromosome, making them more likely to express the disease.
What is the primary biochemical hallmark of urea cycle disorders like OTC deficiency?
Hyperammonemia due to impaired conversion of ammonia to urea.
A 3-day-old male infant presents with lethargy, poor feeding, and vomiting. He has had a tonic-clonic seizure at home. Physical examination reveals jaundice, hypotonia, and tachypnea. Laboratory tests show plasma ammonia of 300 μmol/L (normal: 10-40 μmol/L), a blood urea nitrogen (BUN) of 1.5 mg/dL, and elevated orotic acid in the urine. Which of the following is the most likely diagnosis?
(A) Maple syrup urine disease
(B) Medium-chain acyl-CoA dehydrogenase deficiency (MCAD)
(C) Phenylketonuria (PKU)
(D) Ornithine transcarbamylase (OTC) deficiency
(E) Hereditary fructose intolerance
Answer: (D) Ornithine transcarbamylase (OTC) deficiency
The infant presents with symptoms of hyperammonemia, poor feeding, seizures, and elevated orotic acid, which is characteristic of OTC deficiency, a urea cycle disorder.
A 5-day-old male neonate presents with irritability, poor feeding, and a tonic-clonic seizure. The child is found to have hyperammonemia and elevated orotic acid levels in the urine. Which of the following findings would most likely be present in a genetic analysis of this patient?
(A) Autosomal recessive mutation in the PAH gene
(B) X-linked recessive mutation in the OTC gene
(C) Autosomal recessive mutation in the GALT gene
(D) Autosomal dominant mutation in the LDLR gene
(E) Mitochondrial inheritance mutation in the MTND1 gene
Answer: (B) X-linked recessive mutation in the OTC gene
OTC deficiency is inherited in an X-linked recessive pattern, making this the most likely genetic finding in a patient with hyperammonemia and elevated orotic acid.
A newborn boy is admitted to the neonatal intensive care unit for lethargy, vomiting, and seizures. Laboratory findings reveal a plasma ammonia concentration of 250 μmol/L, low blood urea nitrogen, and increased orotic acid in urine. Which of the following is the primary enzyme deficiency causing these findings?
(A) Carbamoyl phosphate synthetase I (CPS1)
(B) Ornithine transcarbamylase (OTC)
(C) Argininosuccinate synthetase (ASS)
(D) Arginase
(E) N-acetylglutamate synthase (NAGS)
Answer: (B) Ornithine transcarbamylase (OTC)
The elevated ammonia, low BUN, and increased orotic acid are specific for OTC deficiency, where the enzyme ornithine transcarbamylase is deficient.
A 2-year-old girl with a history of recurrent episodes of vomiting, irritability, and lethargy is brought to the emergency department. During a previous hospitalization, she was found to have hyperammonemia, low plasma citrulline levels, and elevated urinary orotic acid. Which of the following dietary modifications is most appropriate for managing her condition long-term?
(A) High-protein diet
(B) Low-fat diet
(C) Low-carbohydrate diet
(D) Low-protein diet
(E) Gluten-free diet
Answer: (D) Low-protein diet
A low-protein diet is essential in managing OTC deficiency to reduce the production of ammonia from the breakdown of dietary proteins
A 4-day-old male infant presents with lethargy, vomiting, poor feeding, and seizures. Laboratory studies reveal hyperammonemia, low blood urea nitrogen (BUN), and elevated orotic acid in the urine. Which of the following medications would most likely be used acutely to reduce the elevated ammonia levels?
(A) Sodium phenylbutyrate
(B) Metronidazole
(C) Glucagon
(D) Furosemide
(E) Aspirin
Answer: (A) Sodium phenylbutyrate
Sodium phenylbutyrate is an ammonia scavenger used to reduce elevated ammonia levels in urea cycle disorders, including OTC deficiency.
What is the difference between direct (conjugated) bilirubin and indirect (unconjugated) bilirubin?
Indirect bilirubin is lipid-soluble and transported bound to albumin; it is converted in the liver to direct bilirubin, which is water-soluble and excreted in bile.
Why is unconjugated bilirubin not excreted in urine?
Because it is lipid-soluble and bound to albumin, making it unable to pass through the kidneys.
Which type of bilirubin is elevated in posthepatic (obstructive) jaundice?
Conjugated (direct) bilirubin is elevated due to impaired excretion from bile duct obstruction.
What are common causes of posthepatic jaundice?
What enzyme deficiency causes unconjugated hyperbilirubinemia in Crigler-Najjar syndrome?
UDP-glucuronyl transferase deficiency.
What lab findings are characteristic of posthepatic jaundice?
Elevated conjugated bilirubin, elevated alkaline phosphatase (ALP), and mildly elevated AST and ALT.
Which imaging studies are useful for diagnosing the cause of posthepatic jaundice?
Ultrasound, MRCP (Magnetic Resonance Cholangiopancreatography), and ERCP (Endoscopic Retrograde Cholangiopancreatography).
Why do patients with posthepatic jaundice have dark urine and pale stools?
A: Dark urine is due to the excretion of conjugated bilirubin in the urine; pale stools result from the lack of bilirubin in the intestines.
What is the pathophysiology of primary sclerosing cholangitis (PSC)?
A: PSC is an autoimmune, inflammatory disease causing fibrosis and strictures of the bile ducts, leading to cholestasis.
Which autoimmune condition is characterized by the destruction of small intrahepatic bile ducts, causing cholestasis?
A: Primary Biliary Cholangitis (PBC).
What is a key sign of posthepatic jaundice on physical examination?
A: Scleral icterus (yellowing of the whites of the eyes) and generalized itching due to bile salt accumulation.
What condition involves a congenital absence or obstruction of the extrahepatic bile ducts in infants, leading to jaundice?
A: Biliary atresia.
Which parasitic infection can lead to biliary obstruction and posthepatic jaundice?
A: Clonorchiasis (caused by the liver fluke Clonorchis sinensis)
Q: What are common clinical symptoms of posthepatic jaundice?
A: Jaundice, pruritus (itching), dark urine, pale stools, and potentially abdominal pain.
How does cholangiocarcinoma cause posthepatic jaundice?
A: By obstructing the bile ducts, preventing bile from reaching the intestines.
What is Pompe disease?
.
A: A lysosomal storage disorder caused by a deficiency of the enzyme acid alpha-glucosidase (acid maltase), leading to glycogen accumulation in various tissues, especially cardiac and skeletal muscles
What enzyme is deficient in Pompe disease?
A: Acid alpha-glucosidase (acid maltase).
What is the inheritance pattern of Pompe disease?
A: Autosomal recessive.
What are the primary clinical features of infantile-onset Pompe disease?
- Hypotonia
- Generalized muscle weakness
- Cardiomegaly
- Hypertrophic cardiomyopathy
- Respiratory distress
- Feeding difficulties
- Failure to thrive.
How does late-onset Pompe disease typically present?
- Progressive muscle weakness (especially proximal muscles)
- Respiratory insufficiency
- Milder or no cardiac involvement.
What is the key diagnostic test for Pompe disease?
A: Enzyme assay showing low acid alpha-glucosidase activity in blood, skin fibroblasts, or muscle biopsy.
What genetic mutation is associated with Pompe disease?
A: Mutations in the GAA gene on chromosome 17.
What is the primary treatment for Pompe disease?
A: Enzyme Replacement Therapy (ERT) with alglucosidase alfa.
Why does Pompe disease cause cardiomegaly?
A: Due to glycogen accumulation in the cardiac muscle cells, leading to hypertrophic cardiomyopathy.
What are common findings on muscle biopsy in a patient with Pompe disease?
A: Vacuoles filled with glycogen in muscle tissue.
What is a mnemonic to remember the key features of Pompe disease?
“Pompe Trashes the Pump”
P: Progressive muscle weakness
O: Organomegaly (hepatomegaly, cardiomegaly)
M: Myopathy (skeletal muscle weakness)
P: Pulmonary issues (respiratory distress)
E: Exercise intolerance
E: Enlargement tongue
What is the typical prognosis of infantile-onset Pompe disease without treatment?
A: Poor prognosis, with death usually occurring within the first year of life due to cardiorespiratory failure
Which organ systems are primarily affected in Pompe disease?
A: Cardiac, skeletal, and smooth muscles
What role does genetic testing play in the diagnosis of Pompe disease?
A: Confirms mutations in the GAA gene and assists with genetic counseling for families.
How does enzyme replacement therapy (ERT) help in Pompe disease?
A: ERT provides a recombinant form of acid alpha-glucosidase, reducing glycogen accumulation, improving muscle function, and prolonging survival.
A 2-year-old girl presents with a history of delayed motor milestones and progressive muscle weakness. Her parents report that she has difficulty walking and breathing, and she has recently been diagnosed with hypertrophic cardiomyopathy. Genetic testing confirms a mutation in the GAA gene. Which of the following is the most appropriate long-term management strategy?
(A) High-protein diet
(B) Enzyme replacement therapy (ERT)
(C) Corticosteroids
(D) Regular blood transfusions
(E) Bone marrow transplantation
A 6-month-old male presents with progressive muscle weakness, difficulty feeding, and respiratory distress. On examination, he is hypotonic with a weak cry and an enlarged tongue. Chest X-ray reveals cardiomegaly. Which of the following enzyme deficiencies is most likely responsible for his symptoms?
(A) Glucose-6-phosphatase
(B) Acid alpha-glucosidase
(C) Hexosaminidase A
(D) Muscle phosphorylase
(E) Lysosomal beta-glucosidase
Answer: (B) Acid alpha-glucosidase
The patient presents with hypotonia, difficulty feeding, respiratory distress, and cardiomegaly, which are characteristic of Pompe disease. This condition is due to a deficiency of acid alpha-glucosidase, leading to glycogen accumulation in muscles
A 1-year-old boy with severe hypotonia and respiratory distress dies suddenly in the hospital. Autopsy reveals massive accumulation of glycogen in the lysosomes of cardiac and skeletal muscle cells. What is the most likely diagnosis?
(A) McArdle disease (Glycogen Storage Disease Type V)
(B) Von Gierke disease (Glycogen Storage Disease Type I)
(C) Pompe disease (Glycogen Storage Disease Type II)
(D) Cori disease (Glycogen Storage Disease Type III)
(E) Anderson disease (Glycogen Storage Disease Type IV)
Answer: (C) Pompe disease (Glycogen Storage Disease Type II)
The autopsy findings of glycogen accumulation in lysosomes of cardiac and skeletal muscle cells are classic for Pompe disease
A muscle biopsy from a 4-year-old boy with a history of progressive muscle weakness reveals vacuoles filled with glycogen in muscle cells. Which of the following laboratory tests would most likely confirm the diagnosis of Pompe disease?
(A) Serum creatine kinase (CK) level
(B) Enzyme assay for acid alpha-glucosidase activity
(C) Blood lactate levels
(D) Genetic testing for DMD gene mutations
(E) Serum alkaline phosphatase level
Answer: (B) Enzyme replacement therapy (ERT)
ERT with recombinant acid alpha-glucosidase is the main treatment for Pompe disease. It helps reduce glycogen accumulation, improve muscle function, and prolong survival.
A 10-month-old infant with Pompe disease is started on enzyme replacement therapy. Which of the following best describes the mechanism by which this therapy works?
(A) Inhibition of glycogen synthesis in the liver
(B) Replacement of deficient acid alpha-glucosidase to break down glycogen in lysosomes
(C) Increase in glucose uptake by skeletal muscles
(D) Enhancement of mitochondrial oxidative phosphorylation
(E) Prevention of oxidative damage to muscle cells
Answer: (B) Enzyme assay for acid alpha-glucosidase activity
Measuring acid alpha-glucosidase activity in blood, skin fibroblasts, or muscle biopsy is the key diagnostic test for confirming Pompe disease.
A 10-month-old infant with Pompe disease is started on enzyme replacement therapy. Which of the following best describes the mechanism by which this therapy works?
(A) Inhibition of glycogen synthesis in the liver
(B) Replacement of deficient acid alpha-glucosidase to break down glycogen in lysosomes
(C) Increase in glucose uptake by skeletal muscles
(D) Enhancement of mitochondrial oxidative phosphorylation
(E) Prevention of oxidative damage to muscle cells
Answer: (B) Replacement of deficient acid alpha-glucosidase to break down glycogen in lysosomes
Enzyme replacement therapy provides the deficient enzyme (acid alpha-glucosidase) to break down glycogen in lysosomes, reducing accumulation and improving symptoms.
What is the main role of glucokinase in the liver?
A: To convert glucose to glucose-6-phosphate after a meal, helping to regulate blood glucose levels by storing or using excess glucose.
Where is glucokinase primarily found?
A: In the liver and pancreatic beta cells
What is the significance of the high Km of glucokinase?
A: It indicates a low affinity for glucose, meaning glucokinase becomes active only when glucose concentrations are high, such as after a carbohydrate-rich meal.
Why is glucokinase not inhibited by glucose-6-phosphate?
A: To allow the liver to continuously take up and phosphorylate glucose even when glucose-6-phosphate levels are high.
How does the high Vmax of glucokinase benefit the liver?
A: It allows the liver to rapidly convert large amounts of glucose to glucose-6-phosphate, efficiently handling high glucose levels after a meal.
What is the primary function of hexokinase?
A: To convert glucose to glucose-6-phosphate in most tissues, providing a steady supply for energy production and biosynthesis.
What are the characteristics of hexokinase?
A: Low Km (high affinity for glucose), low Vmax, and inhibited by glucose-6-phosphate.
Why is hexokinase inhibited by glucose-6-phosphate?
A: To prevent excessive accumulation of glucose-6-phosphate in peripheral tissues, ensuring balance and efficient use of glucose.
How does glucokinase help regulate blood glucose levels after a meal?
A: By converting excess glucose to glucose-6-phosphate, which is then stored as glycogen or used in other metabolic pathways.
Why is glucokinase important in preventing hyperglycemia?
A: It allows the liver to take up large amounts of glucose from the blood after a meal, reducing blood glucose levels.
What is the role of glucokinase in pancreatic beta cells?
A: Acts as a glucose sensor to help regulate insulin secretion in response to blood glucose levels.
What is the main difference in glucose affinity between glucokinase and hexokinase?
A: Glucokinase has a low affinity for glucose (high Km), while hexokinase has a high affinity for glucose (low Km).
Why is glucokinase especially active after a carbohydrate-rich meal?
A: Because its high Km makes it more active at high glucose concentrations, allowing it to manage large amounts of glucose efficiently.
Which enzyme is responsible for glucose metabolism in most tissues, even at low glucose levels?
A: Hexokinase, due to its low Km (high affinity for glucose).
Mnemonic to remember glucokinase function:
A: “Glucokinase Goes for Glucose in Great amounts!”
A 30-year-old woman with type 2 diabetes is being treated with a medication that increases the liver’s ability to store glucose as glycogen after a meal. Which of the following enzymes is most likely to be upregulated by this medication?
(A) Hexokinase
(B) Glucokinase
(C) Pyruvate kinase
(D) Phosphofructokinase-1
(E) Glucose-6-phosphatase
Answer: (B) Glucokinase
Glucokinase is upregulated to increase glucose uptake and storage as glycogen in the liver after a meal, particularly in response to high glucose levels.
A researcher is studying the kinetic properties of an enzyme found in liver cells. This enzyme has a high Michaelis-Menten constant (Km) and is not inhibited by its product, glucose-6-phosphate. Which of the following enzymes is the researcher most likely studying?
(A) Hexokinase
(B) Glucokinase
(C) Pyruvate carboxylase
(D) Phosphorylase kinase
(E) Glycogen synthase
Answer: (B) Glucokinase
The enzyme described has a high Km (low affinity for glucose) and is not inhibited by glucose-6-phosphate, characteristics specific to glucokinase.
A 25-year-old male eats a large carbohydrate-rich meal. Which of the following enzymes in his liver will be most active to help lower his blood glucose levels?
(A) Hexokinase
(B) Glucokinase
(C) Lactate dehydrogenase
(D) Fructokinase
(E) Aldolase B
Answer: (B) Glucokinase
After a carbohydrate-rich meal, glucokinase in the liver becomes most active to phosphorylate and store excess glucose, lowering blood glucose levels.
A scientist observes that a particular enzyme is more active in the liver when blood glucose levels are elevated. This enzyme has a low affinity for glucose (high Km) and is not subject to feedback inhibition by glucose-6-phosphate. Which of the following describes the physiological role of this enzyme?
(A) Ensures constant glucose uptake by muscle cells
(B) Prevents excessive glycolysis in erythrocytes
(C) Promotes glycogen synthesis in the liver after a meal
(D) Inhibits gluconeogenesis during fasting
(E) Increases lipolysis in adipose tissue
Answer: (C) Promotes glycogen synthesis in the liver after a meal
The described enzyme is glucokinase, which is highly active in the liver after a meal to promote glycogen synthesis and reduce blood glucose.
A genetic mutation affecting an enzyme’s ability to phosphorylate glucose is studied. The enzyme has a high Km for glucose and is mainly found in the liver and pancreatic beta cells. Which of the following clinical conditions is most likely to result from this mutation?
(A) Hyperglycemia after meals
(B) Hypoglycemia during fasting
(C) Lactic acidosis
(D) Ketosis in a fed state
(E) Hyperlipidemia
Answer: (A) Hyperglycemia after meals
A mutation in glucokinase affects glucose uptake and phosphorylation in the liver and pancreatic beta cells, leading to postprandial hyperglycemia.
What is the genetic cause of Autosomal Dominant Polycystic Kidney Disease (ADPKD)?
Mutations in the PKD1 gene (on chromosome 16) or PKD2 gene (on chromosome 4).
What are the main clinical features of ADPKD?
- Hematuria
- Flank or back pain
- Hypertension
- Progressive renal insufficiency
- Enlarged kidneys with multiple cysts.
Which cardiovascular complication is commonly associated with ADPKD?
Berry aneurysm (saccular aneurysm) in the circle of Willis, which can lead to subarachnoid hemorrhage.
What are the common extrarenal manifestations of ADPKD?
Hepatic cysts, mitral valve prolapse, colonic diverticula, and pancreatic cysts
Which imaging modality is the first-line test for diagnosing ADPKD?
Ultrasound to detect multiple renal cysts.
What is the inheritance pattern of ADPKD?
Autosomal dominant.
How does ADPKD lead to chronic kidney disease?
Progressive cyst formation and enlargement cause kidney tissue destruction and loss of function, leading to chronic kidney disease and potentially end-stage renal disease (ESRD).
What management strategies are important for patients with ADPKD?
Blood pressure control (ACE inhibitors/ARBs), pain management, monitoring for aneurysms, and management of chronic kidney disease (e.g., dialysis, kidney transplantation).
Why is there an increased risk of urinary tract infections (UTIs) in ADPKD?
Cysts can become infected, leading to recurrent UTIs.
What is a key distinguishing feature between ADPKD and autosomal recessive polycystic kidney disease (ARPKD)?
ADPKD typically presents in adulthood with multiple large cysts and systemic manifestations, whereas ARPKD presents in infancy or early childhood with enlarged kidneys and hepatic fibrosis.
A 38-year-old man with a family history of kidney disease presents with headaches and high blood pressure. Physical examination reveals bilateral flank masses. An ultrasound shows multiple cysts in both kidneys. Which of the following is the most likely genetic defect in this patient?
(A) Mutation in the PKD1 gene on chromosome 16
(B) Mutation in the PKD2 gene on chromosome 5
(C) Mutation in the COL1A1 gene
(D) Mutation in the HNF1B gene
(E) Mutation in the TSC1 gene
Answer: (A) Mutation in the PKD1 gene on chromosome 16
Explanation:
ADPKD is most commonly caused by a mutation in the PKD1 gene on chromosome 16 (about 85% of cases). The PKD2 gene mutation on chromosome 4 accounts for 15% of cases. COL1A1 is associated with osteogenesis imperfecta, HNF1B with renal cysts and diabetes syndrome, and TSC1 with tuberous sclerosis.
A 50-year-old woman with a known history of ADPKD presents to the emergency department with a sudden, severe headache, nausea, and neck stiffness. Her blood pressure is 170/100 mm Hg. Which of the following is the most appropriate initial diagnostic test to evaluate her symptoms?
(A) Electroencephalogram (EEG)
(B) CT angiography of the head
(C) Chest X-ray
(D) Renal ultrasound
(E) Cardiac echocardiogram
Answer: (B) CT angiography of the head
Explanation:
The patient’s sudden severe headache and neck stiffness suggest a possible subarachnoid hemorrhage, which is a known complication of ADPKD due to the risk of Berry aneurysm rupture. CT angiography of the head is the most appropriate initial test to assess for an aneurysm or hemorrhage.
A 45-year-old man with ADPKD is being managed for hypertension. His blood pressure remains uncontrolled despite lifestyle modifications. Which class of medication is preferred for managing hypertension in patients with ADPKD?
(A) Beta-blockers
(B) Calcium channel blockers
(C) Angiotensin-converting enzyme inhibitors (ACE inhibitors)
(D) Diuretics
(E) Alpha-blockers
Answer: (C) Angiotensin-converting enzyme inhibitors (ACE inhibitors)
Explanation:
ACE inhibitors are preferred in managing hypertension in ADPKD patients because they reduce intraglomerular pressure and slow the progression of kidney disease by blocking the effects of angiotensin II, which is especially beneficial in maintaining kidney function.
A 35-year-old woman with ADPKD presents for a routine check-up. She is asymptomatic, but a recent ultrasound revealed multiple liver cysts. What is the most likely explanation for this finding?
(A) Hepatic metastasis
(B) Polycystic liver disease
(C) Hydatid cysts
(D) Hepatocellular carcinoma
(E) Liver abscess
Answer: (B) Polycystic liver disease
Explanation:
Polycystic liver disease is a common extrarenal manifestation of ADPKD, characterized by multiple liver cysts. This condition is generally asymptomatic and does not usually affect liver function.
A 52-year-old man with a diagnosis of ADPKD presents with worsening renal function. His GFR is steadily declining, and he is nearing end-stage renal disease (ESRD). Which of the following is the definitive treatment for ESRD in ADPKD?
(A) Dialysis
(B) Angioplasty
(C) Renal artery stenting
(D) Kidney transplantation
(E) Percutaneous nephrolithotomy
Answer: (D) Kidney transplantation
Explanation:
Kidney transplantation is the definitive treatment for end-stage renal disease (ESRD) in patients with ADPKD. While dialysis can be used as a bridge to transplantation, it is not a definitive cure. Other options (angioplasty, renal artery stenting, and nephrolithotomy) do not address the underlying kidney failure.
What is the most common enzyme deficiency in homocystinuria?
Cystathionine β-synthase (CBS) deficiency.
What are the primary clinical features of homocystinuria?
HOMOCYSTINuria
Homocyteine in urine
Ocular chages (lens dislocation downward and inward)
Marfanoid habitus (tall stature, arachnodactyly)
Osteoporosis
Cardiovascular issues (MI and stroke)
kYphosis
Skin hiperpigmentation
Thrombosis
INtellectual disability
Which test is commonly used to detect elevated homocysteine levels in homocystinuria?
HOMOCYSTINuria
Nitroprusside cyanide test.
What vitamins are used in the management of homocystinuria?
Vitamin B6 (pyridoxine), Vitamin B12 (cobalamin), and Folic acid.
What is the typical inheritance pattern of homocystinuria?
Autosomal recessive.
Which dietary modifications are recommended for patients with homocystinuria?
Low methionine diet with cysteine supplementation.
What differentiates homocystinuria from Marfan syndrome in terms of lens dislocation?
In homocystinuria, the lens dislocation is downward, while in Marfan syndrome, it is upward.
Why are patients with homocystinuria at an increased risk of thromboembolic events?
Elevated homocysteine levels cause endothelial damage and promote coagulation.
What is the role of Betaine in the treatment of homocystinuria?
Betaine acts as an alternative methyl donor to convert homocysteine to methionine.
How can a deficiency in methylenetetrahydrofolate reductase (MTHFR) present in homocystinuria?
It can lead to elevated homocysteine levels due to impaired remethylation of homocysteine to methionine.
Which glucose transporter is primarily responsible for glucose uptake in pancreatic β cells?
A: GLUT 2
What is the main function of GLUT 1 and where is it found?
A: Facilitates basal glucose uptake; found in most tissues, especially the brain and red blood cells (RBCs).
Which glucose transporter is insulin-dependent and found in muscle and adipose tissue?
A: GLUT 4.
How does GLUT 2 contribute to insulin secretion?
A: GLUT 2 allows glucose entry into pancreatic β cells; glucose metabolism raises ATP levels, leading to insulin release.
Where is GLUT 3 mainly located and what is its function?
A: Found primarily in neurons; ensures constant glucose supply to the brain.
Which glucose transporter is involved in fructose transport in the small intestine?
A: GLUT 5.
Which GLUT transporter has a low affinity but high capacity for glucose and is important in glucose sensing?
A: GLUT 2.
What happens to GLUT 4 in response to insulin?
A: GLUT 4 is translocated to the cell surface of muscle and adipose cells, facilitating glucose uptake.
What role does GLUT 1 play in red blood cells (RBCs)?
A: Ensures a continuous supply of glucose for energy, as RBCs rely exclusively on glycolysis.
Which glucose transporter is most important for glucose uptake after meals (postprandial)?
A: GLUT 4 in muscle and adipose tissue.
What does a rightward shift in the oxygen-hemoglobin dissociation curve indicate?
Decreased affinity of hemoglobin for oxygen, promoting oxygen release to tissues.
Which factors cause a rightward shift in the oxygen-hemoglobin dissociation curve?
- Increased 2,3-BPG
- Increased CO₂
- Decreased pH
- Increased temperature.
What does a leftward shift in the oxygen-hemoglobin dissociation curve indicate?
Increased affinity of hemoglobin for oxygen, promoting oxygen binding in the lungs.
Which factors cause a leftward shift in the oxygen-hemoglobin dissociation curve?
*Decreased 2,3-BPG
* Decreased CO₂
* Increased pH
* Decreased temperature.
How does 2,3-Bisphosphoglycerate (2,3-BPG) affect hemoglobin’s oxygen affinity?
2,3-BPG binds to deoxygenated hemoglobin, stabilizing the T state and decreasing oxygen affinity.
What is the Bohr effect?
The effect of pH and CO₂ on hemoglobin’s oxygen affinity; decreased pH and increased CO₂ cause a rightward shift in the curve.
How does carbon monoxide (CO) affect the oxygen-hemoglobin dissociation curve?
CO binds tightly to hemoglobin, forming carboxyhemoglobin, which increases oxygen affinity (leftward shift) but prevents oxygen release
What is the physiological significance of the sigmoidal shape of the oxygen-hemoglobin dissociation curve?
It reflects cooperative binding: hemoglobin’s affinity for oxygen increases as more oxygen molecules bind.
Why is a rightward shift in the oxygen-hemoglobin dissociation curve beneficial during exercise?
It promotes oxygen unloading to active tissues with high metabolic demand.
How does the oxygen-hemoglobin dissociation curve shift in response to high altitude?
Increased 2,3-BPG production causes a rightward shift, facilitating oxygen release to tissues.
A 25-year-old man is hiking at a high altitude where the oxygen concentration is low. Which of the following changes would most likely occur to facilitate oxygen delivery to his tissues?
(A) Decreased levels of 2,3-bisphosphoglycerate (2,3-BPG)
(B) Decreased temperature
(C) Increased levels of 2,3-bisphosphoglycerate (2,3-BPG)
(D) Increased pH
(E) Decreased partial pressure of carbon dioxide (pCO₂)
Answer: (C) Increased levels of 2,3-bisphosphoglycerate (2,3-BPG)
Explanation:
At high altitudes, the body compensates for lower oxygen availability by increasing 2,3-BPG levels, which shifts the oxygen-hemoglobin dissociation curve to the right, promoting oxygen release to tissues.
A 68-year-old woman with a history of chronic obstructive pulmonary disease (COPD) presents with shortness of breath. Her arterial blood gas shows a low pH and elevated pCO₂. How will her hemoglobin’s oxygen affinity most likely be affected?
(A) Decreased affinity due to rightward shift
(B) Increased affinity due to rightward shift
(C) Increased affinity due to leftward shift
(D) Unchanged affinity
(E) Decreased affinity due to leftward shift
Answer: (A) Decreased affinity due to rightward shift
Explanation:
A low pH and elevated pCO₂ cause a rightward shift in the oxygen-hemoglobin dissociation curve (Bohr effect), decreasing hemoglobin’s oxygen affinity and promoting oxygen release to tissues.
A 30-year-old woman with a history of carbon monoxide poisoning presents to the emergency room with dizziness and confusion. Her oxygen saturation is 100% on pulse oximetry, but she remains hypoxic. What is the effect of carbon monoxide on the oxygen-hemoglobin dissociation curve?
(A) Rightward shift with increased oxygen release
(B) Leftward shift with decreased oxygen release
(C) Rightward shift with decreased oxygen binding
(D) No effect on the dissociation curve
(E) Causes anemia without affecting the curve
Answer: (B) Leftward shift with decreased oxygen release
Explanation:
Carbon monoxide (CO) binds tightly to hemoglobin, forming carboxyhemoglobin, which increases hemoglobin’s affinity for oxygen (leftward shift) but prevents oxygen release to tissues, causing hypoxia.
A patient is brought to the emergency department after being found unconscious in a house fire. Which of the following best explains the oxygen-hemoglobin dissociation curve ?
(A) Increased oxygen binding, rightward shift
(B) Decreased oxygen binding, rightward shift
(C) Decreased oxygen release, leftward shift
(D) No change in the oxygen-hemoglobin curve
(E) Increased oxygen delivery to tissues
Answer: (C) Decreased oxygen release, leftward shift
Explanation:
In carbon monoxide poisoning, CO binds to hemoglobin, causing a leftward shift of the oxygen-hemoglobin dissociation curve, which increases oxygen binding but reduces oxygen release to tissues.
A 40-year-old man is undergoing surgery and is receiving mechanical ventilation. The ventilator is set to deliver 100% oxygen. What effect will this have on the oxygen-hemoglobin dissociation curve?
(A) Rightward shift due to increased pCO₂
(B) Rightward shift due to increased pH
(C) No significant change, as hemoglobin is fully saturated
(D) Leftward shift due to decreased pCO₂
(E) Leftward shift due to increased 2,3-BPG
Answer: (D) Leftward shift due to decreased pCO₂
Explanation:
Mechanical ventilation with 100% oxygen will lead to decreased pCO₂ and increased pH, causing a leftward shift in the oxygen-hemoglobin dissociation curve, which increases hemoglobin’s affinity for oxygen.
What is the primary function of the enzyme glucose-6-phosphate dehydrogenase (G6PD)?
To generate NADPH in the pentose phosphate pathway (PPP), protecting cells, especially red blood cells, from oxidative damage.
What are the characteristic findings on a peripheral blood smear in G6PD deficiency?
A: Presence of Heinz bodies (denatured hemoglobin) and bite cells (RBCs with pieces removed by splenic macrophages).
What are common triggers that can precipitate hemolysis in a patient with G6PD deficiency?
A: Infections, certain medications (e.g., sulfa drugs, antimalarials, NSAIDs), and foods like fava beans.
Why are males more commonly affected by G6PD deficiency?
A: Because G6PD deficiency is an X-linked recessive disorder; males have only one X chromosome, so one defective gene results in the condition.
What is the most definitive test for diagnosing G6PD deficiency?
Enzyme assay in red blood cells
(performed several weeks after a hemolytic episode).
Why is G6PD deficiency protective against malaria?
Creating an unfavorable environment for the malaria parasite within red blood cells, reducing its survival.
What clinical symptoms might a patient with G6PD deficiency exhibit during a hemolytic episode?
A: Fatigue, jaundice, dark urine, pallor, back pain, and splenomegaly.
What is the role of NADPH in red blood cells?
A: NADPH maintains glutathione in its reduced form, which detoxifies reactive oxygen species and protects RBCs from oxidative damage.
In which populations is G6PD deficiency most prevalent, and why?
A: Common in African, Mediterranean, Middle Eastern, and South Asian populations due to the selective advantage against malaria.
What is the recommended management for patients with G6PD deficiency?
A: Avoid triggers (oxidative stressors like certain drugs, foods) and provide supportive care (hydration, oxygen, transfusion if severe) during hemolytic episodes.
What is the primary role of parathyroid hormone (PTH)?
A: To regulate calcium and phosphate levels in the blood by acting on the bones, kidneys, and intestines.
How does PTH affect bone?
PTH increases bone resorption by stimulating osteoclast activity, indirectly leading to the release of calcium and phosphate into the bloodstream.
What effect does PTH have on the kidneys?
PTH increases calcium reabsorption in the distal convoluted tubules and decreases phosphate reabsorption in the proximal convoluted tubules.
How does PTH increase calcium absorption in the intestines?
A: PTH stimulates the production of 1,25-dihydroxyvitamin D (calcitriol) in the kidneys, which enhances calcium absorption in the intestines.
What is the effect of PTH on phosphate levels?
A: PTH reduces phosphate reabsorption in the kidneys, promoting phosphate excretion and preventing hyperphosphatemia.
How does serum calcium concentration affect PTH secretion?
A: High serum calcium levels inhibit PTH secretion, while low serum calcium levels stimulate PTH secretion.
What are the main symptoms of hyperparathyroidism?
“Stones, thrones, bones, groans, and psychiatric overtones”
- Renal stones (stones)
- Polyuria (thrones)
- Osteoporosis and pain (bones)
- Constipation (groans)
- Neuropsychiatric disturbances (psychiatric overtones)
What genetic disorders are commonly associated with hyperparathyroidism?
A: Multiple Endocrine Neoplasia (MEN) types 1 and 2A.
What enzyme does PTH stimulate in the kidneys to increase calcitriol production?
A: 1α-hydroxylase, which converts 25-hydroxyvitamin D to 1,25-dihydroxyvitamin D (calcitriol).
What are the consequences of hypoparathyroidism?
A: Hypocalcemia, tetany, and hyperphosphatemia.
What is the most common renal tumor in children?
A: Wilms tumor (Nephroblastoma).
At what age does Wilms tumor most commonly present?
A: Typically in children under 5 years old, with a peak incidence between ages 2-4.
Which genetic mutations are associated with Wilms tumor?
A: WT1 gene mutations/deletions on chromosome 11p13 and WT2 gene abnormalities on chromosome 11p15.
What are the clinical features of WAGR syndrome?
A: Wilms tumor, Aniridia, Genitourinary anomalies, and intellectual Retardation
Which chromosomal deletion is associated with WAGR syndrome?
A: Deletion on chromosome 11p13 affecting the WT1 and PAX6 genes.
What is the triad of Denys-Drash syndrome?
A: Wilms tumor, diffuse mesangial sclerosis (nephropathy), and gonadal dysgenesis.
What gene mutation is commonly associated with Denys-Drash syndrome?
WT1 gene mutation on chromosome 11p13.
What are the characteristic features of Beckwith-Wiedemann syndrome?
- Hemihyperplasia
- Macroglossia
- Macrosomia
- Omphalocele
- Increased risk of Wilms tumor.
Which genetic abnormality is most commonly associated with Beckwith-Wiedemann syndrome?
A: Abnormalities on chromosome 11p15.5, including paternal uniparental disomy (UPD), loss of imprinting, or mutations affecting IGF2 and H19 genes.
What is the recommended surveillance for children with Beckwith-Wiedemann syndrome?
A: Abdominal ultrasounds every 3 months until age 8 for Wilms tumor; alpha-fetoprotein (AFP) monitoring every 3 months until age 4 for hepatoblastoma.
What is the gross appearance of a Wilms tumor on imaging or pathology?
A: A large, solitary, well-circumscribed mass often with areas of hemorrhage, necrosis, or cystic degeneration.
Which histologic pattern is typical for Wilms tumor?
A: A triphasic pattern consisting of blastemal, stromal, and epithelial cell types.
What are the primary treatment options for Wilms tumor?
A: Surgery (nephrectomy), chemotherapy, and radiation therapy for advanced stages or unfavorable histology.
Which genetic syndrome associated with Wilms tumor also includes hemihyperplasia and macroglossia?
A: Beckwith-Wiedemann syndrome.
What is the role of the WT1 gene, and why is its mutation significant in Wilms tumor?
A: The WT1 gene is a tumor suppressor gene involved in kidney and gonadal development. Mutations or deletions lead to an increased risk of Wilms tumor.
How does the prognosis of Wilms tumor vary based on histology?
A: Favorable histology has a high cure rate (>90%), while unfavorable histology (anaplastic) has a poorer prognosis.
Which organ is the most common site of metastasis for Wilms tumor?
A: The lungs are the most common site of metastasis for Wilms tumor.
What is the function of the PAX6 gene, and how does its deletion contribute to WAGR syndrome?
A: The PAX6 gene is crucial for eye development. Its deletion results in aniridia (absence of the iris), a key feature of WAGR syndrome.
Why is prophylactic nephrectomy considered in patients with Denys-Drash syndrome?
A: Due to the high risk of developing bilateral Wilms tumor
How can you differentiate Wilms tumor from neuroblastoma on imaging?
A: Wilms tumor often presents as a unilateral renal mass that does not cross the midline, while neuroblastoma often arises from the adrenal gland and may cross the midline.
Which vitamin deficiency causes night blindness and xerophthalmia?
A: Vitamin A deficiency
What are the clinical manifestations of Vitamin D deficiency in children?
A: Rickets – characterized by bowed legs, rachitic rosary, and growth retardation.
Which vitamin deficiency is characterized by hemolytic anemia and neurological symptoms like ataxia and peripheral neuropathy?
A: Vitamin E deficiency.
What is the role of Vitamin K in the body?
A: Essential for the synthesis of clotting factors (II, VII, IX, X) and proteins C and S involved in coagulation.
What condition is caused by Vitamin K deficiency in newborns?
A: Hemorrhagic disease of the newborn (bleeding due to reduced clotting factor synthesis).
Which vitamin deficiency leads to pellagra, characterized by dermatitis, diarrhea, and dementia?
A: Niacin (Vitamin B3) deficiency.
What are the symptoms of Vitamin C deficiency?
Scurvy – characterized by poor wound healing, gum bleeding, petechiae, and corkscrew hairs.
Which vitamin deficiency is most commonly associated with Wernicke-Korsakoff syndrome?
A: Thiamine (Vitamin B1) deficiency.
Which vitamin deficiency is associated with megaloblastic anemia and neurological symptoms like peripheral neuropathy?
A: Vitamin B12 (cobalamin) deficiency.
Which vitamin deficiency can cause glossitis, cheilosis, and anemia?
A: Riboflavin (Vitamin B2) deficiency.
What is the clinical presentation of folate (Vitamin B9) deficiency?
A: Megaloblastic anemia and risk of neural tube defects in pregnancy.
What is a common cause of Vitamin D deficiency in adults, leading to bone pain and muscle weakness?
A: Osteomalacia.
Which vitamin deficiency causes increased bleeding time and easy bruising in adults?
A: Vitamin K deficiency.
Which vitamin deficiency is associated with sideroblastic anemia and peripheral neuropathy?
A: Pyridoxine (Vitamin B6) deficiency.
What causes beri-beri and what are its symptoms?
A: Thiamine (Vitamin B1) deficiency; symptoms include neuropathy, muscle weakness, cardiac failure, and edema.
What is the primary organelle affected in lysosomal storage disorders?
A: Lysosomes.
What is the underlying cause of lysosomal storage disorders?
A: Deficiency or dysfunction of specific lysosomal enzymes, leading to the accumulation of undegraded substrates.
Which enzyme is deficient in Tay-Sachs disease?
A: β-hexosaminidase A.
What are the classic features of Tay-Sachs disease?
- Developmental delay
- Seizures
- Cherry-red spot on the retina
- Progressive neurodegeneration.
Which enzyme is deficient in Gaucher disease?
A: Glucocerebrosidase.
What are the typical symptoms of Gaucher disease?
- Hepatosplenomegaly
- Bone pain
- Anemia
- Thrombocytopenia
- “Gaucher cells” (lipid-laden macrophages).
Which lysosomal storage disorder is associated with iduronate sulfatase deficiency?
A: Hunter syndrome (MPS II).
What are the key clinical features of Hunter syndrome (MPS II)?
- Coarse facial features
- Joint stiffness
- Hepatosplenomegaly
- Developmental delay.
Which lysosomal enzyme is deficient in Pompe disease?
A: Acid α-glucosidase (acid maltase).
What are the clinical manifestations of Pompe disease?
A: Cardiomegaly, muscle weakness (hypotonia), respiratory distress, and hepatomegaly.
Which lysosomal storage disorder is characterized by a deficiency in arylsulfatase A?
A: Metachromatic leukodystrophy.
What are the symptoms of Metachromatic leukodystrophy?
A: Progressive neurodegeneration, peripheral neuropathy, ataxia, and developmental regression.
Which disorder is associated with a deficiency in sphingomyelinase?
A: Niemann-Pick disease.
What are the characteristic features of Niemann-Pick disease?
A: Hepatosplenomegaly, cherry-red spot on the retina, progressive neurodegeneration, and “foam cells” (lipid-laden macrophages).
How is Hurler syndrome (MPS I) different from Hunter syndrome (MPS II)?
A: Hurler syndrome involves corneal clouding and is more severe, whereas Hunter syndrome does not have corneal clouding and is X-linked recessive.
What is the key diagnostic test for lysosomal storage disorders?
A: Enzyme activity assays in cultured fibroblasts or leukocytes.
What treatment is available for some lysosomal storage disorders, like Gaucher and Pompe diseases?
A: Enzyme replacement therapy (ERT).
Why are enzyme levels often elevated in the serum but deficient in cells in lysosomal storage disorders?
A: Due to defective transport or function of the enzymes within lysosomes, causing them to be released into the serum.
Which genetic pattern is most common among lysosomal storage disorders?
A: Autosomal recessive inheritance.
Which clinical finding is characteristic of Tay-Sachs disease but not of Niemann-Pick disease?
A: Absence of hepatosplenomegaly in Tay-Sachs disease.
A 6-month-old infant presents with progressive developmental delay, a cherry-red spot on fundoscopic examination, and no hepatosplenomegaly. Which enzyme is most likely deficient in this patient?
A. Glucocerebrosidase
B. Hexosaminidase A
C. Sphingomyelinase
D. Arylsulfatase A
Answer: B. Hexosaminidase A
Explanation: The child likely has Tay-Sachs disease, characterized by a deficiency of hexosaminidase A, leading to the accumulation of GM2 ganglioside. The absence of hepatosplenomegaly helps differentiate it from Niemann-Pick disease.
A 4-year-old boy presents with aggressive behavior, joint stiffness, and hearing loss. His urine shows elevated levels of heparan sulfate and dermatan sulfate. He does not have corneal clouding. What is the most likely diagnosis?
A. Hurler syndrome
B. Hunter syndrome
C. Tay-Sachs disease
D. Gaucher disease
Answer: B. Hunter syndrome
Explanation: Hunter syndrome (MPS II) presents with the accumulation of heparan sulfate and dermatan sulfate, but without corneal clouding. It is X-linked and often involves aggressive behavior.
A 3-month-old boy has hepatosplenomegaly, hypotonia, and cherry-red spots on his macula. A liver biopsy reveals lipid-laden macrophages. What enzyme is deficient in this patient?
A. Glucocerebrosidase
B. Hexosaminidase A
C. Sphingomyelinase
D. Arylsulfatase A
Answer: C. Sphingomyelinase
Explanation: This is Niemann-Pick disease, characterized by sphingomyelinase deficiency, leading to sphingomyelin accumulation. The presence of hepatosplenomegaly differentiates it from Tay-Sachs disease.
A 7-year-old boy presents with bone pain, hepatosplenomegaly, and pancytopenia. Examination of his bone marrow shows macrophages with a “crumpled tissue paper” appearance. What substrate is accumulating in this patient?
A. GM2 ganglioside
B. Glucocerebroside
C. Sphingomyelin
D. Cerebroside sulfate
Answer: B. Glucocerebroside
Explanation: This is Gaucher disease, caused by a deficiency of glucocerebrosidase, leading to the accumulation of glucocerebroside in macrophages, giving them the “crumpled tissue paper” appearance.
A 9-month-old infant with developmental delay, peripheral neuropathy, and optic atrophy is found to have galactocerebroside accumulation in his nervous system. What is the most likely diagnosis?
A. Krabbe disease
B. Metachromatic leukodystrophy
C. Niemann-Pick disease
D. Tay-Sachs disease
Answer: A. Krabbe disease
Explanation: Krabbe disease involves a deficiency of galactocerebrosidase, leading to galactocerebroside accumulation. It is characterized by peripheral neuropathy and optic atrophy.
A 4-year-old boy presents with hepatosplenomegaly, coarse facial features, corneal clouding, and developmental delay. Urine tests reveal elevated dermatan sulfate and heparan sulfate. What enzyme is deficient?
A. Arylsulfatase A
B. α-L-iduronidase
C. Glucocerebrosidase
D. Sphingomyelinase
Answer: B. α-L-iduronidase
Explanation: This is Hurler syndrome (MPS I), caused by a deficiency in α-L-iduronidase. It leads to the accumulation of dermatan sulfate and heparan sulfate, with characteristic facial features and corneal clouding
A newborn has coarse facial features, restricted joint movements, and high serum levels of lysosomal enzymes. What cellular process is defective in this disease?
A. Protein synthesis in ribosomes
B. Mannose-6-phosphate tagging in the Golgi apparatus
C. Lipid synthesis in smooth endoplasmic reticulum
D. Lysosomal acidification
Answer: B. Mannose-6-phosphate tagging in the Golgi apparatus
Explanation: This describes I-cell disease, where there is defective mannose-6-phosphate tagging, preventing lysosomal enzymes from reaching the lysosome, leading to their secretion into the serum.
A 5-year-old boy presents with angiokeratomas, peripheral neuropathy, and hypohidrosis. Later in life, he is at risk for renal failure and cardiovascular disease. What enzyme is deficient?
A. α-Galactosidase A
B. Glucocerebrosidase
C. Sphingomyelinase
D. Hexosaminidase A
Answer: A. α-Galactosidase A
Explanation: This is Fabry disease, an X-linked disorder caused by a deficiency of α-galactosidase A, leading to the accumulation of ceramide trihexoside
A patient with central and peripheral demyelination, ataxia, and dementia is found to have an accumulation of cerebroside sulfate. What is the enzyme deficiency in this patient?
A. Glucocerebrosidase
B. Arylsulfatase A
C. Galactocerebrosidase
D. Acid α-glucosidase
Answer: B. Arylsulfatase A
Explanation: This is metachromatic leukodystrophy, caused by a deficiency in arylsulfatase A, leading to the accumulation of cerebroside sulfate
A 2-month-old infant presents with cardiomegaly, hypotonia, and failure to thrive. A muscle biopsy shows glycogen accumulation in lysosomes. What enzyme is deficient?
A. Galactocerebrosidase
B. Hexosaminidase A
C. Acid α-glucosidase
D. Glucocerebrosidase
Answer: C. Acid α-glucosidase
Explanation: This is Pompe disease (Type II glycogen storage disease), characterized by a deficiency in acid α-glucosidase, leading to glycogen accumulation in lysosomes.
A 5-year-old patient with Hurler syndrome presents for a follow-up. Which of the following clinical findings is most likely present in this patient?
A. Angiokeratomas
B. Peripheral neuropathy
C. Corneal clouding
D. Cherry-red spot on macula
Answer: C. Corneal clouding
Explanation: Corneal clouding is a classic feature of Hurler syndrome, along with developmental delay and hepatosplenomegaly.
A newborn with I-cell disease has high levels of lysosomal enzymes in the serum. What is the most likely cause of this finding?
A. Overproduction of lysosomal enzymes
B. Defective enzyme targeting to the lysosome
C. Excessive lysosomal enzyme degradation
D. Inhibition of enzyme activity in the lysosome
Answer: B. Defective enzyme targeting to the lysosome
Explanation: In I-cell disease, defective mannose-6-phosphate tagging prevents enzymes from being directed to the lysosomes, leading to their secretion into the serum.
A 3-year-old child with Hunter syndrome has increased levels of heparan sulfate and dermatan sulfate in his urine. What inheritance pattern does this disorder follow?
A. Autosomal recessive
B. X-linked recessive
C. Autosomal dominant
D. Mitochondrial inheritance
Answer: B. X-linked recessive
Explanation: Hunter syndrome is an X-linked recessive disorder caused by a deficiency in iduronate-2-sulfatase.
A child presents with developmental delay, corneal clouding, and skeletal abnormalities. He is diagnosed with Hurler syndrome. Which enzyme is deficient?
A. Iduronate-2-sulfatase
B. α-L-iduronidase
C. Arylsulfatase A
D. Sphingomyelinase
Answer: B. α-L-iduronidase
Explanation: Hurler syndrome is caused by a deficiency in α-L-iduronidase, leading to the accumulation of glycosaminoglycans such as dermatan sulfate and heparan sulfate.
A 6-month-old child has progressive neurologic decline, hepatosplenomegaly, and a cherry-red spot on the macula. What lipid is accumulating in the patient’s cells?
A. Glucocerebroside
B. GM2 ganglioside
C. Sphingomyelin
D. Galactocerebroside
Answer: C. Sphingomyelin
Explanation: This is Niemann-Pick disease, characterized by the accumulation of sphingomyelin due to a deficiency in sphingomyelinase
HLA-B27
Ankylosing spondylitis
Reactive arthritis (Reiter’s syndrome)
Psoriatic arthritis
Inflammatory bowel disease (IBD)–associated arthritis
HLA-DR2:
Multiple sclerosis
Goodpasture syndrome
Systemic lupus erythematosus (SLE)
HLA-DR3:
Type 1 diabetes mellitus
Graves’ disease
Hashimoto thyroiditis
SLE
Addison’s disease
Pernicious anemia
HLA-DR4:
Rheumatoid arthritis
Type 1 diabetes mellitus
Addison’s disease
HLA-DR5:
Hashimoto thyroiditis
Pernicious anemia
HLA-DQ2/DQ8:
Celiac disease
HLA-B8:
Addison’s disease
Myasthenia gravis
Graves’ disease
HLA-C:
Psoriasis (especially HLA-Cw6)
What are the Glucogen-6-phosphatase deficiency signs and symptoms ?
Infancy onset
Severe hypoglycemia
Hepatomegaly
Lactic acidosis
Hyperuricemia
Which enzyme is deficient?
Infancy onset
Severe hypoglycemia
Hepatomegaly
Lactic acidosis
Hyperuricemia
Glucose-6-phosphatase
Infancy onset
Severe hypoglycemia
Hepatomegaly
Lactic acidosis
Hyperuricemia
What is the name of the disease?
Glycogen Storage Disease Type I (Von Gierke)
What are the Lysosomal α-1,4-glucosidase (acid maltase) deficiency signs and symptoms?
Cardiomegaly
Hypotonia
Exercise intolerance
Early death in severe form
Cardiomegaly
Hypotonia
Exercise intolerance
Early death in severe form
What enzyme is deficient?
Lysosomal α-1,4-glucosidase (acid maltase)
Cardiomegaly
Hypotonia
Exercise intolerance
Early death in severe form
What is the name of the disease?
Glycogen Storage Disease Type II (Pompe)
What are the Debranching enzyme (α-1,6-glucosidase) deficiency signs and symptoms?
Mild hypoglycemia
Hepatomegaly
Muscle Weakness
Gluconeogenesis intact
Mild hypoglycemia
Hepatomegaly
Muscle Weakness
Gluconeogenesis intact
What enzyme is deficient?
Debranching enzyme (α-1,6-glucosidase)
Mild hypoglycemia
Hepatomegaly
Muscle Weakness
Gluconeogenesis intact
What is the name of the disease?
Glycogen Storage Disease Type III (Cori)
What are the Branching enzyme (amylo-1,4-to-1,6 transglucosidase) deficiency signs and symptoms?
Hepatosplenomegaly
Cirrhosis
Failure to thrive
Muscule weakness
Hepatosplenomegaly
Cirrhosis
Failure to thrive
Muscule weakness
What enzyme is deficient and what is the name of the disease?
Branching enzyme (amylo-1,4-to-1,6 transglucosidase)
Glycogen Storage Disease Type IV (Andersen)
What are the Muscle glycogen phosphorylase deficiency signs and symptoms?
Childhood to adolescence
Muscle cramps
Myoglobinuria with exercise
Exercise intolerance
Childhood to adolescence
Muscle cramps
Myoglobinuria with exercise
Exercise intolerance
What enzyme is deficient and what is the name of the disease?
Muscle glycogen phosphorylase
Glycogen Storage Disease Type V (McArdle)
What are the Liver glycogen phosphorylase deficiency signs and symptoms?
Childhood
Mild hypoglicemia
Hepatomegaly
Growth retardation
Childhood
Mild hypoglicemia
Hepatomegaly
Growth retardation
What enzyme is deficient and what is the name of the disease?
Liver glycogen phosphorylase
Glycogen Storage Disease Type VI (Hers)
A 5-year-old girl presents with failure to thrive, developmental delay, and intermittent episodes of lactic acidosis. Blood tests reveal elevated levels of pyruvate, lactate, and alanine. Genetic testing confirms a deficiency in an enzyme that catalyzes the first step of gluconeogenesis. Which of the following is the most likely deficient enzyme in this patient?
A) Pyruvate dehydrogenase
B) PEP carboxykinase
C) Pyruvate carboxylase
D) Fructose 1,6-bisphosphatase
E) Glucose 6-phosphatase
Answer: C) Pyruvate carboxylase
Explanation: Pyruvate carboxylase catalyzes the first step in gluconeogenesis, converting pyruvate to oxaloacetate in the mitochondria. A deficiency in this enzyme leads to elevated levels of pyruvate, lactate, and alanine, as these substrates are diverted into other metabolic pathways, causing lactic acidosis and failure to thrive.
A 30-year-old man runs a marathon without proper carbohydrate loading and experiences fatigue halfway through the race. He had not eaten in 10 hours. During this fasting state, which of the following substances is most likely used by the liver as a substrate for gluconeogenesis?
A) Acetyl-CoA
B) Lactate
C) Even-chain fatty acids
D) Ketone bodies
E) Citrate
Answer: B) Lactate
Explanation: During fasting or prolonged exercise, lactate, derived from anaerobic metabolism in muscles and red blood cells, is used by the liver for gluconeogenesis. Acetyl-CoA and ketone bodies cannot be used directly for glucose production, while even-chain fatty acids are not gluconeogenic.
A 40-year-old man with type 1 diabetes has been taking insulin but has recently skipped several doses. His blood glucose levels are extremely high, and laboratory analysis shows elevated levels of fructose 2,6-bisphosphate. Which of the following best explains how insulin deficiency has affected the patient’s metabolism?
A) Decreased gluconeogenesis due to elevated PEP carboxykinase activity
B) Increased glycolysis due to elevated fructose 2,6-bisphosphate levels
C) Increased gluconeogenesis due to decreased phosphofructokinase-1 activity
D) Decreased glycolysis due to low fructose 2,6-bisphosphate levels
E) Increased glycogen synthesis due to activation of glycogen synthase
Answer: B) Increased glycolysis due to elevated fructose 2,6-bisphosphate levels
Explanation: Fructose 2,6-bisphosphate is a potent activator of phosphofructokinase-1 (PFK-1), which drives glycolysis. In insulin-deficient patients, fructose 2,6-bisphosphate levels can become dysregulated, leading to increased glycolysis despite hyperglycemia, worsening the metabolic disturbance.
A 3-month-old boy presents with hypotonia, hepatomegaly, and severe fasting hypoglycemia. A deficiency in which enzyme would most likely result in an inability to release free glucose from glucose-6-phosphate, leading to glycogen accumulation in the liver and fasting hypoglycemia?
A) Pyruvate carboxylase
B) Fructose 1,6-bisphosphatase
C) Phosphofructokinase
D) Glucose-6-phosphatase
E) Glycogen phosphorylase
Answer: D) Glucose-6-phosphatase
Explanation: Glucose-6-phosphatase is responsible for converting glucose-6-phosphate into free glucose, which can be released into the bloodstream. A deficiency in this enzyme, as seen in glycogen storage diseases like Von Gierke disease, leads to hypoglycemia and glycogen accumulation in the liver.
A patient is given a pharmacologic dose of glucagon to treat severe hypoglycemia. Which of the following changes in enzyme activity would you expect to see in the liver of this patient following glucagon administration?
A) Increased activity of PFK-1
B) Decreased activity of glucose-6-phosphatase
C) Increased activity of fructose 1,6-bisphosphatase
D) Decreased activity of PEP carboxykinase
E) Increased activity of acetyl-CoA carboxylase
Answer: C) Increased activity of fructose 1,6-bisphosphatase
Explanation: Glucagon promotes gluconeogenesis by increasing the activity of fructose 1,6-bisphosphatase, which is responsible for the conversion of fructose 1,6-bisphosphate to fructose 6-phosphate. This process favors glucose production during hypoglycemia.
A 22-year-old man is diagnosed with a rare metabolic disorder that impairs his ability to utilize odd-chain fatty acids for gluconeogenesis. Which intermediate in gluconeogenesis would most likely be reduced in this patient due to the impaired metabolism of odd-chain fatty acids?
A) Citrate
B) Oxaloacetate
C) Acetyl-CoA
D) Propionyl-CoA
E) Fumarate
Answer: D) Propionyl-CoA
Explanation: Odd-chain fatty acids are metabolized to propionyl-CoA, which can then enter gluconeogenesis. A defect in the metabolism of odd-chain fatty acids would reduce the availability of propionyl-CoA, impairing gluconeogenesis from these fatty acids.
A researcher is studying an allosteric enzyme that is involved in gluconeogenesis and found in the mitochondria. This enzyme is activated by high levels of acetyl-CoA and catalyzes the conversion of pyruvate to oxaloacetate. Which of the following metabolic conditions is most likely to increase the activity of this enzyme?
A) High levels of AMP
B) High levels of ATP
C) High levels of NADH
D) High levels of glucose
E) Low levels of acetyl-CoA
Answer: B) High levels of ATP
Explanation: Pyruvate carboxylase is activated by high levels of acetyl-CoA, which signals that the TCA cycle is inhibited due to abundant ATP. This pushes pyruvate into gluconeogenesis rather than into the TCA cycle for energy production, promoting glucose synthesis.
What is the first step of gluconeogenesis and which enzyme is responsible?
The first step of gluconeogenesis is the conversion of pyruvate to oxaloacetate, catalyzed by pyruvate carboxylase. This step requires ATP and biotin as a cofactor.
Front: What are the key molecules that can be used as substrates for gluconeogenesis?
Key substrates include:
Lactate
Alanine (via the alanine cycle)
Glycerol (from triglycerides)
Odd-chain fatty acids (converted to propionyl-CoA)
Some amino acids (glucogenic)
How does fructose 2,6-bisphosphate regulate glycolysis and gluconeogenesis?
High levels of fructose 2,6-bisphosphate activate phosphofructokinase-1 (PFK-1), promoting glycolysis.
Low levels of fructose 2,6-bisphosphate activate fructose 1,6-bisphosphatase, promoting gluconeogenesis.
Which enzyme is responsible for converting glucose-6-phosphate into free glucose during gluconeogenesis?
Glucose-6-phosphatase, found mainly in the liver and kidneys, is responsible for converting glucose-6-phosphate into glucose, which is released into the blood.
What is the role of acetyl-CoA in regulating pyruvate carboxylase?
Acetyl-CoA is an allosteric activator of pyruvate carboxylase, signaling high energy levels and promoting gluconeogenesis by converting pyruvate into oxaloacetate.
Which hormones regulate the levels of fructose 2,6-bisphosphate, and how do they affect metabolism?
Insulin increases the levels of fructose 2,6-bisphosphate, promoting glycolysis.
Glucagon decreases the levels of fructose 2,6-bisphosphate, promoting gluconeogenesis
Which metabolic pathways can pyruvate enter, and how is the choice regulated?
Back: Pyruvate can enter:
TCA cycle (via acetyl-CoA) to generate ATP.
Gluconeogenesis (via oxaloacetate) to synthesize glucose. The choice is regulated by the levels of acetyl-CoA and ATP. High ATP and acetyl-CoA promote gluconeogenesis.
Front: What are the consequences of a deficiency in pyruvate carboxylase?
Back: A deficiency in pyruvate carboxylase leads to the accumulation of pyruvate, which is converted into lactate and alanine, causing lactic acidosis and failure to thrive.
Front: How does biotin function in gluconeogenesis?
Back: Biotin is a cofactor for carboxylase enzymes, including pyruvate carboxylase, and is essential for adding CO₂ to pyruvate to form oxaloacetate in gluconeogenesis.
Front: Why can’t even-chain fatty acids contribute to gluconeogenesis?
Back: Even-chain fatty acids cannot contribute to gluconeogenesis because they are metabolized entirely into acetyl-CoA, which cannot be converted back into glucose. Only odd-chain fatty acids can contribute via propionyl-CoA.
What is the role of glycolysis in energy production?
Back: Glycolysis breaks down glucose (6 carbons) into 2 molecules of pyruvate (3 carbons), generating 2 net ATP and 2 NADH molecules per glucose molecule. It occurs in the cytoplasm of all cells.
What are the three irreversible steps in glycolysis?
Back:
Glucose → Glucose-6-Phosphate (Hexokinase/Glucokinase)
Fructose-6-Phosphate → Fructose-1,6-Bisphosphate (Phosphofructokinase-1)
Phosphoenolpyruvate → Pyruvate (Pyruvate Kinase)
What is the role of NADH in glycolysis?
Back: NADH is produced during glycolysis and carries electrons to the electron transport chain in mitochondria for ATP production in aerobic metabolism. In anaerobic conditions, NADH helps regenerate NAD⁺ by converting pyruvate into lactate.
How does phosphofructokinase-1 (PFK-1) regulate glycolysis?
Back: PFK-1 is the rate-limiting enzyme of glycolysis. It is activated by AMP and Fructose-2,6-Bisphosphate, and inhibited by ATP and Citrate (high-energy signals).
What is the role of fructose-2,6-bisphosphate in glycolysis?
Fructose-2,6-bisphosphate is a key regulator that activates PFK-1 (stimulating glycolysis) and inhibits fructose-1,6-bisphosphatase (inhibiting gluconeogenesis).
How do insulin and glucagon regulate glycolysis through PFK-2?
Insulin dephosphorylates PFK-2, increasing fructose-2,6-bisphosphate levels, activating glycolysis.
Glucagon phosphorylates PFK-2, reducing fructose-2,6-bisphosphate levels, favoring gluconeogenesis.
What is the difference between hexokinase and glucokinase in glycolysis?
Hexokinase: Found in most tissues, has low Km (high affinity for glucose), inhibited by glucose-6-phosphate.
Glucokinase: Found in liver/pancreas, high Km (low affinity, only active in high glucose), induced by insulin, inhibited by fructose-6-phosphate.
What is the clinical significance of pyruvate kinase deficiency?
Pyruvate kinase deficiency impairs glycolysis, especially in red blood cells, leading to hemolytic anemia, splenomegaly, and a range of severity based on enzyme activity.
What happens in lactic acidosis related to glycolysis?
Back: In low oxygen conditions, pyruvate is converted to lactate to regenerate NAD⁺, which is required for glycolysis. This increases lactate production, leading to lactic acidosis (e.g., in sepsis, bowel ischemia, exercise).
How much ATP is produced in glycolysis under aerobic vs. anaerobic conditions?
Back:
Aerobic: 30-32 ATP per glucose (with oxygen and mitochondria).
Anaerobic: 2 ATP per glucose (without oxygen or mitochondria, producing lactate).
What is the role of the alanine cycle in glucose metabolism?
Back: In the alanine cycle, muscles break down protein, producing alanine, which is sent to the liver for conversion into glucose via gluconeogenesis. Alanine inhibits pyruvate kinase, slowing glycolysis in the liver.
How does 2,3-Bisphosphoglycerate (2,3-BPG) influence oxygen delivery?
2,3-BPG, produced from glycolysis in red blood cells, binds to hemoglobin and helps release oxygen to tissues, especially during hypoxia (e.g., at high altitudes).
A 35-year-old man presents with muscle cramps during intense exercise. Blood work reveals an elevated lactate level and an increased NADH/NAD⁺ ratio. Which of the following processes is directly impaired in this patient due to the elevated NADH levels?
A) Gluconeogenesis
B) Glycolysis
C) TCA cycle
D) Electron transport chain
E) Beta-oxidation of fatty acids
Answer: C) TCA cycle
Explanation:
In intense exercise, the lack of oxygen and the increased NADH/NAD⁺ ratio inhibit the TCA cycle because NAD⁺ is needed to carry electrons. The buildup of NADH shifts metabolism toward lactate production to regenerate NAD⁺ and keep glycolysis running. This anaerobic condition impairs oxidative processes like the TCA cycle.
28-year-old woman with poorly controlled type 1 diabetes presents to the emergency department with confusion and hyperventilation. Labs show a blood pH of 7.2, bicarbonate of 12 mEq/L, and a markedly elevated anion gap. Which of the following metabolic pathways is most likely being upregulated in this patient to regenerate NAD⁺?
A) Conversion of pyruvate to acetyl-CoA
B) Conversion of pyruvate to oxaloacetate
C) Conversion of pyruvate to lactate
D) Conversion of pyruvate to alanine
E) Conversion of lactate to pyruvate
Answer: C) Conversion of pyruvate to lactate
Explanation:
In diabetic ketoacidosis, anaerobic conditions promote the conversion of pyruvate to lactate via lactate dehydrogenase. This allows for the regeneration of NAD⁺, enabling glycolysis to continue despite a lack of oxygen or mitochondrial function. This results in lactic acidosis.
A 10-year-old boy presents with hemolytic anemia and splenomegaly. Peripheral blood smear shows numerous deformed red blood cells. Genetic testing reveals a deficiency in pyruvate kinase. What is the primary cause of this patient’s red blood cell deformities?
A) Increased 2,3-BPG production
B) Impaired ATP production
C) Increased oxidative stress
D) Accumulation of pyruvate
E) Impaired NADH regeneration
Answer: B) Impaired ATP production
Explanation:
Pyruvate kinase deficiency results in decreased ATP production, which is essential for maintaining the shape and integrity of red blood cells. Without sufficient ATP, red blood cells become deformed and are destroyed in the spleen, leading to hemolysis and splenomegaly.
A researcher is studying the regulation of glycolysis in liver cells. In the presence of high insulin levels, which of the following would most likely be observed?
A) Increased fructose-2,6-bisphosphate levels
B) Increased activity of fructose-1,6-bisphosphatase
C) Decreased glycolysis rate
D) Increased glucagon receptor activation
E) Decreased activity of phosphofructokinase-1
Answer: A) Increased fructose-2,6-bisphosphate levels
Explanation:
Insulin promotes glycolysis by increasing the levels of fructose-2,6-bisphosphate, which activates phosphofructokinase-1 (PFK-1) and inhibits fructose-1,6-bisphosphatase. This shift favors glycolysis over gluconeogenesis in the liver.
A 24-year-old medical student is performing a high-intensity workout. As glycolysis ramps up in his skeletal muscles, the buildup of AMP levels leads to increased activation of which of the following enzymes?
A) Glucokinase
B) Pyruvate kinase
C) Phosphofructokinase-1
D) Hexokinase
E) Phosphofructokinase-2
Answer: C) Phosphofructokinase-1
Explanation:
During intense exercise, AMP levels increase, which activates phosphofructokinase-1 (PFK-1), the rate-limiting enzyme of glycolysis. This activation ensures that glycolysis proceeds quickly to meet the energy demands of the muscle.
A 40-year-old woman presents with fatigue and difficulty concentrating. Laboratory tests reveal hyperglycemia and a genetic mutation in the gene coding for glucokinase. Which of the following best explains her hyperglycemia?
A) Reduced insulin secretion from the pancreas
B) Increased gluconeogenesis in the liver
C) Increased glycolysis in peripheral tissues
D) Increased glycogen storage in the liver
E) Impaired fructose-1,6-bisphosphatase activity
Answer: A) Reduced insulin secretion from the pancreas
Explanation:
Glucokinase is found in the liver and pancreas and plays a key role in glucose sensing. A mutation in glucokinase reduces insulin secretion from the pancreas because it impairs the ability of pancreatic β-cells to sense elevated glucose levels and release insulin, leading to hyperglycemia.
A 5-year-old boy presents with developmental delay and severe fasting hypoglycemia. Genetic testing reveals a deficiency in phosphofructokinase-1 (PFK-1). Which of the following would most likely be decreased in this patient?
A) Glucose-6-phosphate levels
B) Fructose-2,6-bisphosphate levels
C) Pyruvate levels
D) Lactate levels
E) NADH levels
Answer: C) Pyruvate levels
Explanation:
PFK-1 is the rate-limiting enzyme in glycolysis. A deficiency in PFK-1 would result in decreased glycolytic flux, leading to reduced production of pyruvate, the end product of glycolysis.
A 32-year-old marathon runner presents with extreme fatigue and muscle cramps. Laboratory results reveal a low blood pH and elevated levels of lactate. Which of the following explains the primary mechanism of NAD⁺ regeneration in this patient during his exercise?
A) Conversion of pyruvate to oxaloacetate
B) Conversion of acetyl-CoA to citrate
C) Conversion of lactate to pyruvate
D) Conversion of pyruvate to lactate
E) Beta-oxidation of fatty acids
Answer: D) Conversion of pyruvate to lactate
Explanation:
In anaerobic conditions during intense exercise, pyruvate is converted to lactate via lactate dehydrogenase. This regenerates NAD⁺, allowing glycolysis to continue producing ATP even without oxygen.
A 45-year-old patient with metabolic syndrome is found to have elevated levels of fructose-2,6-bisphosphate. Which of the following is most likely contributing to this finding?
A) Decreased insulin levels
B) Increased glucagon levels
C) Decreased PFK-1 activity
D) Decreased gluconeogenesis
E) Increased fructose-1,6-bisphosphatase activity
Answer: D) Decreased gluconeogenesis
Explanation:
Fructose-2,6-bisphosphate promotes glycolysis by activating PFK-1 and inhibiting fructose-1,6-bisphosphatase, which reduces gluconeogenesis. In metabolic syndrome, high insulin levels elevate fructose-2,6-bisphosphate, favoring glycolysis and reducing gluconeogenesis.
Where does the electron transport chain (ETC) occur?
A: In the inner mitochondrial membrane.
What is the main purpose of the electron transport chain?
A: To generate ATP by transferring electrons from NADH and FADH₂ to oxygen.
What are the main electron carriers that feed into the ETC?
A: NADH and FADH₂, both generated from the TCA cycle, glycolysis, and β-oxidation of fatty acids.
What is the role of Complex I in the ETC, and what other name does it have?
A: Complex I, also known as NADH dehydrogenase, transfers electrons from NADH to coenzyme Q (ubiquinone), and pumps protons into the intermembrane space.
What is unique about Complex II, and what is its other name?
A: Complex II, also called succinate dehydrogenase, is part of both the TCA cycle and the ETC, and it transfers electrons from FADH₂ to coenzyme Q without pumping protons.
What is the function of coenzyme Q (ubiquinone) in the ETC?
A: Coenzyme Q transfers electrons from Complex I and Complex II to Complex III.
What is the role of Complex III in the ETC, and what is its other name? A: Complex III, also called cytochrome bc₁ complex, transfers electrons from coenzyme Q to cytochrome C and pumps protons into the intermembrane space
A: Complex III, also called cytochrome bc₁ complex, transfers electrons from coenzyme Q to cytochrome C and pumps protons into the intermembrane space
What is the function of cytochrome C in the ETC?
A: Cytochrome C shuttles electrons from Complex III to Complex IV.
What is the function of Complex IV, and what are its alternative names?
A: Complex IV, also called cytochrome a₃ or cytochrome c oxidase, transfers electrons to oxygen, forming water and pumping protons into the intermembrane space.
How is ATP synthesized in the ETC?
A: Protons flow back into the mitochondrial matrix through ATP synthase (Complex V), driving the production of ATP from ADP and inorganic phosphate.
What is the purpose of the malate-aspartate shuttle?
A: It transfers NADH from glycolysis (cytosol) into the mitochondria by converting oxaloacetate to malate, which crosses the mitochondrial membrane.
What is the purpose of the glycerol-3-phosphate shuttle?
A: It transfers electrons from NADH in the cytosol to FADH₂ in the mitochondria, which is less efficient than the malate-aspartate shuttle.
What happens when the ETC is uncoupled?
A: Proton gradient dissipation occurs without ATP generation, leading to heat production (e.g., via uncoupling proteins or 2,4-dinitrophenol).
What is the mechanism of action of rotenone?
A: Rotenone inhibits Complex I, preventing electron transfer from NADH to coenzyme Q.
How does cyanide inhibit the ETC?
A: Cyanide binds to the Fe³⁺ in Complex IV (cytochrome c oxidase), preventing electron transfer to oxygen and halting ATP production.
How does carbon monoxide affect the ETC?
A: Carbon monoxide binds to Fe²⁺ in Complex IV, preventing oxygen binding and disrupting electron transfer.
How many ATP are produced per NADH and FADH₂?
A: NADH yields approximately 2.5 ATP, and FADH₂ yields approximately 1.5 ATP.
What is antimycin A, and how does it affect the ETC?
A: Antimycin A inhibits Complex III, preventing electron transfer from coenzyme Q to cytochrome C.
What is the difference between substrate-level phosphorylation and oxidative phosphorylation?
A: Substrate-level phosphorylation directly generates ATP via an enzyme, while oxidative phosphorylation generates ATP through the proton gradient in the ETC.
What is the proton motive force in the ETC?
A: The proton motive force is the electrochemical gradient of protons across the inner mitochondrial membrane, driving ATP synthesis through ATP synthase.
A 45-year-old man presents to the emergency department with complaints of severe headaches, dizziness, and confusion. He works as a maintenance worker in an old building, and recent renovations involved using insecticides. Physical examination reveals tachycardia and hypertension. Laboratory studies show elevated lactate levels. Which of the following best explains the mechanism of his symptoms?
A. Inhibition of Complex I of the electron transport chain
B. Inhibition of Complex II of the electron transport chain
C. Inhibition of Complex III of the electron transport chain
D. Inhibition of ATP synthase (Complex V)
E. Uncoupling of oxidative phosphorylation
A. Inhibition of Complex I of the electron transport chain
Explanation:
The patient’s exposure to insecticides, his symptoms, and elevated lactate levels suggest rotenone poisoning, which is an inhibitor of Complex I of the ETC. Inhibition of Complex I prevents the transfer of electrons from NADH to coenzyme Q, disrupting ATP production and leading to increased anaerobic metabolism (lactic acidosis).
A researcher is studying a mitochondrial enzyme that participates in both the TCA cycle and the electron transport chain. The enzyme is responsible for transferring electrons from succinate to coenzyme Q via FADH₂. Which of the following best describes this enzyme?
A. NADH dehydrogenase
B. Cytochrome C oxidase
C. Succinate dehydrogenase
D. ATP synthase
E. Ubiquinone
C. Succinate dehydrogenase
Explanation:
Succinate dehydrogenase is the only enzyme that participates in both the TCA cycle (by converting succinate to fumarate) and the electron transport chain (as Complex II). It transfers electrons from FADH₂ to coenzyme Q (ubiquinone) in the ETC.
A 30-year-old woman is admitted to the hospital after accidentally ingesting a large amount of cyanide. She becomes tachypneic and develops confusion. Bright red venous blood is drawn from her, and she is treated with sodium nitrite. What is the primary mechanism by which cyanide affects oxidative phosphorylation?
A. Inhibition of Complex I, preventing electron transfer from NADH
B. Inhibition of Complex III, preventing electron transfer to cytochrome C
C. Inhibition of Complex IV, preventing electron transfer to oxygen
D. Uncoupling of proton gradient from ATP synthase
E. Inhibition of ATP synthase directly, preventing ATP formation
C. Inhibition of Complex IV, preventing electron transfer to oxygen
Explanation:
Cyanide binds to the Fe³⁺ in cytochrome a₃ (part of Complex IV), preventing electron transfer to oxygen. This halts oxidative phosphorylation, leading to cellular hypoxia despite adequate oxygen in the blood, which explains the bright red venous blood and confusion. Sodium nitrite works by generating methemoglobin, which binds cyanide and protects cytochrome a₃.
A 22-year-old male research assistant accidentally spills a chemical on his skin while working in a laboratory. The chemical, 2,4-dinitrophenol (DNP), is known to affect mitochondrial function. His skin becomes flushed, and he feels unusually warm. What is the mechanism by which DNP affects the electron transport chain?
A. Direct inhibition of Complex I, reducing ATP production
B. Uncoupling of the proton gradient, causing increased heat production
C. Inhibition of cytochrome C, preventing electron transfer to Complex IV
D. Direct inhibition of ATP synthase, preventing ATP formation
E. Disruption of the malate-aspartate shuttle, preventing NADH entry into the mitochondria
B. Uncoupling of the proton gradient, causing increased heat production
Explanation:
2,4-Dinitrophenol (DNP) is an uncoupling agent that causes protons to leak across the mitochondrial membrane without passing through ATP synthase. This disrupts ATP production and instead releases energy as heat, causing the patient’s feeling of warmth.
A 65-year-old man with a history of hypertension is receiving nitroprusside for hypertensive emergency. After several days of continuous infusion, he develops confusion, tachycardia, and a bright red venous blood sample is drawn. His lactate levels are elevated. Which of the following mechanisms best explains the toxicity observed in this patient?
A. Inhibition of cytochrome c oxidase in Complex IV
B. Inhibition of Complex I by rotenone
C. Direct inhibition of ATP synthase
D. Uncoupling of oxidative phosphorylation
E. Inhibition of Complex III by antimycin A
A. Inhibition of cytochrome c oxidase in Complex IV
Explanation:
Nitroprusside toxicity can cause cyanide poisoning, as it releases cyanide. Cyanide inhibits Complex IV (cytochrome c oxidase), leading to lactic acidosis, confusion, and bright red venous blood. This disrupts ATP production by preventing the transfer of electrons to oxygen.
A 28-year-old man presents with muscle pain and weakness after beginning statin therapy for hypercholesterolemia. His physician prescribes a supplement known to replenish a molecule reduced by statins. Which of the following molecules is involved in electron transport and is thought to be decreased by statin therapy, potentially causing muscle symptoms?
A. Cytochrome C
B. Ubiquinone (coenzyme Q)
C. ATP synthase
D. NADH dehydrogenase
E. FADH2
B. Ubiquinone (coenzyme Q)
Explanation:
Statins reduce cholesterol synthesis by inhibiting HMG-CoA reductase, which also lowers the levels of coenzyme Q (ubiquinone), an essential component of the electron transport chain. Reduced coenzyme Q may contribute to statin-induced myopathy, and patients often take supplements to alleviate symptoms.
A newborn is found to have higher levels of brown adipose tissue than normal. Brown adipose tissue contains a unique protein that causes a decrease in ATP production but increases heat generation. Which of the following proteins is responsible for this uncoupling of oxidative phosphorylation?
A. Ubiquinone
B. Thermogenin
C. Cytochrome C
D. Succinate dehydrogenase
E. NADH dehydrogenase
B. Thermogenin
Explanation:
Thermogenin (uncoupling protein 1, UCP-1) is found in brown adipose tissue. It uncouples oxidative phosphorylation by allowing protons to leak back into the mitochondrial matrix, generating heat instead of ATP. This is crucial in newborns and hibernating animals to maintain body temperature.
A medical student is studying the energy production from the electron transport chain. He learns that Complex V, also known as ATP synthase, plays a crucial role in ATP generation. Which of the following best describes the function of ATP synthase?
A. Converts NADH to ATP directly
B. Pumps protons into the intermembrane space
C. Uses the proton gradient to synthesize ATP
D. Transfers electrons from cytochrome C to oxygen
E. Transports NADH across the mitochondrial membrane
C. Uses the proton gradient to synthesize ATP
Explanation:
ATP synthase (Complex V) uses the proton gradient generated by the electron transport chain to synthesize ATP from ADP and inorganic phosphate. Protons flow down their concentration gradient through ATP synthase, which drives ATP production.
A 37-year-old patient takes an overdose of aspirin. He is febrile and tachycardic. The increased body temperature is due to the uncoupling of oxidative phosphorylation. Which of the following best describes the effect of uncoupling on the electron transport chain?
A. Inhibition of Complex IV, preventing electron transfer to oxygen
B. Dissipation of the proton gradient, generating heat instead of ATP
C. Direct inhibition of Complex III, blocking cytochrome C function
D. Inhibition of ATP synthase, preventing ATP generation
E. Prevention of NADH from entering the mitochondria
B. Dissipation of the proton gradient, generating heat instead of ATP
Explanation:
Aspirin overdose can uncouple oxidative phosphorylation, allowing protons to leak across the mitochondrial membrane. This dissipates the proton gradient, preventing ATP production and instead generating heat, leading to the patient’s fever.
A biochemist is studying the ATP yield from glucose oxidation in different tissues. He finds that some cells produce 30 ATP per glucose molecule while others produce 32 ATP. What accounts for this difference?
A. Use of malate-aspartate vs glycerol phosphate shuttle
B. Use of NADH vs FADH₂ for electron transport
C. Efficiency of Complex I vs Complex II in electron transfer
D. Number of ATP molecules produced in glycolysis
E. Differences in TCA cycle activity between tissues
A. Use of malate-aspartate vs glycerol phosphate shuttle
Explanation:
The difference in ATP yield (30 vs. 32 ATP per glucose molecule) depends on which shuttle system is used to transport NADH from glycolysis into the mitochondria. The malate-aspartate shuttle yields 32 ATP, while the glycerol phosphate shuttle yields 30 ATP due to the conversion of NADH to FADH₂, which generates fewer ATP.
What are the two main steps in ethanol metabolism?
Answer:
Ethanol is converted to acetaldehyde by alcohol dehydrogenase (ADH) in the cytosol.
Acetaldehyde is converted to acetate by aldehyde dehydrogenase (ALDH) in the mitochondria.
How does excessive ethanol consumption lead to hypoglycemia?
Answer: High NADH levels shunt oxaloacetate to malate, reducing its availability for gluconeogenesis, leading to hypoglycemia, especially in individuals with low glycogen stores.
Why does alcohol consumption lead to ketosis?
Answer: High NADH inhibits the TCA cycle, causing acetyl-CoA to be diverted into ketone body production, leading to ketosis.
What causes lactic acidosis in alcoholism?
Answer: High NADH levels inhibit pyruvate dehydrogenase, leading to the shunting of pyruvate to lactate, resulting in lactic acidosis.
How does ethanol metabolism contribute to fatty liver?
Answer: High NADH levels inhibit beta-oxidation and increase fatty acid synthesis, while glycerol-3-phosphate accumulates, leading to the formation of triglycerides and resulting in a fatty liver.
What is the role of the MEOS in ethanol metabolism?
Answer: The MEOS (microsomal ethanol-oxidizing system) metabolizes excess ethanol via a cytochrome P450 pathway, generating free radicals and depleting NADPH, contributing to liver damage.
How does disulfiram work in the treatment of alcoholism?
Answer: Disulfiram inhibits aldehyde dehydrogenase (ALDH), causing a buildup of acetaldehyde, leading to unpleasant symptoms (e.g., flushing, nausea) when alcohol is consumed.
How is methanol or ethylene glycol poisoning treated?
Answer: Fomepizole is used to inhibit alcohol dehydrogenase (ADH), preventing the formation of toxic metabolites such as formic acid (from methanol) and oxalate (from ethylene glycol).
What causes alcohol flushing syndrome and which population is more commonly affected?
Answer: Alcohol flushing syndrome is caused by a deficiency in aldehyde dehydrogenase (ALDH2), leading to the accumulation of acetaldehyde. It is more common in Asian populations.
A 42-year-old man consumes a large amount of alcohol at a party. A few hours later, he feels dizzy, weak, and develops nausea. Ethanol is metabolized to acetaldehyde, which is then further metabolized. Which of the following is the main consequence of increased NADH levels due to alcohol metabolism?
A) Increased gluconeogenesis
B) Increased pyruvate conversion to oxaloacetate
C) Inhibition of beta-oxidation
D) Increased activity of the TCA cycle
E) Increased glycogen synthesis
C) Inhibition of beta-oxidation
Explanation: Ethanol metabolism generates large amounts of NADH. High levels of NADH inhibit processes that require NAD+, including beta-oxidation of fatty acids. This leads to the accumulation of fatty acids and contributes to the development of fatty liver in chronic alcohol users.
A 50-year-old man with a history of alcoholism is prescribed disulfiram to help him quit drinking. He consumes alcohol after missing a few doses of his medication. Shortly afterward, he develops flushing, nausea, and palpitations. What is the mechanism of disulfiram in inducing these symptoms?
A) Inhibition of alcohol dehydrogenase
B) Inhibition of aldehyde dehydrogenase
C) Increased excretion of ethanol via the kidneys
D) Inhibition of the microsomal ethanol-oxidizing system (MEOS)
E) Increased ethanol metabolism
B) Inhibition of aldehyde dehydrogenase
Explanation: Disulfiram (Antabuse) inhibits aldehyde dehydrogenase, leading to the accumulation of acetaldehyde when alcohol is consumed. The buildup of acetaldehyde causes unpleasant symptoms such as flushing, nausea, and palpitations, which act as a deterrent to alcohol consumption.
A 35-year-old woman drinks large amounts of alcohol over the weekend but has not eaten for two days. She is brought to the emergency department in a confused state. Blood tests reveal hypoglycemia. Which of the following best explains why hypoglycemia occurs in this patient?
A) Increased glycogenolysis
B) Increased gluconeogenesis due to high NADH levels
C) Inhibition of gluconeogenesis due to oxaloacetate shunting to malate
D) Increased fatty acid oxidation
E) Increased insulin secretion due to alcohol metabolism
C) Inhibition of gluconeogenesis due to oxaloacetate shunting to malate
Explanation: High levels of NADH produced during alcohol metabolism shunt oxaloacetate to malate, reducing the availability of oxaloacetate for gluconeogenesis. As a result, gluconeogenesis is impaired, leading to hypoglycemia, especially when glycogen stores are depleted.
A 45-year-old homeless man is brought to the emergency department with vomiting, confusion, and dehydration after heavy alcohol consumption over several days. Laboratory results reveal elevated anion gap metabolic acidosis, increased serum ketones, and normal glucose levels. Which of the following mechanisms most likely explains his ketosis?
A) Increased gluconeogenesis
B) Increased conversion of acetate to acetyl-CoA
C) Inhibition of pyruvate dehydrogenase
D) Depletion of glycogen stores
E) Decreased beta-oxidation of fatty acids
B) Increased conversion of acetate to acetyl-CoA
Explanation: Ethanol metabolism produces acetate, which is converted into acetyl-CoA. When the TCA cycle is inhibited by high NADH levels, acetyl-CoA is shunted toward ketone body production, leading to ketoacidosis in chronic alcoholics.
A 40-year-old man with a long history of alcohol abuse presents to the hospital with severe nausea and abdominal pain. Laboratory results reveal a high anion gap metabolic acidosis and an elevated serum lactate. Which of the following best explains the development of lactic acidosis in chronic alcohol abuse?
A) Excessive acetaldehyde production
B) Decreased gluconeogenesis
C) Inhibition of pyruvate dehydrogenase by NADH
D) Excess production of ketones
E) Increased beta-oxidation of fatty acids
C) Inhibition of pyruvate dehydrogenase by NADH
Explanation: High NADH levels inhibit pyruvate dehydrogenase, preventing pyruvate from entering the TCA cycle. Instead, pyruvate is converted to lactate, leading to lactic acidosis, a common complication in chronic alcohol abuse.
A 55-year-old man with a history of chronic alcohol use presents with fatigue and an enlarged liver on physical examination. Liver biopsy reveals fatty infiltration. Which of the following mechanisms most likely contributes to fatty liver development in this patient?
A) Increased glycogen synthesis in the liver
B) Excess conversion of oxaloacetate to malate
C) Inhibition of alcohol dehydrogenase
D) Decreased fatty acid synthesis due to increased NADH
E) Increased glycerol-3-phosphate leading to triglyceride formation
E) Increased glycerol-3-phosphate leading to triglyceride formation
Explanation: In alcoholics, high levels of NADH inhibit beta-oxidation and promote fatty acid synthesis. Glycerol-3-phosphate accumulates because its metabolism is impaired, and it combines with fatty acids to form triglycerides, contributing to fatty liver.
A 30-year-old man of East Asian descent experiences facial flushing, nausea, and palpitations shortly after consuming a small amount of alcohol. Which of the following genetic enzyme deficiencies is most likely responsible for his symptoms?
A) Alcohol dehydrogenase
B) Acetyl-CoA carboxylase
C) Aldehyde dehydrogenase
D) Pyruvate dehydrogenase
E) Glucose-6-phosphate dehydrogenase
C) Aldehyde dehydrogenase
Explanation: Alcohol flushing syndrome is caused by a deficiency in aldehyde dehydrogenase (ALDH2), leading to the accumulation of acetaldehyde after alcohol consumption. This condition is more common in individuals of East Asian descent.
A 48-year-old man is brought to the emergency room after accidentally ingesting methanol. He is started on fomepizole. What is the mechanism of action of fomepizole in methanol poisoning?
A) Inhibits acetaldehyde dehydrogenase
B) Inhibits alcohol dehydrogenase
C) Stimulates gluconeogenesis
D) Increases NADPH production
E) Activates the TCA cycle
B) Inhibits alcohol dehydrogenase
Explanation: Fomepizole inhibits alcohol dehydrogenase, preventing the metabolism of methanol into toxic metabolites like formaldehyde and formic acid. This treatment reduces the formation of toxic byproducts that lead to methanol poisoning.
A chronic alcoholic presents to the hospital with symptoms of liver failure. In addition to the typical ethanol metabolism by alcohol dehydrogenase, which alternative pathway becomes more active with excessive alcohol consumption and contributes to liver damage?
A) Gluconeogenesis pathway
B) Beta-oxidation pathway
C) Microsomal ethanol-oxidizing system (MEOS)
D) Fatty acid synthesis pathway
E) Pentose phosphate pathway
C) Microsomal ethanol-oxidizing system (MEOS)
Explanation: The MEOS pathway, part of the cytochrome P450 system, becomes more active with excessive alcohol consumption. It generates free radicals and consumes NADPH, contributing to oxidative stress and liver damage, which can lead to hepatitis and cirrhosis in alcoholics.
A 58-year-old man presents with acute gouty arthritis in his big toe. He reports consuming excessive alcohol the night before. Elevated levels of lactic acid are found in his serum. Which of the following mechanisms best explains the development of hyperuricemia in this patient?
A) Alcohol increases uric acid production
B) Alcohol decreases lactic acid metabolism
C) High lactic acid competes with uric acid for excretion in the kidney
D) Alcohol enhances the reabsorption of uric acid
E) Alcohol inhibits uric acid synthesis
C) High lactic acid competes with uric acid for excretion in the kidney
Explanation: High levels of lactic acid in alcoholics compete with uric acid for excretion in the proximal tubule via the URAT1 transporter. This results in decreased uric acid excretion and hyperuricemia, which can trigger gout attacks, especially after excessive alcohol consumption.
Lead poisoning:
a) Affected enzymes
b) Accumulated Substrate
c) Signs and Symptoms
a) Ferrochelatase and ALA dehydratase
b) Protoporphirin and ALA (blood)
c) Mycrocytic anemia
peripheral smear: basophilic stippling
bone marrow: ringed sideroblasts
GI and kidney disease
Children: Mental deterioration
Adult: headache, memory loss, demyelination (peripheral neuropathy)
