Explanation

Correct answer: C

This patient has been affected by arsenic poisoning. Arsenic is a water contaminant in many developing countries. It inhibits the Krebs cycle as follows: pyruvate dehydrogenase converts pyruvate to acetyl-CoA, which combines to oxaloacetate to form citrate. 5 cofactors are required for pyruvate dehydrogenase to function: pyrophosphate, FAD, NAD, CoA, lipoic acid. Arsenic allosterically inhibits enzymes that require lipoic acid. This causes accumulation of pyruvate, which leads to the gastrointestinal symptoms mentioned in the case (classically "rice water stools"). Severe toxicity cause neurological disturbances and death.

(A) is incorrect. Although lead can cause gastrointestinal problems, the lack of basophilic stippling of RBC makes it somewhat unlikely. Also, lead poisoning does not affect the Krebs cycle, and does not cause “garlic” breath.

(B) is incorrect. Although consumption of garlic can cause garlic smell in the breath, it is not known to gastrointestinal side effects. It does not affect enzymatic pathways, such as the Krebs cycle

(D) is incorrect. Carbon monoxide is most likely to occur as a result of exposure to fire, which is an absent feature in this case. Although CO poisoning has more widespread effects, it does not commonly affect the gastrointestinal system. It affects the cardiovascular system, causing tachycardia, hypertension, and sometimes myocardial ischemia. It also affects the central nervous system, leading to headache, dizziness and confusion. Other organs affected are the lungs, kidneys and muscles.

(E) is incorrect. Mercury poisoning typically causes sensory impairment (vision, hearing, and speech), disturbed sensation and a lack of coordination. Affected individuals commonly present with peripheral neuropathy (presenting as paresthesia or itching, burning or pain), skin discoloration (pink cheeks, fingertips and toes), edema (swelling), and desquamation (dead skin peels off in layers).

Educational objectives:

Arsenic interferes with cellular longevity by allosteric inhibition of an essential metabolic enzyme pyruvate dehydrogenate (PDH) complex, which catalyzes the oxidation of pyruvateto acetyl-CoA by NAD. With the enzyme inhibited, the energy system of the cell is disrupted resulting in a cellular apoptosis episode. Biochemically, arsenic prevents use of thiamine resulting in a clinical picture resembling thiamine deficiency. Poisoning with arsenic can raise lactate levels and lead to lactic acidosis. Low potassium levels in the cells increases the risk of experiencing a life-threatening heart rhythm problem from arsenic trioxide.

References:

"Arsenic Poisoning". IHC World. Retrieved 2 May 2014

Explanation

Correct answer: E

Tachypnea in term infants may result from brain injuries or metabolic diseases that irritate the respiratory center. The increased respiratory rate removes ("blows off") carbon dioxide from the lung alveoli and lowers blood CO2, forcing a shift in the indicated equilibrium toward the left:

CO2 + H2O H2CO3 H+ + HCO3-

Carbonic acid (H2CO3) can be ignored because negligible amounts are present at physiologic pH, leaving the equilibrium: CO2 + H2O H+ + HCO3-

The leftward shift to replenish exhaled CO2 decreases the hydrogen ion (H+) concentration and increases the pH (- log10[H+]) to produce alkalosis (blood pH above the physiologic norm of 7.4). This respiratory alkalosis is best treated by diminishing the respiratory rate to elevate the blood [CO2], force the above equilibrium to the right, elevate the [H+], and decrease the pH. The newborn does not have acidosis, defined as a blood pH below 7.4, either from excess blood acids (metabolic acidosis) or from increased [CO2] (respiratory acidosis). The baby also does not have metabolic alkalosis, caused by loss of hydrogen ion from the kidney (e.g., with defective tubular filtration) or stomach (e.g., with severe vomiting).

All A, B, C, D answers are incorrect, because the diagnosis is wrong.

Educational objectives:

Respiratory alkalosis is a medical condition in which increased respiration elevates the blood pH (a condition generally called alkalosis). Respiratory alkalosis generally occurs when some stimulus makes a person hyperventilate. Therefore, decreasing the respiratory rate can be used to treat respiratory alkalosis.

References:

Krapf, Reto; Jaeger, Philippe; Hulter, Henry N (10 April 1992), "Chronic respiratory alkalosis induces renal PTH-resistance, hyperphosphatemia and hypocalcemia in humans", Kidney International (42): 727–734

Explanation

Correct answer: E

This woman suffers from vitamin B12 deficiency (choice E). Signs and symptoms of this include a macrocytic anemia, glossitis, and neurologic findings (paresthesias, and optic neuropathy, and subacute combined degeneration. Vitamin B12 functions as cofactor for homocysteine methyltransferase (transfers CH3 groups as methylcobalamin) and methylmalonyl-CoA mutase (for heme synthesis). Vitamin B12 also have neurological effects, through an indirect mechanism. Adequate methionine is needed to make S-adenosyl-methionine (SAMe), which is in turn necessary for methylation of myelin sheath phospholipids.  Therefore, deficiency of vitamin B12 causes subacute combined degeneration due to demyelination of dorsal column, corticospinal tract and spinocerebellar tract.

(A) Folate deficiency also causes a macrocytic anemia, but it does not cause neurologic symptoms.

(B) Iron deficiency causes a microcytic anemia.

(C)Vitamin B2, or riboflavin, is a cofactor in oxidation and reduction. Deficiency causes angular stomatitis, cheilosis, and corneal vascularization.

(D) Vitamin B3, or niacin, is also used in oxidation and reduction reactions. Deficiency causes pellagra, which manifests as diarrhea, dermatitis, and dementia.

Educational objectives:

Vitamin B12 is cofactor for homocysteine methyltransferase and methylmalonyl-CoA mutase. Deficiency is usually caused by insufficient intake for many years (e.g., veganism), malabsorption (e.g., sprue, enteritis, Diphyllobothrium latum), lack of intrinsic factor (pernicious anemia, gastric bypass surgery), or absence of terminal ileum (Crohn disease). Typical clinical presentations are macrocytic, megaloblastic anemia; hypersegmented PMNs; paresthesias, and subacute combined degeneration (degeneration of dorsal columns, lateral corticospinal tracts, and spinocerebellar tracts) due to abnormal myelin.

References:

First Aid for USMLE Step 1, 2013: p93

 Herbert, V.; Drivas, G.; Foscaldi, R.; Manusselis, C.; Colman, N.; Kanazawa, S.; Das, K.; Gelernt, M.; Herzlich, B.; Jennings, J. (1982). "Multivitamin/Mineral Food Supplements Containing Vitamin B12May Also Contain Analogues of Vitamin B12". New England Journal of Medicine 307 (4): 255–256.

Explanation

Correct answer: A

Hemoglobinopathies (A) are qualitative defects in hemoglobin, typically due to genetic mutations in globin genes. This leads to amino acid substitutions, which affects the structure, function, and stability of the hemoglobin. The most common mutation is that of beta-globin, leading to the HbS of sickle cell disease. Hemoglobinopathies imply structural abnormalities in the globin proteins themselves. Thalassemias, in contrast, usually result in underproduction of normal globin proteins, often through mutations in regulatory genes. This patient's appearance, ancestry, and family history make a hemoglobinopathy most likely.

Choice (B) Iron-deficiency anemia can be caused by many disease processes such as blood loss or inadequate dietary intake, but would be unlikely to cause systemic disease as this patient manifests.

Choice (C) Prothrombotic state can be genetic or acquired. This patient's presentation and appearance are not suggestive of a prothrombotic state, and his young age also makes this relatively less likely.

Choice (D) Porphyrias can be inherited or acquired. They are caused by excessive production, accumulation and excretion of porphyrins or their precursors. These are much rarer than hemoglobinopathies, especially in Africans.

Choice (E) Thalassemia is a quantitative deficiency of hemoglobin caused by an unbalanced synthesis of globin chains. Typically, an entire chain is deficient, either lacking an alpha-chain or a beta-chain. If the patient does not have a hemoglobinopathy, this diagnosis may be worth exploring.

Educational objectives:

Hemoglobinopathy is a kind of genetic defect that results in abnormal structure of one of the globin chains of the hemoglobin molecule. Hemoglobinopathies are inherited single-gene disorders; in most cases, they are inherited as autosomal co-dominant traits.  Common hemoglobinopathies include sickle-cell disease. Hemoglobinopathies are most common in ethnic populations from Africa, the Mediterranean basin and Southeast Asia.

References:

Weatherall DJ, Clegg JB. Inherited haemoglobin disorders: an increasing global health problem. Bull World Health Organ. 2001;79(8):704-712.

Explanation

Correct answer: E

Oncogenes are genes which promote cell growth and reproduction. Tumor suppressor genes are genes which inhibit cell division and survival. Malignant transformation can occur through the formation of novel oncogenes, the inappropriate over-expression of normal oncogenes, or by the under-expression or disabling of tumor suppressor genes. Genetic changes can occur at different levels and by different mechanisms. 

Genetic changes can occur at different levels and by different mechanisms. The gain or loss of an entire chromosome can occur through errors in mitosis. More common are mutations, which are changes in the nucleotide sequence of genomic DNA.

Large-scale mutations involve the deletion or gain of a portion of a chromosome. Genomic amplification occurs when a cell gains many copies (often 20 or more) of a small chromosomal locus, usually containing one or more oncogenes and adjacent genetic material. Translocation occurs when two separate chromosomal regions become abnormally fused, often at a characteristic location. A well-known example of this is the Philadelphia chromosome, or translocation of chromosomes 9 and 22, which occurs in chronic myelogenous leukemia, and results in production of the BCR-abl fusion protein, an oncogenic tyrosine kinase.

Small-scale mutations include point mutations, deletions, and insertions, which may occur in the promoter region of a gene and affect its expression, or may occur in the gene's coding sequence and alter the function or stability of its protein product.

(A) Oncogene activation, but not deletion, promotes carcinogenesis.

(B) Oncogene activation, but not inactivation, promotes carcinogenesis.

(C)Tumor suppressor gene inactivation, but not activation, promotes carcinogenesis.

(D) Tumor suppressor gene inactivation, but not amplification, promotes carcinogenesis.

Educational objectives:

Any event that disrupts the function of a tumor suppressor gene or enhances the function of an oncogene is usually associated with cancer. Therefore, deletion of a tumor suppressor gene (E), such as p53, is the Correct answer. The other answer choices are not commonly implicated in cancer pathogenesis. On the contrary, an inactivating mutation of a tumor suppressor gene, or an activating mutation/amplification of an oncogene are common events in the pathogenesis of cancer.

References:

Kimball's Biology Pages. "Oncogenes" Free full text

Yokota J (Mar 2000). "Tumor progression and metastasis". Carcinogenesis. 21 (3): 497–503.