UW4 glycogen storage diseases Flashcards
question
D.
This patient most likely has a herpes simplex virus (HSV) infection. HSV classically presents with multiple, painful genital ulcers with a characteristic erythematous base, dysuria (likely due to irritation of the ulcers), tender bilateral lymphadenopathy (common with primary genital HSV infection), and systemic symptoms (eg, fever, headache) in the setting of a new sexual partner.
The appearance of genital HSV lesions can vary and mimic other disease processes as the lesions change from vesicles to ulcers. Therefore, a suspected clinical diagnosis of genital HSV requires laboratory confirmation via PCR, viral culture (low sensitivity, particularly as lesions heal), direct fluorescence antibody testing, or Tzanck smear (showing multinucleated giant cells).
Question
B. Fluticasone
This patient’s autopsy findings of lung hyperinflation and bronchial inflammation are suggestive of uncontrolled asthma, a disease characterized by chronic airway inflammation, airway hyperresponsiveness, and intermittent bronchoconstriction. Chronic inflammation, composed mainly of eosinophils, helper T cells, and mast cells, causes airway remodeling (ie, bronchial wall thickening, increased smooth muscle), which further worsens airway obstruction and asthma symptoms.
Corticosteroids inhibit the production of inflammatory mediators (eg, cytokines, prostaglandins, leukotrienes), reduce leukocyte extravasation into the respiratory epithelium, and induce apoptosis of inflammatory cells. In addition, corticosteroids decrease smooth muscle proliferation and mucus production by goblet cells.
Systemic corticosteroids (eg, oral prednisone) are used in short courses to treat acute asthma exacerbations, whereas inhaled corticosteroids (eg, fluticasone) reduce the frequency and severity of exacerbations and are used for long-term asthma control in patients with persistent symptoms. Suppression of airway inflammation is evident within hours of administration but reaches maximal effect after several months of inhaled therapy. Nonadherence to long-term therapy can increase the risk of life-threatening asthma exacerbation.
Question
A. Decreased Cholecystokinin release due to lack of enteral stimulation
Cholesterol is secreted in bile, where it is solubilized by bile salts and phosphatidylcholine. If there is more cholesterol than can be dissolved by the bile salts, the cholesterol will precipitate into insoluble crystals, leading to the formation of gallstones. Risk factors for gallstone formation include obesity or rapid weight loss, female sex, glucose intolerance, and hypomotility of the gallbladder (eg, pregnancy, prolonged fasting).
A prolonged course of total parenteral nutrition (TPN) is often complicated by gallstones. In normal individuals, enteral passage of fat and amino acids into the duodenum triggers release of cholecystokinin (CCK), leading to contraction of the gallbladder. The absence of normal enteral stimulation in patients receiving TPN leads to decreased CCK release and subsequent biliary stasis. In addition, patients with extensive resection of the ileum can have disruption to the normal enterohepatic circulation of bile acids, leading to inadequate solubilization of biliary cholesterol and formation of cholesterol crystals.
A 62-year-old man comes to the office due to an intensely pruritic facial rash for the past 3 days. The patient uses no facial cosmetic products but has frequently dyed his hair during the past year; he last dyed his hair 5 days ago and also recalls developing a similar rash the previous time he used hair dye. The patient has a history of asthma, hypertension, and diabetes mellitus. He does not use tobacco, alcohol, or illicit drugs. Vital signs are within normal limits. Physical examination findings are shown in the exhibit. Which of the following are primarily involved in the pathogenesis of this patient’s rash?
CD8+ T cells and INF gamma
This patient developed erythema and pruritus on the scalp, face, and neck 2 days after reexposure to hair dye. Hair products, including dye, frequently contain allergenic molecules (eg, p-phenylenediamine) that can cause allergic contact dermatitis (ACD). ACD is a type IV hypersensitivity (delayed-type) reaction that occurs in 2 phases:
Sensitization: Cutaneous Langerhans cells take up haptens (small molecules that bind to proteins and alter their immune appearance) and present hapten-peptide complexes to naive CD4+ and CD8+ T cells in regional lymph nodes, resulting in clonal expansion of hapten-sensitive T cells. This phase takes 10-14 days and does not result in cutaneous lesions.
Elicitation: On reexposure to the hapten, sensitized T cells are recruited to skin for activation by hapten-protein conjugates displayed on cutaneous antigen-presenting cells. Activated CD8+ T cells, the main effector cells in ACD, release cytotoxins (eg, perforin, granzymes) and express Fas ligand to induce keratinocyte apoptosis. They also amplify the inflammatory response by releasing cytokines (eg, interferon gamma) and recruiting additional inflammatory cells (eg, macrophages). This phase occurs 2-3 days following reexposure to the hapten and results in erythema, pruritus, and vesicles.
Question
C. IL-4
There are 2 classes of CD4+ T-helper cells, Th1 cells and Th2 cells. Th1 cells contribute to cell-mediated adaptive immunity (targeting intracellular pathogens) and type IV (delayed-type) hypersensitivity reactions. On the other hand, Th2 cells play a prominent role in allergic response and type I hypersensitivity reactions.
One hypothesis for the pathogenesis of asthma is an excess of Th2 cell activity relative to Th1 cell activity, resulting in excessive IgE production, an abnormal propensity for type I hypersensitivity reactions, and associated chronic eosinophilic bronchitis. In the asthma sensitization phase, inhaled antigens stimulate Th2 cells to secrete IL-4 and other lymphokines to stimulate B-cell antibody production as part of humoral adaptive immunity. Th2 cells also release IL-13, which, together with IL-4, promotes B-cell immunoglobulin class switching to IgE and leads to mast cell priming.
Repeat exposure to inhaled antigens leads to mast cell degranulation of inflammatory substances (eg, histamine, leukotrienes) and further activation of eosinophils with release of tissue-damaging substances (eg, major basic protein).
(Choice D) IL-5 is secreted by activated Th2 cells and stimulates the growth and differentiation of eosinophils. However, IL-5 promotes the class switching of B-cell immunoglobulin synthesis to IgA rather than to IgE.
Question
A. Acid alpha glucosidase
This patient most likely has glycogen storage disease type II (Pompe disease). This condition is caused by deficiency of acid alpha-glucosidase (alpha-1,4 glucosidase or acid maltase), an enzyme responsible for breaking down glycogen within the acidic environment of lysosomes. Although most glycogen is degraded in the cytoplasm, a small percentage is inadvertently engulfed by lysosomes, especially in cells containing high amounts of glycogen such as hepatocytes and myocytes. Deficiency of acid maltase results in pathologic accumulation of glycogen within liver and muscle lysosomes. Cardiac and skeletal muscle are particularly susceptible because the ballooning lysosomes interfere with contractile function.
The classic form of the disease presents in early infancy with marked cardiomegaly, severe generalized hypotonia, macroglossia, and hepatomegaly. Blood glucose levels are normal, unlike with glycogen storage diseases that primarily affect the liver (eg, von Gierke disease). A key distinguishing feature is that muscle biopsy will show accumulation of glycogen in lysosomes.
Type II Pompe Disease pathophyisiology
This condition is caused by deficiency of acid alpha-glucosidase (alpha-1,4 glucosidase or acid maltase), an enzyme responsible for breaking down glycogen within the acidic environment of lysosomes. Although most glycogen is degraded in the cytoplasm, a small percentage is inadvertently engulfed by lysosomes, especially in cells containing high amounts of glycogen such as hepatocytes and myocytes. Deficiency of acid maltase results in pathologic accumulation of glycogen within liver and muscle lysosomes. Cardiac and skeletal muscle are particularly susceptible because the ballooning lysosomes interfere with contractile function.
The classic form of the disease presents in early infancy with marked cardiomegaly, severe generalized hypotonia, macroglossia, and hepatomegaly. Blood glucose levels are normal, unlike with glycogen storage diseases that primarily affect the liver (eg, von Gierke disease). A key distinguishing feature is that muscle biopsy will show accumulation of glycogen in lysosomes.
Acid alpha-glucosidase deficiency
Type 2 Pompe Disease
Key features of Pompe Disease
Severe Cardiomegaly
glycogen accumulation in lysosomes
Normal Glucose Levels
Glucose-6-phosphatase deficiency
Type 1 Von Gierke Disease
Key features Type 1 Von Gierke Disease
Hepatomegaly
Steatosis
Fasting hypoglycemia
Lactic acidosis
Hyperuricemia
hyperlipidemia
Type 3 Cori Disease pathophysiology
Deficiency of Debranching Enzyme (alpha-1, 6-glucosidase)
or
Debranching Enzyme (alpha-1, 4-transferase)
Debranching enzyme (alpha-1, 6-glucosidase) deficiency
Type 3 Cori Disease
Key features of Type 3 Cori Disease
Hepatomegaly
Ketotic hypoglycemia
Hypotonia & weakness
abnormal glycogen with very short outer chains
Debranching Enzyme (alpha-1, 4-transferase) Deficiency
Type 3 Cori Disease
Glycogen Phosphorylase deficiency
Type 5 McArdle Disease
Type 5 McArdle Disease pathophysiology
Glycogen phosphorylase Deficiency
Key Features Type 5 McArdle Disease
Muscle Phosphorylase deficiency
Weakness & fatigue with exercise
No rise in blood lactate levels after exercise
Galactokinase Deficiency
Galactokinase catalyzes the phosphorylation of galactose to galactose-1-phosphate in the first committed step of galactose catabolism. Galactokinase deficiency causes neonatal cataract formation due to accumulation of galactitol in the lens
Question
F. Sphingomyelin
Niemann-Pick disease is an autosomal recessive disorder common among Ashkenazi Jews and is characterized by sphingomyelinase deficiency. Sphingomyelinase is responsible for the breakdown of sphingomyelin, a lipid constituent of cell membranes. In Niemann-Pick disease, sphingomyelin accumulation within lysosomes results in cells that appear enlarged, foamy, and vacuolated on electron microscopy. These lipid-laden foam cells accumulate in the liver and spleen and cause hepatosplenomegaly. Progressive neuronal accumulation is responsible for hypotonia and neurologic degeneration (eg, failure to progress developmentally, loss of milestones). Retinal accumulation leads to a cherry-red macular spot.
This patient is presenting with the classic infantile type A variant that results in hepatosplenomegaly, progressive neurologic deterioration, and death by age 3 years.
(Choice E) Patients with Tay-Sachs disease are deficient in β-hexosaminidase A, which leads to GM2 accumulation in neurons. Neurologic regression and cherry-red macular spots are classic symptoms (similar to Niemann-Pick disease), but hepatosplenomegaly is absent.
Niemann Pick Disease Pathophysiology
Niemann-Pick disease is an autosomal recessive disorder common among Ashkenazi Jews and is characterized by sphingomyelinase deficiency.
Sphingomyelinase is responsible for the breakdown of sphingomyelin, a lipid constituent of cell membranes. In Niemann-Pick disease, sphingomyelin accumulation within lysosomes results in cells that appear enlarged, foamy, and vacuolated on electron microscopy. These lipid-laden foam cells accumulate in the liver and spleen and cause hepatosplenomegaly. Progressive neuronal accumulation is responsible for hypotonia and neurologic degeneration (eg, failure to progress developmentally, loss of milestones). Retinal accumulation leads to a cherry-red macular spot.
Niemann Pick Histology
sphingomyelin accumulation within lysosomes results in cells that appear enlarged, foamy, and vacuolated on electron microscopy
Identify
Question
C. Diffuse Atelectasis
This preterm infant with increased work of breathing and hypoxia has diffuse ground-glass opacities and air bronchograms on imaging. These findings are consistent with neonatal respiratory distress syndrome (RDS). RDS is caused by immaturity of type 2 pneumocytes, which normally produce alveolar surfactant. Lack of surfactant causes decreased compliance and increased surface tension of alveoli, leading to alveolar collapse at the end of expiration. This diffuse atelectasis results in the characteristic reticular or ground-glass opacities on chest x-ray. Unlike alveoli, larger airways remain patent and filled with air due to their cartilaginous walls, making them visible (air bronchograms) against the reticular background.
Management of RDS is respiratory support (to maintain alveolar pressure and prevent collapse) and surfactant (to reduce surface tension). During the first week of life, type 2 pneumocytes begin to release endogenous surfactant, and respiratory distress typically begins to improve.
When do fetuses start producing enough surfactant?
A baby normally begins producing surfactant sometime between weeks 24 and 28 of pregnancy. Most babies produce enough to breathe normally by week 34. If your baby is born prematurely, they may not have enough surfactant in their lungs.
Question
G. Wilson Disease
This patient’s auditory hallucinations, mood and personality changes associated with neurologic features (slurred speech, tremor, gait instability), and abnormal liver function tests suggest a diagnosis of Wilson disease. Wilson disease is an autosomal recessive condition marked by copper accumulation in the liver, brain, and cornea, which most commonly manifests in childhood, adolescence, or early adulthood with hepatic involvement and/or neuropsychiatric symptoms.
Psychiatric symptoms range from subtle personality changes to depression, mania, and/or psychosis. These symptoms may predate hepatic or neurologic manifestations and be mistaken for normal adolescence or primary psychiatric illness. Evaluation includes a ceruloplasmin level, 24-hour urinary copper excretion, and slit-lamp examination for copper deposition in the cornea (Kayser-Fleischer rings).
Wilson Disease Pathophysiology
Autosomal recessive mutation of ATP7B → hepatic copper accumulation → leak from damaged hepatocytes → deposits in tissues (eg, basal ganglia, cornea)
Wilson Disease Clinical findings
Hepatic (acute liver failure, chronic hepatitis, cirrhosis)
Neurologic (parkinsonism, gait disturbance, dysarthria)
Psychiatric (depression, personality changes, psychosis)
Wilson Disease Diagnosis
↓ Ceruloplasmin & ↑ urinary copper excretion
Kayser-Fleischer rings on slit-lamp examination
↑ Copper content on liver biopsy
Wilson Disease Tx
Chelators (eg, D-penicillamine, trientine)
Zinc (interferes with copper absorption)
Question
Hepcidin is an acute phase reactant synthesized by hepatic parenchymal cells that acts as the central regulator of iron homeostasis. High iron levels and inflammatory conditions increase the synthesis of hepcidin, while hypoxia and increased erythropoiesis act to lower hepcidin levels. Hepcidin influences body iron storage through its interaction with ferroportin, a transmembrane protein responsible for transferring intracellular iron to the circulation. Upon binding hepcidin, ferroportin is internalized and degraded, decreasing intestinal iron absorption and inhibiting the release of iron by macrophages.
Regulation of intestinal iron absorption is crucial for maintaining iron homeostasis, since blood loss is the only way of removing large amounts of iron from the body. Iron absorption from the proximal small intestine is facilitated by the divalent metal transporter-1 (DMT-1). Once inside the intestinal cells, iron may take 1 of 2 paths:
Iron may bind to ferritin (a primarily intracellular iron-binding protein) and remain stored within the enterocyte. The stored iron is excreted in the stool as enterocytes slough off and are replaced
Iron may enter the circulation through ferroportin, the basolateral iron transporter of the enterocyte. Free iron released into the circulation is transported throughout the body by transferrin (an iron-binding transport protein), which becomes internalized after interacting with transferrin receptors present on all cells
Secretin Function
Secretin is a hormone produced by duodenal S-cells and released in response to increased duodenal H+ concentrations. Secretin stimulates pancreatic ductal cells to increase bicarbonate secretion in order to neutralize the acidity of the gastric contents entering the duodenum. Remember that pancreatic juice is an isotonic secretion, which normally contains Na+ and K+ in the same concentrations as found in plasma, a higher HCO3- concentration than in plasma and a lower Cl- concentration than in plasma. As pancreatic juice flow rates and secretin stimulation increase, the concentration of HCO3- increases and the concentration of Cl- decreases.
Question
C. High Lipophilicity
The kidney is the primary site of excretion of most drugs, with or without prior chemical modification in the liver. The liver is the major site of drug biotransformation and metabolism, but some drugs are also predominately eliminated by the liver into the bile and feces. Drugs with high intrinsic hepatic clearance tend to have high lipophilicity and a high volume of distribution. Highly lipophilic drugs tend to be poorly eliminated in the kidney as these agents rapidly cross tubular cell membranes after filtration to reenter the tissues.
High lipophilicity (lipid solubility) allows the drug to cross cellular barriers more easily and enter hepatocytes. It can then be excreted in the bile or through other methods of elimination. In addition, high lipid solubility assures a wide distribution to many different tissues including the brain, liver, and adipose tissue.
Question
E.
This patient with a recent upper respiratory infection has dyspnea, lower extremity edema, and an S3; this presentation suggests decompensated heart failure (DHF), likely due to dilated cardiomyopathy from viral myocarditis. The pathophysiology of DHF involves reduced cardiac output leading to decreased renal blood flow, which triggers neurohormonal adaptations that perpetuate a cycle of decompensation (Choice F). These ultimately maladaptive neurohormonal changes include the following:
Renin-angiotensin-aldosterone system (RAAS) activation, leading to increased proximal tubular sodium reabsorption (direct effect of angiotensin II)
Antidiuretic hormone release, resulting in increased free water reabsorption in the collecting ducts
Sympathetic nervous system activation, resulting in systemic vasoconstriction
In the short term, these adaptions increase blood volume and maintain systemic perfusion, allowing for a relatively normal glomerular filtration rate (GFR). However, over time, vasoconstriction-induced increased afterload and ventricular overfilling lead to decreased pump efficiency and decompensated failure. Renal dysfunction (eg, acute kidney injury) occurs in up to 60% of patients with DHF; it is often due to cardiorenal syndrome, a complication of the vicious cycle of DHF.
In cardiorenal syndrome, back pressure from the failing heart increases central venous and renal venous pressure (Choice C) to the point that the glomerular capillary filtration gradient drops substantially (due to interstitial edema causing increased hydrostatic pressure in Bowman capsule) and GFR significantly decreases. Characteristic laboratory findings in cardiorenal syndrome reflect activation of the RAAS and indicate a prerenal etiology, with low urine sodium (ie, fractional excretion of sodium <1%) and bland urine sediment. Urea passively follows sodium reabsorption in the proximal tubule, leading to an elevated blood urea nitrogen/creatinine ratio (>20:1).
Cycle of Decompensated Heart Failure
The RAAS and sympathetic pathways overpower the natriuretic pathways leading to net increased volume overload and increased Afterload and preload
Pathophysiology of Renal venous congestion in heart failure
Cardiorenal Syndrome
venous congestion and reduced forward flow leads to a decreased GFR and activation of the RAAS which leads to further vasoconstriction and Na+ and water reabsorption
Question
D. ileum
This patient likely has gallstone ileus, an uncommon complication of longstanding cholelithiasis that usually occurs in elderly women. A large (typically >2.5 cm) gallstone causes formation of a cholecystoenteric fistula between the gallbladder and adjoining gut (most often the duodenum) due to pressure necrosis and erosion of these tissues.
Fistula formation allows passage of the gallstone into the small bowel, where it travels freely until it becomes trapped in the ileum, the narrowest portion of the intestine. Patients consequently develop symptoms/signs of small bowel obstruction, including abdominal pain/distension, nausea/vomiting, high-pitched (tinkling) bowel sounds, and tenderness to palpation. Abdominal x-ray may reveal dilated loops of bowel with air-fluid levels due to intestinal obstruction. Communication between the intestine and gallbladder may also allow gas to enter the biliary tree (pneumobilia).
Question
B. Hippocampus
This patient’s sudden-onset confusion, memory loss, and anterograde amnesia (ie, inability to form new memories) resolving within 2 hours is consistent with transient global amnesia (TGA). The inability to retain new information during a TGA episode frequently causes patients to ask repetitive questions. In addition to prominent anterograde amnesia, patients with TGA have varying degrees of retrograde amnesia (ie, lack of recall of information prior to the episode). They remain fully alert and oriented to self but are typically disoriented to place. Other cognitive functions remain intact during the episode, and neurologic examination is normal. Episodes are self-limited, and amnestic symptoms resolve fully (except for events that occurred during the TGA episode itself) within 24 hours by definition.
Risk factors for TGA in this patient include older age and history of migraine. Although the specific etiology of TGA is uncertain, the clinical symptoms and neuroimaging studies implicate dysfunction of the hippocampus, the area of the brain critical for formation of new memories.
Arcuate Fasiculus
The arcuate fasciculus is an association fiber tract connecting Broca area and Wernicke area in the brain. Dysfunction in this tract correlates with conduction aphasia.
Nucleus accumbens
The nucleus accumbens is part of the basal ganglia. It mediates reward and pleasure and plays an important role in addiction.
Piriform cortex
The piriform cortex is the brain region associated with processing olfactory information.
Pontine reticular formation
The pontine reticular formation is located in the brainstem and regulates arousal, attention, sleep, and muscle tone. Dysfunction in this area is associated with delirium, which is characterized by fluctuating levels of arousal.
Question
B. 1-3 days
Postmortem histopathology of this patient’s myocardium reveals a dense neutrophilic infiltrate surrounded by relatively normal myocytes consistent with the morphologic changes expected in the border zone of ischemic injury 1-3 days after myocardial infarction (MI). Myocardial cells are highly metabolically active and susceptible to ischemic injury after as little as 3-4 minutes of oxygen deprivation due to coronary artery blockage.
4-12 hours after MI light microscopy changes
Wavy fibers with narrow elongated myocytes
10-14 days after myocardial infarction light microscopy
Well-developed granulation tissue with neovascularization
2-8 weeks after myocardial infarction light microscopy
Progressive collagen deposition & scar formation
Question
F. Wet mount saline microscopy
Trichomoniasis histology
Wet mount saline microscopy of trichomoniasis typically shows characteristic motile, flagellated protozoans
Bacterial vaginosis pathogen and features
Gardnerella vaginalis
Trichomoniasis pathogen and features
Candida vaginitis pathogen and features
Neisseria gonorrhoeae histology
A Gram stain may show gram-negative diplococci in polymorphonuclear leukocytes
Question
B. Inactivation of 60S ribosomal subunits
This patient has bloody diarrhea due to Escherichia coli O157:H7, or Shiga toxin–producing E coli (STEC). The transmission of STEC occurs primarily via consumption of contaminated beef products, but isolated cases without a clear source can occur.
After colonization and adherence to intestinal epithelial cells, STEC elaborates Shiga toxin (virtually identical to that produced by Shigella dysenteriae). Enterocytes bind to Shiga toxins, which then inactivate the 60S ribosomal subunit within the host cells by cleaving an adenine nucleobase from the integrated 28S RNA. This leads to inhibition of protein synthesis and apoptosis of intestinal epithelial cells. Clinical manifestations include watery diarrhea that becomes bloody within 1-3 days.
In a minority of cases, Shiga toxin can spread through the damaged intestinal epithelium to the bloodstream and capillary endothelial cells in the kidney, leading to hemolytic uremic syndrome approximately a week after gastrointestinal symptoms. Manifestations include thrombocytopenia, microangiopathic hemolytic anemia, and renal insufficiency.
Question
D. Rostral neuropore closure
The gross pathology of this fetus is consistent with anencephaly, an open neural tube defect (NTD). Open NTDs are caused by a defect in primary neurulation. This process normally begins with formation of the neural plate, the lateral ends of which elevate to become neural folds during the third week of fetal development. These folds form the neural tube by fusing in the midline, starting in the cervical region and extending rostrally and caudally to the anterior and posterior neuropores, respectively.
Failure of either neuropore to close results in an open NTD, and failure of anterior (rostral) neuropore closure specifically leads to anencephaly, a fatal condition in which the skull and meninges fail to form. The fetal brain is then exposed to amniotic fluid, resulting in degeneration of the developing forebrain, as seen here. Maternal serum alpha fetoprotein is markedly elevated due to direct leakage from the open neural tube into the amniotic fluid. Prenatal ultrasound shows absence of the brain and skull superior to the orbits.
Many fetuses with anencephaly die in utero; those born with anencephaly may retain spontaneous breathing and brainstem reflexes (eg, suck, Moro) but die soon after birth.
Anencephaly
anencephaly, an open neural tube defect (NTD). Open NTDs are caused by a defect in primary neurulation. This process normally begins with formation of the neural plate, the lateral ends of which elevate to become neural folds during the third week of fetal development. These folds form the neural tube by fusing in the midline, starting in the cervical region and extending rostrally and caudally to the anterior and posterior neuropores, respectively.
Failure of either neuropore to close results in an open NTD, and failure of anterior (rostral) neuropore closure specifically leads to anencephaly, a fatal condition in which the skull and meninges fail to form. The fetal brain is then exposed to amniotic fluid, resulting in degeneration of the developing forebrain, as seen here. Maternal serum alpha fetoprotein is markedly elevated due to direct leakage from the open neural tube into the amniotic fluid. Prenatal ultrasound shows absence of the brain and skull superior to the orbits.
Many fetuses with anencephaly die in utero; those born with anencephaly may retain spontaneous breathing and brainstem reflexes (eg, suck, Moro) but die soon after birth.
Question
B. Blood Lead Level
This patient’s constipation, abdominal pain, irritability, and pallor (suggesting anemia) are most likely due to lead poisoning. Policy efforts resulted in the elimination of lead, a toxic metal, in gasoline (1985) and paint (1977). Current lead exposure occurs through contact with dust/paint in homes built before 1978; this is the most likely cause of this patient’s condition given the onset of symptoms after moving.
Lead binds to sulfhydryl groups on proteins, replaces calcium in calcium-dependent cellular functions, and directly inhibits enzymes in heme synthesis. Symptoms of lead poisoning are neurologic (cognitive impairment, irritability), gastrointestinal (constipation, abdominal pain), renal (interstitial nephritis), and hematologic (anemia).
Risk factors include having a sibling with prior elevated lead levels and living in older homes with recent renovation/construction. Because irreversible neurodevelopmental effects occur during exposure to low lead levels, screening is recommended for young children at high risk. Diagnosis is made by measuring the blood lead level. Urine δ-aminolevulinic acid (heme synthesis substrate) is also elevated.
Lead poisioning in children features
Question
D. Increased pulmonary vascular resistance
This newly postpartum patient most likely has amniotic fluid embolus syndrome (AFES), which is a rare but catastrophic obstetric emergency. AFES occurs when amniotic fluid enters the maternal circulation through sites of maternofetal connections (eg, endocervical veins, uterine incisions) and initiates an anaphylactoid reaction with the widespread release of proinflammatory and vasoactive substances, resulting in cardiovascular collapse.
The hemodynamic effects of AFES are complex, but the primary disturbance is typically within the pulmonary vasculature, with marked elevation in pulmonary pressures due to potent pulmonary arterial vasoconstriction and possible vascular obstruction by cellular and acellular debris; the hemodynamic effects of this increased pulmonary vascular resistance are most consistent with obstructive shock.
Impeded cardiopulmonary blood flow leads to elevated central venous pressure, which is a reflection of right atrial pressure and right ventricular preload (Choice A). The decreased forward flow leads to reduced pulmonary capillary wedge pressure, which is a reflection of left atrial pressure and representative of left ventricular preload (Choice C). As less blood is pumped to the left side of the heart, the cardiac index decreases, resulting in hypotension (Choice B). In response, systemic vascular resistance is increased in an attempt to maintain adequate tissue perfusion pressure.
AFES also commonly involves a consumptive coagulopathy (ie, disseminated intravascular coagulation), which manifests clinically with uterine hemorrhage and bleeding from incisions and intravenous lines.
Question
D. Impaired clearance of airway secretions
This patient with chronic lung problems has autopsy findings consistent with cystic fibrosis (CF), an autosomal recessive disorder caused by a genetic mutation (eg, ΔF508) affecting the CF transmembrane conductance regulator. A defect in this chloride channel prevents normal hydration of mucus and results in the accumulation of thick, viscous secretions throughout the body (eg, lungs, pancreas, vas deferens).
Respiratory disease, the most common CF manifestation, is the predominant cause of morbidity and mortality. Patients typically have chronic cough due to impaired clearance of inspissated secretions in the bronchioles. This buildup leads to mucus plugging (ie, obstructive lung disease), bacterial colonization (ie, recurrent pneumonia), and chronic infiltration of inflammatory cells. Over time, elastase produced by neutrophils causes bronchiectasis (weakened, dilated bronchial walls) and parenchymal destruction. Advanced disease is associated with irreversible damage, progressive respiratory failure, and shortened life expectancy.
Question
D. Excessivbe liver production of IGF-1
This patient most likely has gigantism, a condition caused by hypersecretion of growth hormone (GH) during childhood. GH is a peptide hormone secreted by the anterior pituitary that acts as both a growth promoter and stress hormone (increasing glucose and free fatty acid levels). Although GH has direct effects on target tissue (eg, chondrogenesis, myocyte protein synthesis), its growth-promoting effects are primarily mediated by insulin-like growth factor-1 (IGF-1), which is released from the liver following stimulation of hepatic GH receptors. IGF-1 binds to a specific receptor tyrosine kinase and stimulates cell growth and proliferation in bone, cartilage, skeletal muscle, and other soft tissues.
Gigantism occurs in children and adolescents before fusion of the epiphyseal growth plates, resulting in rapid linear growth along with large hands and feet, thickening of the calvarium, protrusion of the jaw (prognathism), excessive sweating, and oily skin. The adult variant, acromegaly, has no effect on stature because the epiphyseal growth plates have already fused.
Question
B. Left Circumflex Artery
Coronary dominance is determined by the coronary artery that supplies blood to the posterior descending artery (PDA [or posterior interventricular artery]). The PDA originates from one of the following:
Right coronary artery in approximately 70%-80% of the population (right dominant)
Left circumflex artery in approximately 5%-10% of the population (left dominant)
Both right coronary and left circumflex artery in 10%-20% of the population (codominant)
The atrioventricular (AV) nodal artery most often arises from the dominant coronary artery. This patient has left-dominant coronary circulation; therefore, his atherosclerotic lesion is most likely in the left circumflex artery. Involvement of the AV nodal artery during myocardial infarction can cause varying degrees of AV block.
Left dominant coronary circulation
Left circumflex artery in approximately 5%-10% of the population supplies the posterior descending artery denoting left dominant
Anterior view of coronary arteries
Question
B. Decreases glucagon secretion
This patient has undiagnosed type 1 diabetes mellitus and is now presenting with diabetic ketoacidosis (polyuria, polydipsia, altered mental status, fruity breath [exhaled ketones]). Diabetic ketoacidosis results from a deficiency of insulin coupled with an excess of counterregulatory hormones (ie, glucagon, epinephrine).
Blood glucose levels are normally maintained within a tight range by the opposing effects of insulin (secreted by beta cells) and glucagon (secreted by alpha cells). In the fasting state, low blood glucose levels stimulate secretion of glucagon, which increases blood glucose levels by upregulating glycogenolysis and gluconeogenesis in the liver. In contrast, insulin is released in response to high glucose levels and functions to decrease hepatic glucose production (Choice D) and increase glucose uptake by insulin-responsive tissues. Insulin also suppresses glucagon by directly acting on the alpha cells, enhancing the metabolic effects of insulin.
In type 1 diabetes mellitus, unsuppressed glucagon secretion due to insulin deficiency contributes to excess blood glucose levels.
Question
H. Serotonin
This patient’s fear of contamination leading to compulsive washing rituals is consistent with obsessive-compulsive disorder (OCD). OCD is characterized by obsessions or compulsions, with most patients experiencing both. Common themes include contamination obsessions with cleaning compulsions; obsession with symmetry and compulsions involving ordering and counting; and fear of harm with checking compulsions (eg, stove off, doors locked). Patients with OCD typically engage in time-consuming rituals (>1 hr/day) that cause significant distress and/or functional impairment. Patients with washing compulsions may present with skin conditions.
Selective serotonin reuptake inhibitor (SSRI) antidepressants are considered first-line treatment for OCD. SSRIs block the reuptake of serotonin into the presynaptic neuron, leading to an immediate increase in availability of synaptic serotonin and a subsequent cascade of downstream neurobiological effects.
Question
C. Imprinting
Question
B. Carbamazepine
This patient has symptomatic hyponatremia (eg, somnolence, lethargy), and her laboratory studies (eg, low serum osmolality, high urine osmolality) are consistent with the syndrome of inappropriate antidiuretic hormone secretion (SIADH). Antidiuretic hormone (ADH) secretion by the hypothalamus and posterior pituitary stimulates the renal collecting ducts to reabsorb water into the systemic circulation. This action lowers serum osmolality and sodium and increases extracellular volume. Patients with excessive ADH activity (ie, SIADH) typically have the following manifestations:
Serum sodium and osmolality decrease, leading to hypotonic hyponatremia.
Urinary water excretion decreases, increasing urine osmolality and creating a concentrated urine.
Clinical euvolemia, which is reflected by an absence of edema, lung crackles, and jugular venous distention (signs of hypervolemia) along with absence of dry mucous membranes and elevated blood urea nitrogen (BUN) and creatinine (signs of hypovolemia).
In this case, the patient’s SIADH is likely due to carbamazepine, an antiepileptic drug that induces ADH production and increases renal sensitivity to ADH. Other medications associated with SIADH include antidepressants (eg, selective serotonin reuptake inhibitors and tricyclic antidepressants), anticancer drugs (eg, cyclophosphamide), certain antidiabetic drugs (eg, chlorpropamide), and drugs of abuse (eg, MDMA [ie, ecstasy]).
Questions
B. Phentolamine
Development of venous blanching along with induration and pallor of the tissues surrounding the norepinephrine infusion site are signs of norepinephrine extravasation. The norepinephrine leak causes intense α1 receptor mediated vasoconstriction which can lead to local tissue necrosis. Such necrosis can be prevented by infiltration (using a syringe with a fine hypodermic needle) throughout the affected area with phentolamine, an α receptor blocker leading to vasodilatation (thus counteracting the vasoconstrictive effects of norepinephrine). This antidote must be given within 12 hours of extravasation to be effective.
(Choice D) Isoproterenol can mediate vasodilation via β2 receptor activation, particularly in striated muscle, renal, and mesenteric vascular beds, leading to decreased peripheral vascular resistance with increased cardiac output. Subcutaneous tissue blood vessels have a relatively low β2 receptor density compared to α1 receptors, thus, an alpha blocker would likely be more effective in reversing α1 receptor mediated vasoconstriction.
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C. Rectus Femoris
The major muscles responsible for hip flexion are the rectus femoris, iliopsoas, and sartorius. These muscles originate on the pelvis and spinal column and cross the hip joint anteriorly, giving them the capacity to carry out this motion. This patient has impairment not only with hip flexion but also with knee extension. Of these muscles, only the sartorius and rectus femoris (part of quadriceps femoris) also cross the knee and therefore can influence both hip and knee movements.
The rectus femoris originates from the anterior inferior iliac spine and the ilium and inserts at the base of the patella via the quadriceps tendon, allowing it to flex the hip and also extend the knee upon contraction. The rectus femoris (and quadriceps as a whole) also provides stability and control during ambulation, deceleration (eg, landing a jump), and rapid changes in movement (eg, cutting in soccer).
Hamstring muscle group
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C. Liver
This patient’s right coronary artery (RCA) shows significant occlusion by a large atheromatous plaque with a soft, yellow, lipid core composed mainly of cholesterol and cholesterol esters. Presumably, this patient died from a complication of advanced atherosclerosis, such as a myocardial infarction. His father’s similar fate at a young age suggests a familial condition, most likely familial hypercholesterolemia. Familial hypercholesterolemia is one of the most common inherited disorders, and results from autosomal dominant mutations of the LDL receptor gene.
The liver LDL receptor is normally the greatest contributor to the removal of cholesterol-containing IDL and LDL particles from the circulation. Although numerous other cell types, including smooth muscle cells, adrenocortical cells, fibroblasts, and lymphocytes also express high-affinity LDL receptors, approximately 70% of the plasma LDL is normally cleared by the liver. Heterozygotes with one mutant LDL receptor gene have a 2- to 3-fold elevation of plasma cholesterol from birth, due to reduced hepatic IDL and LDL uptake. Homozygotes may have a 5- to 6-fold elevation. In both heterozygotes and homozygotes, the progression of atherosclerosis with aging is accelerated. Complications include coronary artery disease at an unusually young age, as was the case for the patient in the vignette.
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B. Hemianopia
This patient has a large pituitary adenoma (macroadenoma). In addition to metabolic effects related to alterations in pituitary hormone production, large adenomas can cause symptoms due to compression of surrounding structures; mass effect headaches are common.
Because of the close approximation of the pituitary to the optic chiasm, pituitary tumors can cause compression of optic nerve fibers (CN II) as they decussate at the chiasm, leading to impaired vision in the temporal fields (ie, bitemporal hemianopia). Unusually severe or acute pituitary enlargement (eg, pituitary apoplexy) can also occasionally affect the oculomotor nerve (CN III), leading to diplopia.
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D. Negative Coagulase test
Staphylococcus epidermidis is a low-virulence skin commensal that rarely causes infection in healthy patients. However, those with prosthetic devices (eg, indwelling catheters, artificial heart valves, artificial joints) are at risk because the pathogen produces adhesion and biofilm proteins that allow it to grow on artificial surfaces. S epidermidis is one of the most common contaminants of blood cultures, but infection should be suspected when multiple blood cultures grow the bacteria and/or the patient has symptoms of clinical infection such as fever, malaise, and leukocytosis.
Staphylococcus species are gram-positive cocci that grow in grape-like clusters. They are differentiated from streptococci by the catalase test: Streptococci are catalase-negative whereas staphylococci are catalase-positive (Choice C). Further speciation of staphylococci leverages the coagulase test (the ability to clot blood plasma), which differentiates S aureus from coagulase-negative staphylococci such as S epidermidis, S haemolyticus, and S saprophyticus.
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E.
During pregnancy, the increased metabolic demand required for fetal growth and development leads to multiple physiologic maternal adaptations, particularly cardiovascular changes. These changes both benefit the fetus and protect the patient against the risks of delivery (eg, hemorrhage).
The driving force behind maternal hemodynamic changes is a significant decrease in systemic vascular resistance (SVR) due to both increased release of peripheral vasodilators (eg, nitric oxide, prostacyclin) and formation of a high-flow, low-resistance uteroplacental circuit (increases blood flow to the placenta and fetus). There is also significantly increased blood volume. These changes have the following effects on cardiac preload and afterload:
Both increased blood volume and decreased SVR (which allows blood to return to the heart more quickly and easily) contribute to increased cardiac venous return (ie, increased preload).
The marked reduction in SVR leads to decreased blood pressure (ie, reduced afterload).
Both the increased preload and decreased afterload facilitate an increase in stroke volume, which is the primary cause of increased cardiac output (ie, stroke volume x heart rate) in early pregnancy. As the pregnancy progresses, the stroke volume decreases but maternal heart rate gradually increases, contributing to an overall increase in cardiac output of up to 30%-50% during pregnancy.
Maternal cardiopulmonary adaptations
