Blue print pathology block 3

1 / 100
How many glycogen storage diseases are there?
Click the card to flip 👆
Terms in this set (100)
A6-year-oldgirlisbeingevaluatedforrecurrentepisodesoflightheaded- ness and sweating due to hypoglycemia. These symptoms are not improved by subcutaneous injection of epinephrine. Physical examination reveals an enlarged liver and a single subcutaneous xanthoma. An abdominal computed tomography (CT) scan reveals enlargement of the liver along with bilateral enlargement of the kidneys. Laboratory examination reveals increased serum uric acid and cholesterol with decreased serum glucose levels. Following oral administration of fructose, there is no increase in blood glucose levels. A liver biopsy specimen reveals increased amounts of glycogen in hepatocytes, which also have decreased levels of glucose-6-phosphatase. Which of the following is the most likely diagnosis?
a. Andersen's syndrome (type IV glycogen storage disease)
b. Cori's disease (type III glycogen storage disease)
c. McArdle's syndrome (type V glycogen storage disease)
d. Pompe's disease (type II glycogen storage disease)
e. von Gierke's disease (type I glycogen storage disease)
The answer is e. (Kumar, pp 165-167. Rubin, pp 255-257.) The glyco- gen storage diseases are due to defective metabolism of glycogen, and at least 11 syndromes stemming from genetic defects in the responsible enzymes have been described. Most of these glycogenoses are inherited as autosomal recessive disorders. von Gierke's disease (type I) results from deficiency of glucose-6-phosphatase, the hepatic enzyme needed for con- version of G6P to glucose, with glycogen accumulation particularly in the enlarged liver and kidney and hypoglycemia. Diagnosis requires biopsy demonstration of excess liver glycogen plus either absent or low liver glu- cose-6-phosphatase activity, or a diabetic glucose tolerance curve, or hyper- uricemia. von Gierke's disease is the major hepatic or hepatorenal type of glycogenosis. Lysosomal glucosidase deficiency causes Pompe's disease (type II). Glycogen storage is widespread but most prominent in the heart (cardiomegaly). In brancher glycogenosis (type IV) there is accumulation of amylopectin or abnormal glycogen in the liver, heart, skeletal muscle, and brain. The major myopathic form, McArdle's disease (type V), is due to lack of muscle phosphorylase.
A 25-year-old woman stops going to her aerobic exercise class because of severe muscle cramps that have occurred during every session for the past 2 months. Several hours after each session, she notices that her urine is a brown color. On physical examination, she has normal muscle development and strength. An inherited defect in which of the following substances is most likely to explain these findings?
□ (A) Dystrophin
□ (B) Fibrillin
□ (C) Glucose-6-phosphatase
□ (D) Hexosaminidase
□ (E) Lysosomal glucosidase
□ (F) Muscle phosphorylase
□ (G) Spectrin
(F) This woman has McArdle syndrome, a form of glycogen storage disease with onset in young adulthood. In this disorder, a deficiency of muscle phosphorylase enzyme causes glycogen to accumulate in skeletal muscle. Because strenuous exercise requires glycogenolysis and use of anaerobic metabolism, muscle cramps ensue, and the blood lactate level does not rise. Myoglobinuria is seen in about half of cases. A lack of the muscle membrane protein dystrophin characterizes Duchenne muscular dystrophy. A fibrillin gene mutation can lead to Marfan syndrome. Glucose-6- phosphatase deficiency leads to von Gierke disease, characterized by hepatomegaly, renomegaly, and impaired gluconeogenesis leading to hypoglycemia and hyperlipidemia. Hexosaminidase A deficiency occurs in Tay-Sachs disease, causing severe neurologic impairment, poor motor development, and blindness beginning in infancy. Lysosomal glucosidase deficiency is seen in Pompe disease, characterized by marked cardiomegaly and heart failure beginning in infancy. Abnormal spectrin, a red blood cell membrane cytoskeletal protein, leads to a condition known as hereditary spherocytosis.
6-month-old male infant is brought to the physician because of failure to thrive and abdominal enlargement. His parents are concerned that he has shown minimal movement since birth. On physical examination, the infant has marked muscle weakness and hepatosplenomegaly. A chest radiograph shows marked cardiomegaly. He dies of congestive heart failure at age 19 months. The microscopic appearance of myocardial fibers at autopsy is shown in the figure. A deficiency of which of the following enzymes is most likely to be present in this infant?
□ (A) Glucocerebrosidase □ (B) Glucose-6-phosphatase □ (C) Hexosaminidase A □ (D) Homogentisic oxidase □ (E) Lysosomal glucosidase □ (F) Myophosphorylase □ (G) Sphingomyelinase
(E) This infant has Pompe disease, a form of glycogen storage disease that results from a deficiency in lysosomal glucosidase (acid maltase). The glycogen stored in the myocardium results in massive cardiomegaly and heart failure within 2 years. Glucocerebrosidase deficiency occurs in Gaucher disease. In the most common form of the disease, there is no neurologic impairment, and patients have splenomegaly and skeletal disease as a consequence of increased lysosomal glucocerebrosides in cells of the mononuclear phagocyte system. Glucose-6-phosphatase deficiency leads to von Gierke disease, characterized by hepatomegaly, renomegaly, and impaired gluconeogenesis leading to hypoglycemia and hyperlipidemia. Hexosaminidase A deficiency occurs in Tay-Sachs disease and is associated with severe neurologic impairment, poor motor development, and blindness beginning in infancy. Homogentisic oxidase deficiency leads to alkaptonuria with ochronosis or to deposition of a blue-black pigment in joints, resulting in arthropathy. Myophosphorylase deficiency leads to McArdle disease, characterized by muscle cramping after strenuous exercise. Sphingomyelinase deficiency occurs in Niemann-Pick disease; affected individuals with type A have hepatosplenomegaly, lymphadenopathy, and severe motor and mental impairment.
Image: 6-month-old male infant is brought to the physician because of failure to thrive and abdominal enlargement. His parents are concerned that he has shown minimal movement since birth. On physical examination, the infant has marked muscle weakness and hepatosplenomegaly. A chest radiograph shows marked cardiomegaly. He dies of congestive heart failure at age 19 months. The microscopic appearance of myocardial fibers at autopsy is shown in the figure. A deficiency of which of the following enzymes is most likely to be present in this infant?
□ (A) Glucocerebrosidase □ (B) Glucose-6-phosphatase □ (C) Hexosaminidase A □ (D) Homogentisic oxidase □ (E) Lysosomal glucosidase □ (F) Myophosphorylase □ (G) Sphingomyelinase
A 41-year-old woman presents with increasing fatigue, lethargy, and muscle weakness. Her CBC reveals decreased numbers of erythro- cytes, leukocytes, and platelets along with an increase in the MCV of the erythrocytes. The associated picture is from a smear of her peripheral blood. Which of the following substances is most likely to be deficient in this individual? a. Aminolevulinic acid b. Ascorbic acid c. Folic acid d. Retinoic acid e. Vanillylmandelic acidTheanswerisc.(Kumar,pp638-639,642-643.Rubin,pp1073-1076.) In contrast to a normal, mature neutrophil, which has from two to five nuclear lobes, the neutrophil shown has at least six lobes and is an illustra- tion of neutrophilic hypersegmentation. Granulocytic hypersegmentation is significant and among the first hematologic findings in the peripheral blood of patients who have megaloblastic anemia in its developmental stages. Neu- trophilic hypersegmentation is generally considered a sensitive indicator of megaloblastic anemia, which can be caused by a deficiency in vitamin B12, in folate, or in both. This deficiency impairs DNA synthesis and delays mitotic division, which in turn causes the nuclei to be enlarged. The synthesis of RNA and cytoplasmic elements is not affected, however, so there is nuclear- cytoplasmic asynchrony. These cellular changes affect all rapidly proliferating cells in the body, but in the bone marrow they result in enlarged erythroid precursors, which are referred to as megaloblasts. These abnormal cells pro- duce abnormally enlarged red cells, which are called macroovalocytes. These megaloblasts also undergo autohemolysis within the bone marrow, resulting in ineffective erythropoiesis. Granulocyte precursors are also enlarged and are called giant metamyelocytes. These abnormal cells produce enlarged hypersegmented neutrophils. The megakaryocytes are large and have nuclear abnormalities, but, although the platelet count is decreased, the platelets are not enlarged. Tetrahydrofolate (FH4) acts as an intermediate in the transfer of one- carbon units from compounds such as formiminoglutamic acid (FIGlu), a breakdown product of histidine. Excess urinary levels of FIGlu are a useful clinical indicator of a folate deficiency. Folate deficiency may result from dietary deficiency, impaired absorption, or impaired utilization. Dietary defi- ciency most often occurs in chronic alcoholics or the elderly. Impaired absorption occurs in malabsorptive states, while impaired utilization can occur with folate antagonists, an example being methotrexate. Increased requirements for B12 and folate may be seen in pregnancy, cancer, and chronic hemolytic anemia; if these needs are not met, deficiency states can result. Note that folate deficiency during pregnancy has been associated with the development of open neural tube defects in the fetus. Folate supplements are recommended for all women prior to and after conception.Vitamin B12 deficiency- Macrocytic RBC hypersegementated neutrophils - Glossitis - Decrecresed serum B12 - Increased homocysteine (risk thrombosis) - increased methylmalonic In myelin cells - spinal cord degeneration - Schilling testCauses of vitamin B12 deficiency?anemia malabsorption (crohns) Pancreatic insufficiencyA 39-year-old woman sees her physician because she has experienced abdominal pain and intermittent low-volume diarrhea for the past 3 months. On physical examination, she is afebrile. A stool sample is positive for occult blood. A colonoscopy is performed, and biopsy specimens from the terminal ileum and colon show microscopic findings consistent with Crohn's disease. Because she has failed to respond to medical therapy, surgery is warranted, and part of the colon and terminal ileum are removed. She is transfused with 2 U of packed RBCs during surgery. Several weeks later, she appears healthy, but complains of easy fatigability. On investigation, CBC findings show hemoglobin of 10.6 g/dL, hematocrit of 31.6%, RBC count of 2.69 million/μL, MCV of 118 μm3, platelet count of 378,000/mm3, and WBC count of 9800/mm3. The reticulocyte count is 0.3%. Which of the following is most likely to produce these findings? □ (A) Hemolytic anemia □ (B) Aplastic anemia □ (C) Chronic blood loss □ (D) Vitamin B12 deficiency □ (E) Anemia of chronic disease □ (F) Bone marrow metastases(D) The high MCV indicates a marked macrocytosis, greater than would be accounted for by a reticulocytosis alone. The two best-known causes for such an anemia (also known as megaloblastic anemia when characteristic megaloblastic precursors are seen in the bone marrow) are vitamin B12 and folate deficiency. Because vitamin B12 is absorbed in the terminal ileum, its removal can cause vitamin B12 deficiency. Hemolytic anemia is unlikely several weeks after blood transfusion. Chronic blood loss and iron deficiency produce a microcytic pattern of anemia, as does dietary iron deficiency. Anemia of chronic disease is generally a normocytic anemia. Inflammatory bowel diseases (e.g., Crohn disease) increase the risk of malignancy, but myelophthisic anemias (from space-occupying lesions of the marrow) are usually normocytic to mildly macrocytic (from reticulocytosis)A clinical study is performed to assess outcomes in patients who have macrocytic anemias. A comparison of laboratory testing strategies shows that the best strategy includes testing for vitamin B12 (cobalamin) and folate. What is the most important reason for ordering these tests simultaneously? □ (A) Both nutrients are absorbed similarly □ (B) Therapy for one deficiency also treats the other □ (C) The peripheral blood smear appears the same for both deficiencies □ (D) Aplastic anemia can result from lack of either nutrient □ (E) Neurologic injury must be avoided(E) Although folate and vitamin B12 deficiency give rise to a macrocytic anemia, a deficiency of vitamin B12 also can result in demyelination of the posterior and lateral columns of the spinal cord. The anemia caused by vitamin B12 deficiency can be ameliorated by increased administration of folate; this masks the potential neurologic injury by improving the anemia. Treating vitamin B12 deficiency does not improve the anemia caused by folate deficiency, however. Folate has no cofactor for absorption, but vitamin B12 must be complexed to intrinsic factor and secreted by gastric parietal cells, and then the complex must be absorbed in the terminal ileum, so diseases such as atrophic gastritis and Crohn's disease can affect vitamin B12 absorption more than folate. The peripheral smear could appear the same and offers no means for distinguishing these deficiencies. An aplastic anemia is unlikely to result from a nutritional deficiency.pituitary adenomaa benign tumor of anterior pituitary gland - hormone producing - Psammoma bodies (prolactinoma) - Galactorrhea - Amenorrhea - Infertility - Decreased libio (& headaches in males) - increased prolactin levelsPhysiological prolactinomaPregnancy Sucking (lactate) StressPathological prolactinomaLactotroph hyperplasiaA 25-year-old woman who has never been pregnant presents with amenorrhea for 3 months and a milky discharge from her nipple. She states that her menstrual cycles have been irregular for the past year. Laboratory tests show that her serum LH and estradiol levels are below normal, and a pregnancy test is negative. Which of the following is the most likely cause of these signs and symptoms? a. Craniopharyngioma of the hypothalamus b. Germinoma of the pineal gland c. Islet cell adenoma of the pancreas d. Medullary carcinoma of the thyroid gland e. Prolactinoma of the pituitary glandThe answer is e. (Kumar, pp 1158-1161. McPhee, pp 544-548.) Pitu- itary adenomas are the most common neoplasms of the pituitary gland. These benign neoplasms are classified according to the hormone or hor- mones that are produced by the neoplastic cells. The cell types, in order of decreasing frequency, are the following: lactotrope adenomas (which secrete prolactin), null cell adenomas (which do not secrete hormones), somatotrope adenomas (which secrete growth hormone), corticotrophic adenomas (which secrete ACTH), gonadotrope adenomas (which secrete FSH and LH), and thyrotrope cell adenomas (which secrete TSH). Prolactin- secreting tumors (lactotrope adenomas or prolactinomas) produce symp- toms of hypogonadism and galactorrhea (milk secretion not associated with pregnancy). In females this hypogonadism produces amenorrhea and infertility, while in males it produces impotence and decreased libido. The same symptoms that are seen with a prolactin-secreting pituitary adenoma can also be produced by certain drugs, such as methyldopa and reserpine.Acromegaly_ Hypersensecretion GH (Hepatic secretion IGF-1) - Increased bone density - Enlarged jaw - Visceral organ growth - Cardiac failureA 42-year-old man presents with increasing fatigue and occasional headaches. He states that recently he has had to change his shoe size from 9 to 10, and he also thinks that his hands and jaw are now slightly larger. Physical examination reveals a prominent forehead and lower jaw, enlarged tongue, and large hands and feet. Initial laboratory examination reveals increased serum glucose. Which of the following is the most likely expla- nation for this constellation of clinical findings? a. Acromegaly b. Apoplexy c. Cretinism d. Diabetes e. GigantismThe answer is a. (Henry, pp 304-306, 1034. Kumar, pp 1161-1162.) The second most common type of functioning pituitary adenoma is a growth-hormone--secreting somatotropic adenoma. This tumor can pro- duce gigantism if it occurs in children prior to the closure of the epiphyseal plates or acromegaly if it occurs in adults after the closure of the epiphyseal plates. The latter is characterized by cartilaginous-periosteal soft tissue growth of the distal extremities (acromegaly) and growth of the skull and face bones. Additional findings in patients with excess growth hormone production include thickening of the skin, diabetes mellitus, and enlarge- ment of the viscera, including increased size of the heart, kidneys, liver, and spleen. Cardiac failure is usually the mechanism of death. In contrast, cretinism is caused by a deficiency of thyroid hormone in infants, while apoplexy refers to the sudden loss of sensation and consciousness, usually caused by pressure on the brain, or referring to infarction of the pituitary.A 40-year-old woman notices that her gloves from the previous winter no longer fit her hands. Her friends remark that her facial features have changed in the past year, and that her voice seems deeper. On physical examination, she is afebrile. Her blood pressure is 140/90 mm Hg. She has coarse facial features. There is decreased sensation to pinprick over the palms in the distribution of her thumb and first two fingers. A radiograph of the foot shows an increased amount of soft tissue beneath the calcaneus. A chest radiograph shows cardiomegaly. Laboratory studies indicate a fasting serum glucose level of 138 mg/dL and hemoglobin A1c level of 8.6%. Which of the following additional test results is most likely to indicate the cause of these physical and laboratory findings? □ (A) Elevated serum prolactin level □ (B) Failure of growth hormone suppression □ (C) Increased serum cortisol level □ (D) Abnormal glucose tolerance test result □ (E) Increased serum TSH level(B) Failure to suppress growth hormone (GH) levels by glucose infusion suggests autonomic GH production. The patient's symptoms suggest acromegaly, and a GH-secreting adenoma is most likely. Acromegaly causes an overall increase in soft tissue in adults because of the anabolic effects of the increase in GH. Because the epiphyses of the long bones are closed in adults, there is not the increase in height, or gigantism, that would be seen in children with a pituitary adenoma that is secreting excessive GH. Instead, an increase in soft tissue mass occurs, which can manifest as increasing shoe or glove size, carpal tunnel syndrome, and coarse facial features. A prolactinoma would cause amenorrhea and galactorrhea. Cushing syndrome from an adrenal tumor could be accompanied by glucose intolerance, hypertension, and truncal obesity, but there is no overall increase in soft tissues. This woman probably has an abnormal glucose tolerance test result, but this does not indicate the underlying cause of diabetes mellitus. A TSH-secreting adenoma of the pituitary can give rise to hyperthyroidism. The increased metabolic rate found in hyperthyroidism is most likely to lead to weight loss, and glucose intolerance is not a feature of hyperthyroidism. Functional pituitary tumors can be detected clinically before they become large enough to cause pressure symptoms such as visual disturbances.Sheehans syndrom- Pregnant - Need increase in hormones - pituitary doubles in size - blood cant sufficiently supple - pituitary infraction - Poor lactation - loss of pubic hair - fatigueA 25-year-old woman presents with the acute onset of cessation of lactation. She delivered her first child several months ago and has been breast-feeding since then. She reports that she has not menstruated since the delivery. She also says that lately she has been tired and has been "feel- ing cold" all of the time. Laboratory workup reveals a deficiency of ACTH and other anterior pituitary hormones. Which of the following is the most likely cause of this patient's signs and symptoms? a. Craniopharyngioma b. Cushing's disease c. Empty sella syndrome d. Nonsecretory chromophobe adenoma e. Sheehan's syndromeThe answer is e. (Kumar, pp 1162-1163. Rubin, pp 1156-1158.) Hypopituitarism results from destructive processes that involve the adeno- hypophysis (anterior pituitary). These processes may be acute (sudden) or chronic. Sheehan's syndrome, also known as postpartum pituitary necrosis, results from the sudden infarction of the anterior lobe of the pituitary. This can occur with obstetric complications, such as hemorrhage or shock. The pituitary gland normally doubles in size during pregnancy; hypovolemia during delivery decreases blood flow and may result in infarction of the anterior pituitary. Sheehan's syndrome produces symptoms of hypopitu- itarism. The initial sign is cessation of lactation, which may be followed by secondary amenorrhea due to the loss of gonadotropins. Other signs of hypopituitarism include hypothyroidism and decreased functioning of the adrenal gland. Acute destruction of the pituitary is also associated with DIC and thrombosis of the cavernous sinus. Chronic causes of hypopituitarism include nonsecretory chromophobe pituitary adenomas, empty sella syn- drome, and suprasellar (hypothalamic) tumors. Nonsecretory chromo- phobe adenomas present as space-occupying lesions that cause decreased hormone production. The gonadotropins are lost first, which results in signs of hypogonadism. Types of chromophobe adenomas include null cell adenomas (no cytoplasmic granules), chromophobes (sparse granules), and oncocytic adenomas (increased cytoplasmic mitochondria). The term pituitary apoplexy refers to spontaneous hemorrhage into a pituitary tumor, while the empty sella syndrome is caused by a defective diaphragma sellae, which permits CSF from the third ventricle to enter the sella. It may also be secondary to infarction or necrosis. A CT scan reveals the sella to be enlarged or to appear empty.A 21-year-old woman delivers a term infant after an uncomplicated pregnancy. The placenta cannot be delivered, however, and there is substantial hemorrhage, requiring transfusion of 10 U of packed RBCs. She must undergo a hysterectomy. Over the next 3 months, she is unable to produce sufficient breast milk to breastfeed her infant, and she becomes increasingly fatigued. Laboratory studies show Na+, 134 mmol/L; K+, 5.2 mmol/L; Cl−, 88 mmol/L; CO2, 23 mmol/L; glucose, 59 mg/dL; calcium, 9.3 mg/dL; phosphorus, 3.5 mg/dL; and creatinine, 0.9 mg/dL. Over the next 5 months, her menstrual cycles do not return. Which of the following laboratory findings is now most likely to be reported? □ (A) Decreased oxytocin □ (B) Elevated dopamine □ (C) Failure of growth hormone stimulation □ (D) Increased antidiuretic hormone □ (E) Increased corticotropin □ (F) Lack of corticotropin-releasing hormone(C) This patient has Sheehan syndrome, or postpartum pituitary necrosis. The pituitary enlarges during pregnancy, causing its blood supply to be more tenuous so that hypotension with obstetric bleeding complications (e.g., the placenta accreta in this patient) predisposes to infarction. The anterior pituitary is at greater risk than the posterior pituitary. The laboratory findings in this patient suggest adrenal insufficiency, and her inability to breastfeed is caused by lack of prolactin; loss of menstrual cycles suggests that follicle-stimulating hormone and luteinizing hormone levels are deficient. Oxytocin release from the posterior pituitary is probably not affected. She does not have syndrome of inappropriate antidiuretic hormone, which is usually a consequence of a paraneoplastic syndrome or head trauma. Dopamine production is not affected. If she were to have primary adrenal failure, the corticotropin (ACTH) level would be increased, but in her case, ACTH is low because of anterior pituitary failure. Because the hypothalamus is unaffected, corticotropin-releasing hormone would still be present.Diabetes insipidus- ADH deficiency - Cause: tumour, trama, infectioin, inflammation - loss of. free water - polyuria and polydipsia - Hypernatremia - increased serum gravitywhat is used to diagnose Diabetes inspidus?H20 deprivation test--> UO doesn't increaseA 5-year-old girl is brought to the doctor's office by her mother, who states that the girl has been drinking a lot of water lately and has been uri- nating much more often than normal. Physical examination reveals a young girl whose eyes protrude slightly. An x-ray of her head reveals the presence of multiple lytic bone lesions involving her calvarium and the base of her skull, a biopsy of which reveals aggregates of Langerhans cells with intracytoplasmic Birbeck's granules. Which of the following sets of laboratory values is most consistent with the expected findings for this girl's disorder? Serum Sodium a. Hypernatremia Low osmolarity and low specific gravity b. Hypernatremia High osmolarity and high specific gravity c. Hyponatremia Low osmolarity and low specific gravity d. Hyponatremia High osmolarity and high specific gravity e. Normal Normal osmolarity and normal specific gravityThe answer is a. (Kumar, pp 701-702, 1163-1164. Rubin, pp 1161, 1364-1365.) Diabetes insipidus (DI) results from a deficiency of antidi- uretic hormone (ADH) and is characterized by polyuria and polydipsia, but not the polyphagia or hyperglycemia of diabetes mellitus. The hallmark of DI is a dilute urine (low urine osmolarity) with an increased serum sodium (hypernatremia). Many cases of diabetes insipidus are of unknown cause (idiopathic), but DI may be the result of hypothalamic tumors, inflamma- tions, surgery, or radiation therapy. Multifocal Langerhans cell histiocytosis (Hand-Schüller-Christian disease) is one of the Langerhans cell histiocy- toses (histiocytosis X). The disorder, which usually begins between the sec- ond and sixth years of life, is associated with the characteristic triad of bone lesions (particularly in the calvarium and the base of the skull), diabetes insipidus, and exophthalmos.A 42-year-old man sees his physician because he has had polyuria and polydipsia for the past 4 months. His medical history shows that he fell off a ladder and hit his head just before the onset of these problems. On physical examination, there are no specific findings. Laboratory findings include serum Na+, 155 mmol/L; K+, 3.9 mmol/L; Cl−, 111 mmol/L; CO2, 27 mmol/L; glucose, 84 mg/dL; creatinine, 1 mg/dL; and osmolality, 350 mOsm/mL. The specific gravity of urine is 1.002. This patient is most likely to have a deficiency of which of the following hormones? □ (A) Oxytocin □ (B) Antidiuretic hormone □ (C) Corticotropin □ (D) Prolactin □ (E) Melatonin(B) This patient has developed diabetes insipidus with a lack of antidiuretic hormone. There is failure of resorption of free water in the renal collecting tubules—hence the diluted urine. Oxytocin is involved in lactation. Corticotropin stimulates the adrenal glands, mainly with the effect of increasing cortisol secretion. Prolactin and melatonin deficiencies have no identifiable specific clinical effect in men.SIADH- Excessive ADH secretion - ectopic production - CNS Trama, pulmonary infraction - Hyponatremia - Decreased serum osmolarity - mental status change - seizuresA 49-year-old man who smokes two packs of cigarettes a day pre- sents with a lung mass on x-ray and recent weight gain. Laboratory exam- ination shows hyponatremia with hyperosmolar urine. Which of the following is the most likely cause of these clinical findings? a. Renal failure b. Pituitary failure c. Conn's syndrome d. Cardiac failure e. Excess ADHThe answer is a. (Kumar, pp 701-702, 1163-1164. Rubin, pp 1161, 1364-1365.) Diabetes insipidus (DI) results from a deficiency of antidi- uretic hormone (ADH) and is characterized by polyuria and polydipsia, but not the polyphagia or hyperglycemia of diabetes mellitus. The hallmark of DI is a dilute urine (low urine osmolarity) with an increased serum sodium (hypernatremia). Many cases of diabetes insipidus are of unknown cause (idiopathic), but DI may be the result of hypothalamic tumors, inflamma- tions, surgery, or radiation therapy. Multifocal Langerhans cell histiocytosis (Hand-Schüller-Christian disease) is one of the Langerhans cell histiocy- toses (histiocytosis X). The disorder, which usually begins between the sec- ond and sixth years of life, is associated with the characteristic triad of bone lesions (particularly in the calvarium and the base of the skull), diabetes insipidus, and exophthalmos.69-year-old man has become progressively obtunded over the past week. On physical examination, he is afebrile and normotensive. A head CT scan shows no intracerebral hemorrhages. Laboratory findings include serum Na+ of 115 mmol/L, K+ of 4.2 mmol/L, Cl− of 85 mmol/L, and bicarbonate of 23 mmol/L. The serum glucose is 80 mg/dL, urea nitrogen is 19 mg/dL, and creatinine is 1.7 mg/dL. Which of the following neoplasms is most likely to be present? □ (A) Pituitary adenoma □ (B) Adrenal cortical carcinoma □ (C) Renal cell carcinoma □ (D) Pheochromocytoma □ (E) Pulmonary small-cell carcinoma(E) This man has syndrome of inappropriate antidiuretic hormone (SIADH) secretion, which results in increased free water resorption by the kidney and hyponatremia. SIADH is most often a paraneoplastic effect, and oat cell carcinoma of the lung is the most likely candidate among probable malignant neoplasms. Anterior pituitary adenomas do not produce antidiuretic hormone (ADH). Adrenal cortical carcinomas can secrete cortisol or sex steroids, but not ADH. Renal cell carcinomas are known for various paraneoplastic effects, but SIADH is not a high probability. Pheochromocytomas secrete catecholamines.Cretinism- Hypothyroidism - Mental retardation - Impaired brain and skeletal development - Dwarfism - enlarged tongue (Myxedema) - Umbilical HerniaCause of cretinismMaternal hypothyroidism (early pregnancy) Thyroid agenesis (doesnt develop thyroid) Mutation thyroid peroxidase gene iodine deficiencyAn 8-month-old infant is being evaluated for growth and mental retardation. Physical examination reveals a small infant with dry, rough skin; a protuberant abdomen; periorbital edema; a flattened, broad nose; and a large, protuberant tongue. Which of the following disorders is the most likely cause of this infant's signs and symptoms? a. Graves' disease b. Cretinism c. Toxic multinodular goiter d. Toxic adenoma e. Struma ovariiThe answer is b. (Kumar, pp 1167-1169. McPhee, pp 561, 567-571.) The consequences of excess or inadequate thyroid hormone are directly attributed to abnormalities involving the normal functioning of thyroid hormones, such as regulation of body processes. For example, excess thy- roid hormone (hyperthyroidism) results in weight loss (increased lipolysis) despite increased food intake, heat intolerance, increased heart rate, tremor, nervousness, and weakness (due to loss in muscle mass). Inade- quate levels of thyroid hormone (hypothyroidism) produce different signs and symptoms in children than in older children and adults. In young chil- dren hypothyroidism produces cretinism, a disease that is characterized by marked retardation of physical and mental growth (severe mental retarda- tion). Patients develop dry, rough skin and a protuberant abdomen. Char- acteristic facial features include periorbital edema; a flattened, broad nose; and a large, protuberant tongue. In contrast, hypothyroidism in older chil- dren and adults produces myxedema. This disease is characterized by a decrease in the metabolic rate, which can result in multiple signs and symptoms, such as cold intolerance and weight gain. Neurologic features of this abnormality include slowing of intellectual and motor function (fatigue, lethargy, and slow speech), apathy, sleepiness, depression, para- noia, and prolonged relaxation phase in deep tendon reflexes ("hung-up" reflexes). Other signs and symptoms of hypothyroidism include dry skin and brittle hair, which can produce hair loss; decreased erythropoiesis, which produces a normochromic normocytic anemia; increased choles- terol, which increases the risk of atherosclerosis; and myxedema, which is the increased interstitial deposition of mucopolysaccharides. The latter abnormality can result in diffuse nonpitting edema of the skin, hoarseness, and enlargement of the heart. Other systems affected by hypothyroidism include the heart, the GI tract, and the GU tract. Patients may develop a slowed heart rate and decreased stroke volume (resulting in cool, pale skin) and constipation, as well as impotence (in men) or menorrhagia and anovulatory cycles (in women).A 2-year-old child is brought to the family physician because of failure to thrive. Physical examination shows that the child is short and has coarse facial features, a protruding tongue, and an umbilical hernia. As the child matures, profound mental retardation becomes apparent. A deficiency of which of the following hormones is most likely to explain these findings? □ (A) Cortisol □ (B) Norepinephrine □ (C) Somatostatin □ (D) Thyroxine (T4) □ (E) InsulinD) The child has cretinism, a condition that is uncommon when there is routine testing and treatment at birth for hypothyroidism. Hypothyroidism that develops in older children and adults is known as myxedema. A lack of cortisol from primary adrenal failure leads to Addison disease, or a 21-hydroxylase deficiency could produce congenital adrenal hyperplasia. There is no deficiency caused by a lack of norepinephrine or somatostatin. An absolute deficiency of insulin leads to type 1 diabetes mellitus.Cushing syndrome- Hypercortisolism - Muscle weakness - Thin extremities - Moon face - buffalo hump - Truncal obesity - abdominal stria - Osteoporosis - HTN (production a-1)Cause of Cushing's Syndrome- Exogenous cortisol - primary adrenal adenoma - Hyperplasia, carcinoma (aka cushings increase) - ACTH secreting pituitary adenoma - pancreoplastic ACTH (small cell carcinoma)A 55-year-old woman presents with increasing muscle weakness and fatigue. Physical examination finds an obese adult woman with purple abdominal stria and increased facial hair. The excess adipose tissue is mainly distributed in her face, neck, and trunk. Laboratory evaluation finds increased plasma levels of cortisol and glucose. Which of the follow- ing is the most likely diagnosis? a. Addison's disease b. Bartter's syndrome c. Conn's syndrome d. Cushing's syndrome e. Schmidt's syndromeThe answer is d. (Kumar, pp 1207-1210. McPhee, pp 588-597.) The clinical effects of excess cortisol are called Cushing's syndrome. Many of the symptoms of Cushing's syndrome that result from excess cortisol produc- tion can be directly related to the normal function of cortisol. Because cor- tisol is a glucocorticoid, its major function involves the maintenance of normal blood glucose levels. In this regard cortisol increases gluconeogen- esis and glycogen storage in the liver. To provide the protein for liver glu- coneogenesis, muscle is broken down. Because muscle is primarily located in the extremities, patients lose muscle in the extremities. This produces muscle wasting and proximal muscle weakness. Cortisol, in contrast to insulin, inhibits glucose uptake by many tissues. Therefore, excess cortisol causes symptoms of glucose intolerance, hyperglycemia, and diabetes mel- litus. Cortisol also stimulates the appetite and lipogenesis in certain adi- pose tissues (the face and trunk), while promoting lipolysis in the extremities. Therefore, excess cortisol is associated with truncal obesity, "moon" face, and "buffalo hump." Excess cortisol inhibits fibroblasts, which in turn leads to loss of collagen and connective tissue. This produces thinning of the skin and weakness of blood vessels, which in turn results in easy bruising (ecchymoses), purple abdominal striae, and impaired wound healing. Cortisol also decreases the intestinal absorption of calcium, decreases the renal reabsorption of calcium and phosphorus, and increases the urinary excretion of calcium (hypercalcinuria). The combination of decreased bone formation and increased bone resorption with excess corti- sol produces osteoporosis (decreased bone mass). Hypertension also occurs in a majority of patients with Cushing's syndrome; the exact mech- anism is unknown. Cortisol enhances erythropoietin function, resulting in secondary polycythemia, which is seen clinically as plethora. Cortisol also normally functions to inhibit many inflammatory and immune reactions. Hypercortisolism produces decreased neutrophil adhesion in blood vessels and increased destruction of lymphocytes and eosinophils. This results in an absolute neutrophilia, absolute lymphopenia, eosinopenia, and increased vulnerability to microbial infections. Patients with Cushing's syn- drome also develop psychiatric symptoms that include euphoria, mania, and psychosis. Gonadal dysfunction also is frequent, which in pre- menopausal women leads to hirsutism, acne, amenorrhea, and infertility. In contrast to Cushing's syndrome, which results from excess cortisol, Conn's syndrome results from excess aldosterone. Addison's disease results from hypofunctioning, not hyperfunctioning, of the adrenal cortex. It most commonly results from autoimmune destruction of the adrenal cortex. Finally, Schmidt's syndrome, which is a type of polyglandular autoimmune syndrome, is characterized by the combination of Hashimoto's disease, per- nicious anemia, and type I diabetes mellitus.A 51-year-old man has noted increasing weakness and weight gain over the past 5 months. He has experienced low back pain for the past week. On physical examination, vital signs include temperature of 37.3°C, pulse of 80/min, respirations of 15/min, and blood pressure of 155/95 mm Hg. He has bilateral breast enlargement, testicular atrophy, and a prominent fat pad in the posterior neck and back. Abdominal cutaneous striae are present. Laboratory findings include Na+, 139 mmol/L; K+, 4.1 mmol/L; Cl−, 96 mmol/L; CO2, 23 mmol/L; glucose, 163 mg/dL; creatinine, 1.3 mg/dL; calcium, 8.9 mg/dL; and phosphorus, 4.1 mg/dL. His serum ACTH level is low. A radiograph of the spine shows decreased bone density with a compression fracture at T9. Which of the following radiographic findings is most likely to be present in this patient? □ (A) Decreased radionuclide uptake in a thyroid gland nodule □ (B) Left adrenal 10-cm solid mass with abdominal CT scan □ (C) Pulmonary 6-cm right hilar mass on chest radiograph □ (D) Retroperitoneal 5-cm mass at the aortic bifurcation on pelvic MRI scan □ (E) Sella turcica enlargement with erosion on head CT scan(B) This patient has clinical findings of Cushing syndrome and feminization, suggesting an adrenal cortical carcinoma. The low ACTH level helps to rule out the possibility of a pituitary adenoma or ectopic ACTH from a neoplasm such as lung carcinoma. A "cold" nodule of the thyroid gland can represent a thyroid medullary carcinoma seen in multiple endocrine neoplasia type II in association with adrenal pheochromocytomas, but Cushing syndrome is not part of this complex. The location of a mass at the aortic bifurcation could be the "infamous" extra-adrenal pheochromocytoma of the obscure organ of Zuckerkandl, which explains hypertension with excess catecholamine release, but not the other features of Cushing syndrome.Primary hyperaldosteronismAdenocortical adenoma --> cohns syndrome - increased aldosterone - Decreased renin - Hypernatermia - HTN - Hypokalemia - Metabolic alkalosis - Take Na --> excrete KA 47-year-old man presents with headaches, muscle weakness, and leg cramps. He is not currently taking any medications. Physical examina- tion finds a thin adult man with mild hypertension. Laboratory examina- tion reveals slightly increased sodium, decreased serum potassium level, and decreased hydrogen ion concentration. Serum glucose levels are within normal limits. A CT scan reveals a large tumor involving the cortex of his left adrenal gland. Which of the following combinations of serum labora- tory findings is most likely to be present in this individual? a. Decreased aldosterone with increased renin b. Decreased cortisol with decreased ACTH c. Increased aldosterone with decreased renin d. Increased cortisol with increased ACTH e. Increased deoxycorticosterone with increased cortisol421. The answer is c. (Kumar, pp 1207-1210. Rubin, pp 1189-1194.) Excess aldosterone secretion may be due to an abnormality of the adrenal gland (primary aldosteronism) or an abnormality of excess renin secretion (secondary aldosteronism). Causes of primary hyperaldosteronism (Conn's syndrome), which is independent of the renin-angiotensin-aldosterone (RAA) system, include adrenal cortical adenomas (most commonly), hyper- plastic adrenal glands, and adrenal cortical carcinomas. These diseases are associated with decreased levels of renin. The signs of primary hyperaldos- teronism include weakness, hypertension, polydipsia, and polyuria. The underlying physiologic abnormalities include increased serum sodium and decreased serum potassium, the latter due to excessive potassium loss by the kidneys, which together with the loss of hydrogen ions produces a hypokalemic alkalosis. The elevated level of serum sodium causes expan- sion of the intravascular volume. In contrast to Conn's syndrome, sec- ondary hyperaldosteronism results from conditions causing increased levels of renin, such as renal ischemia, edematous states, and Bartter's syn- drome. Causes of renal ischemia include renal artery stenosis and malig- nant nephrosclerosis, while Bartter's syndrome results from renal juxtaglomerular cell hyperplasia.A 28-year-old, otherwise healthy man sees his physician because he has had headaches for the past 2 weeks. Physical examination yields no remarkable findings except for a blood pressure of 170/110 mm Hg. An abdominal CT scan shows an enlarged right adrenal gland. A right adrenalectomy is done; the figure shows the gross appearance of the specimen. Which of the following laboratory findings was most likely reported in this patient? □ (A) Hyponatremia □ (B) Hyperglycemia □ (C) Low serum renin level □ (D) Hyperkalemia □ (E) Low serum corticotropin levelC) The gross specimen shows a tumor in the adrenal cortex. In young, otherwise healthy individuals who are hypertensive, a surgically curable cause of hypertension must be sought. This patient had an adrenal cortical adenoma that secreted aldosterone (Conn syndrome). Hyperaldosteronism reduces the synthesis of renin by the juxtaglomerular apparatus in the kidney. Adrenal adenomas can be nonfunctional or can secrete glucocorticoids or mineralocorticoids. Had this been a glucocorticoid-secreting adenoma, the patient could be hypertensive, but he also would have some clinical features of Cushing syndrome. Aldosterone does not exhibit feedback suppression of the anterior pituitary, and corticotropin levels are not affected. Patients with hyperaldosteronism have low serum potassium levels and sodium retention. There is no effect on blood glucosehydronephrosisobstructive uropathy - Dilation of renal pelvis - Dilation of Calyces - Progressive atrophy of kidneys due to obstruction of outflow of urineA 72-year-old man with Alzheimer disease dies of pneumonia. The gross appearance of the right kidney at autopsy is shown in the figure. The left kidney is normal in size, with a smooth cortical surface and a single 0.6-cm, fluid-filled cyst. The appearance of the right kidney is most suggestive of renal injury from which of the following? □ (A) Ureteral obstruction □ (B) Benign nephrosclerosis □ (C) Analgesic abuse □ (D) Chronic pyelonephritis □ (E) Diabetes mellitus(A) The ureteral, pelvic, and calyceal dilation results from long-standing obstruction leading to hydroureter and hydronephrosis. With benign nephrosclerosis, the kidneys become smaller and develop granular surfaces, but there is no dilation. The scarring that accompanies analgesic nephropathy or chronic pyelonephritis can be marked; it is associated with significant loss of renal parenchyma, but not with pelvic dilation. There are many renal complications of diabetes mellitus, mostly from vascular, glomerular, or interstitial injury, but there is no obstruction. In some patients, diabetes is complicated by a neurogenic bladder, and this can lead to functional obstruction. In such cases, both kidneys and ureters would be affected.Poststreptococcal glomerulonephritis- Nephritic syndrome - Hematuria (cola-coloured urine) - Oliguria - Hypertention and periorbital edema - usual In children - Ana-Dnase titer - sub epithelial humps - M protein virulence factor - hypercellular inflamed glomeruliPoststreptococcal glomerulonephritis causeOccurs after strep A or B of the spine or pharynx 2/3 weeks after infectionA 7-year-old boy is recovering from impetigo. Physical examination shows a few honey-colored crusts on his face. The crusts are removed, and a culture of the lesions grows group A Streptococcus pyogenes. He is treated with antibiotics. One week later, he develops malaise with nausea and a slight fever and passes dark brown urine. Laboratory studies show a serum antistreptolysin O titer of 1:1024. Which of the following is the most likely outcome? □ (A) Development of rheumatic heart disease □ (B) Chronic renal failure □ (C) Lower urinary tract infection □ (D) Complete recovery without treatment □ (E) Progression to crescentic glomerulonephritis(D) These findings are characteristic of poststreptococcal glomerulonephritis. The strains of group A streptococci that cause poststreptococcal glomerulonephritis differ from the strains that cause rheumatic fever. Most children with poststreptococcal glomerulonephritis recover, although perhaps 1% develop a rapidly progressive glomerulonephritis. Progression to chronic renal failure occurs more frequently in affected adults. A urinary tract infection is not likely to accompany poststreptococcal glomerulonephritis because the organisms that caused the immunological reaction are no longer present when symptoms of glomerulonephritis appear.A 6-year-old boy presents with bilateral swelling around his eyes. His parents state that the child's eyes have become "puffy" over the past several weeks, and his urine has become smoky-colored. Physical examination reveals mild bilateral periorbital edema, but peripheral edema is not found. The boy is afebrile and his blood pressure is slightly elevated. A urinary dip- stick reveals mild proteinuria, while microscopic examination of the boy's urine reveals hematuria with red blood cell casts. Laboratory tests reveal increased ASO titers and decreased serum C3 levels, but C2 and C4 levels are normal. A microscopic section from the kidney reveals increased numbers of cells within the glomeruli. An electron microscopic section of the kidney reveals large electron-dense deposits in the glomeruli that are located between the basement membrane and the podocytes. The foot processes of the podocytes are otherwise unremarkable. Which one of the listed infections did this child most like recently have that precipitated this renal disease? a. An E. coli infection of the small or large intestines b. A fungal infection of the urethra or urinary bladder c. A staphylococcal infection of the skin or mouth d. A streptococcal infection of the pharynx or skin e. A viral infection of the upper or lower respiratory tractThe answer is d. (Kumar, pp 974-976. Rubin, pp 882-884.) The most common cause of the nephritic syndrome in children is acute proliferative glomerulonephritis (APGN). In children, this illness typically begins 1 to 4 weeks after a group A β-hemolytic streptococcal infection of the pharynx or skin (impetigo or scarlet fever). As such, it is also called acute poststreptococ- cal glomerulonephritis (PSGN). Patients develop hematuria, red cell casts, mild periorbital edema, and increased blood pressure. Laboratory tests reveal increased ASO titers and decreased C3. Throat cultures taken at the time of presentation with renal symptoms are negative. Light microscopy reveals dif- fuse endothelial and mesangial cell proliferation with neutrophil infiltration, so that narrowing of capillary lumina and enlargement of the glomerular tuft to fill the Bowman's space occur. Electron microscopy reveals the mesangial deposits and large, hump-shaped subepithelial deposits in peripheral capillary loops that are characteristic. Immunofluorescence shows granular deposits containing IgG, C3, and often fibrin in glomerular capillary walls and mesangium. Children with poststreptococcal glomerulonephritis usually recover, and therapy is supportive only.Malignant Nephrosclerosis HTN- Renal disease associated with HTN - Endothelial injury ( increased fibrinogen premeability) - Fiberous necrosis - GF released (proliferation and hyperplasia) - Hyperplastic arteriosclerosisMalignant Nephrosclerosis HTN Pt. 2- marked renal Ischemia - decreased kidney size pinpoint peticheal hemorrhage (flea bitten kidney) - Onion skinning - HTN (>180/120) papilloedema - CNS and CVS changes - Proteinuria HematuriaOver the past 72 hours, a 44-year-old man has experienced worsening headache, nausea, and vomiting. On physical examination, his blood pressure is 276/158 mm Hg, and there is bilateral papilledema. Urinalysis shows 2+ proteinuria; 1+ hematuria; and no glucose or ketones. Which of the following renal lesions is most likely to be present in this patient? □ (A) Papillary necrosis □ (B) Acute infarction □ (C) Necrotizing arteriolitis □ (D) Acute tubular necrosis □ (E) Acute pyelonephritis(C) This patient has malignant hypertension. Necrotizing arteriolitis and hyperplastic arteriolosclerosis are the distinctive vascular lesions of malignant hypertension. Papillary necrosis is more likely to complicate diabetic nephropathy or analgesic nephropathy. Infarction of the kidney may result from emboli originating in the systemic circulation. Malignant hypertension does not damage the large systemic vessels, however. Acute tubular necrosis is seen in hypoxic or toxic injury to the renal tubules. Acute pyelonephritis is a febrile illness, without severe blood pressure elevation.A 53-year-old man presents with severe headaches, nausea, and vomiting. He also relates seeing spots before his eyes and is found to have a diastolic blood pressure of 160 mmHg. Microscopic examination of a renal biopsy demonstrates hyperplastic arteriolitis. Gross examination of his kidneys is most likely to reveal which one of the following changes? a. A finely granular appearance to the surface b. Multiple small petechial hemorrhages on the surface c. Diffuse, irregular cortical scars overlying dilated calyces d. Cortical scars overlying dilated calyces in renal poles e. Depressed cortical areas overlying necrotic papillae of varying stagesThe answer is b. (Kumar, pp 1006-1008. Rubin, pp 894-895.) Malig- nant hypertension is characterized clinically by finding a diastolic blood pressure greater than 130 mmHg. Additional clinical signs and symptoms of malignant hypertension include severe headache, ear noises, flame-shaped retinal hemorrhages with AV-nicking, and papilledema. The renal changes associated with malignant hypertension are called malignant nephrosclerosis. These characteristic changes include fibrinoid necrosis of arterioles (necrotiz- ing arteriolitis), hyperplastic arteriolosclerosis (onion-skinning), necrotizing glomerulitis, and often a thrombotic microangiopathy. Grossly the kidney has a "flea-bitten" appearance with multiple red petechiae. The clinical course is often downhill, with only 50% of patients surviving 5 years; marked pro- teinuria, hematuria, cardiovascular problems, and finally renal failure con- tribute to death. The disease is often associated with accelerated preexisting benign essential hypertension, chronic renal disease (glomerulonephritis), or scleroderma. In contrast to malignant nephrosclerosis, benign nephrosclerosis (renal disease occurring in benign hypertension) is characterized by hyaline arteri- olosclerosis with thickened, hyalinized arteriolar walls and narrowed lumina. Fibroelastic hyperplasia occurs in the larger muscular arteries. Small kidneys with a finely granular surface often result because of ischemic atrophy of nephrons. Broad U-shaped cortical scars overlying dilated calyces in the renal poles are seen with chronic pyelonephritis (reflux causes scars involving poles only, while obstruction produces scars all over the kidney), depressed cortical areas overlying necrotic papillae of varying stages are seen with analgesic nephropathy and diabetes mellitus, multiple small white areas on the surface are seen with acute pyelonephritis, and wedge-shaped (i.e., V-shaped) pale cortical scars are seen with renal infarcts.Calcium stone Nephrolithiasis- Calcium oxalate (Hypocitraturia) - Radioopaque (dumbell /envelope shaped) - Idiopathic hypercalcuria (not because of hypercalcemia) - Ethylene glycol ingestion (antifreeze) - Decreased urinare pH - malabsorption (crohns)Ammonium magnesium phosphate stones (Nephrolithiasis)- increased pH - Radiopaque - Coffin lid (sarcophagus) - Alkaline urine --> urease (ex. proteus/klebsella) - Staghorn calculi - Caused by infection - Triphosphate crystalsA 24-year-old man is awakened at night because of severe lower abdominal pain that radiates to the groin. The pain is very intense and comes in waves. The next morning, he notices blood in his urine. He has no underlying illnesses and has been healthy all his life. On physical examination, he is afebrile and has a blood pressure of 110/70 mm Hg. Laboratory studies show serum Na+, 142 mmol/L; K+, 4 mmol/L; Cl−, 96 mmol/L; CO2, 25 mmol/L; glucose, 74 mg/dL; creatinine, 1.1 mg/dL; calcium, 9.1 mg/dL; and phosphorus, 2.9 mg/dL. Urinalysis shows a pH of 7; specific gravity of 1.020; and no protein, glucose, ketones, or nitrite. The patient is advised to drink more water. He likes iced tea and consumes large quantities over the course of a hot summer. He continues to have similar episodes. Which of the following substances is most likely to be increased in his urine? □ (A) Calcium oxalate □ (B) Cystine □ (C) Magnesium ammonium phosphate □ (D) Mucoprotein □ (E) Uric acid(A) This patient has ureteral colic from the passage of a stone down the ureter. About 70% of all renal stones are composed of calcium oxalate crystals. Patients with these stones tend to have hypercalciuria without hypercalcemia. Uric acid stones and cystine stones are radiolucent and tend to form in acidic urine. Cystine stones are rare. Triple phosphate (magnesium ammonium phosphate) stones tend to occur in association with urinary tract infections, particularly infections caused by urease-positive bacteria, such as Proteus. Mucoproteins may coalesce into hyaline casts, which are too small to produce signs and symptoms.A 28-year-old, previously healthy man suddenly develops severe abdominal pain and begins passing red urine. There are no abnormalities on physical examination. Urinalysis shows a pH of 7; specific gravity 1.015; 1+ hematuria; and no protein, glucose, or ketones. The patient is given a device to use in straining the urine for calculi. The next day, the patient recovers a 0.3-cm stone that is sent for analysis. The chemical composition is found to be calcium oxalate. What underlying condition is most likely to be present? □ (A) Gout □ (B) Acute cystitis □ (C) Diabetes mellitus □ (D) Primary hyperparathyroidism □ (E) Idiopathic hypercalciuria(E) Calcium oxalate stones are the most common type of urinary tract stone. Approximately 50% of patients with calcium oxalate stones have increased excretion of calcium without hypercalcemia. The basis of hypercalciuria is unclear. Most uric acid stones are formed in acidic urine and are not related to gout. It is thought that these patients have an unexplained tendency to excrete acidic urine. At low pH, uric acid is insoluble, and stones form. Infections can predispose to the formation of magnesium ammonium phosphate stones. Diabetes mellitus is an uncommon cause of urinary tract lithiasis; although infections are more common in diabetics, most are not caused by urea-splitting bacteria. Hyperparathyroidism predisposes affected individuals to form stones containing calcium, but few patients with urinary tract stones have this condition.A 51-year-old woman has had recurrent urinary tract infections for the past 15 years. On many of these occasions, Proteus mirabilis was cultured from her urine. For the past 4 days, she has had a burning pain on urination and urinary frequency. On physical examination, her temperature is 37.9°C, pulse is 70/min, respirations are 15/min, and blood pressure is 135/85 mm Hg. There is marked tenderness on deep pressure over the right costovertebral angle and on deep abdominal palpation. Urinalysis shows a pH of 7.5; specific gravity 1.020; 1+ hematuria; and no protein, glucose, or ketones. Microscopic examination of the urine shows many RBCs, WBCs, and triple-phosphate crystals. Which of the following renal lesions is most likely to be present? □ (A) Renal cell carcinoma □ (B) Acute tubular necrosis □ (C) Malignant nephrosclerosis □ (D) Staghorn calculus □ (E) Papillary necrosis(D) Recurrent urinary tract infections with urea-splitting organisms such as Proteus can lead to formation of magnesium ammonium phosphate stones. These stones are large, and they fill the dilated calyceal system. Because of their large size and projections into the calyces, such stones are sometimes called "staghorn calculi." Infections are not a key feature of renal cell carcinoma. Cases of acute tubular necrosis typically occur from toxic or ischemic renal injuries. Malignant nephrosclerosis is primarily a vascular process that is not associated with infection. Papillary necrosis can complicate diabetes mellitus.uric acid- Decreased pH - Radiolucent - Rhomboid or rosettes - Hydration & alkalization of urine (KHCO3) - Allopurinol for gout --> Decreases uric acidCause of uric acidGout Hyperuricemia (gout) LeukemiaA 28-year-old man is diagnosed with acute myelogenous leukemia (M2). After induction with a multiagent chemotherapy protocol, he has an episode of lower abdominal pain accompanied by passage of red-colored urine. He has no fever, dysuria, or urinary frequency. On physical examination, there are no remarkable findings. Urinalysis shows a pH of 5.5; specific gravity 1.021; 2+ hematuria; and no protein, ketones, or glucose. There are no remarkable findings on an abdominal radiograph. Which of the following additional urinalysis findings is most likely to be reported for this patient? □ (A) Bence Jones protein □ (B) Eosinophils □ (C) Myoglobin □ (D) Oval fat bodies □ (E) RBC casts □ (F) Triple phosphate crystals □ (G) Uric acid crystals □ (H) Waxy casts □ (I) WBC casts(G) The rapid cell turnover in acute leukemias and cell death from treatment cause the release of purines from the cellular DNA breakdown. The resulting hyperuricemia can predispose to the formation of uric acid stones. Renal stones can produce colicky pain when they pass down the ureter and through the urethra, and the local trauma to the urothelium can produce hematuria. Uric acid stones form in acidic urine. In contrast to stones containing calcium, uric acid stones are radiolucent and are not visible on a plain radiograph. The urine dipstick is sensitive to albumin, but not to globulins; a separate test for Bence Jones protein may be positive, although the dipstick protein result is negative. Bence Jones proteinuria is characteristic of multiple myeloma, however, not of leukemias or lymphomas. Eosinophils may appear in the urine in drug-induced interstitial nephritis. Myoglobin can cause the dipstick reagent for blood to become positive in the absence of RBCs or hemoglobin. Myoglobinuria results most often from rhabdomyolysis, which can occur after severe crush injuries. Oval fat bodies are sloughed tubular cells containing abundant lipid; they are characteristic of nephrotic syndromes. RBC casts appear in nephritic syndromes as a result of glomerular injury. Triple phosphate crystals are typical of infections with urease-positive bacteria, such as Proteus. Waxy casts form in dilated, damaged tubules. WBC casts alone are most indicative of acute pyelonephritis, but they can appear in conjunction with other cellular elements in severe glomerular injury.For the past 4 months, a 51-year-old man has noticed episodes of intense local pain involving his left foot. Each episode follows a meal in which he consumes a bottle of wine (Merlot), and the pain may last hours to several days. Physical examination identifies the right metatarsophalangeal joint as the focus of this pain. There is tenderness and swelling, but minimal loss of joint mobility. A painless, 2-cm nodule with overlying ulcerated skin is present on the lateral aspect of the metatarsophalangeal joint. Beneath the eroded skin is a chalky white deposit of soft material surrounded by erythematous soft tissue. A firm, 1-cm subcutaneous nodule is present on the extensor surface of the left elbow. The nodule is excised and has the microscopic appearance shown in the figure. Which of the following mechanisms is most important in causing joint injury in his disease? □ (A) Activation of neutrophils by phagocytosis of urate crystals □ (B) Chronic inflammation caused by Borrelia burgdorferi infection □ (C) Release of TNF causing acute joint inflammation □ (D) Deposition of serum cholesterol into the synovium □ (E) Granulomatous inflammation caused by Mycobacterium tuberculosis infection □ (F) Reduced metabolism of homogentisic acid(A) The histologic picture is that of a central amorphous aggregate of urate crystals surrounded by reactive fibroblasts and mononuclear inflammatory cells. This is a gouty tophus. Tophi are large collections of monosodium urate crystals that can appear in joints or soft tissues of patients with gout. Large superficial tophi can erode the overlying skin. Precipitation of urate crystals into the joints produces an acute inflammatory reaction in which neutrophils and monocytes can be found. Neutrophils phagocytize urate crystals, which cannot be digested, but cause release of destructive neutrophilic lysosomal enzymes and oxygen free radicals. Release of crystals from the neutrophils perpetuates this cycle of inflammatory response. Borrelia burgdorferi infection causes Lyme disease in which there is arthritis that can mimic rheumatoid arthritis, but there are no subcutaneous nodules containing crystals. Inflammation of the joints involves different mechanisms depending on the etiology. In rheumatoid arthritis, release of tumor necrosis factor (TNF) by macrophages plays a central role, as evidenced by the dramatic relief provided by anti-TNF agents (e.g., adalimumab) currently in clinical use. Marked hypercholesterolemia, as occurs in familial hypercholesterolemia, can lead to deposition of cholesterol in tendons and elsewhere. When deposited in tendons, the yellowish lesions are called xanthomas; the cholesterol crystals appear microscopically as clefts in the tissue. Extrapulmonary Mycobacterium tuberculosis infection can cause granulomatous inflammation and chronic arthritis and skin lesions, but there is caseous necrosis with epithelioid cells and no urate crystals. Tuberculous arthritis, in contrast to gouty arthritis, almost never begins in the metatarsophalangeal joint. Reduced metabolic breakdown of homogentisic acid occurs in the inborn error of metabolism known as alkaptonuria, and deposition of homogentisic acid (ochronosis) in cartilage causes an arthritis that typically affects large joints, such as knees, intervertebral disks, hips, and shoulders, but small joints of the hands and feet are spared.Autosomal recessive PKD- Juvenile (infancy) - PKHD1 Mutation - Worsening renal failure and HTN - Hepatic fibrosis is associated - Hepatic cysts Cystic dilation of collecting ductHow do the kidneys appear in Autosomal recessive PKD?symmetrically enlarged kidneys composed of small, radial arranged cystsA 20-year-old woman, G1, P0, who is in the third trimester, has felt minimal fetal movement. An ultrasound scan shows a markedly decreased amniotic fluid index characteristic of oligohydramnios. She gives birth to a stillborn male fetus at 33 weeks' gestation. At autopsy, there are deformations resulting from marked oligohydramnios, including flattening of the facies, varus deformities of the feet, and marked pulmonary hypoplasia. Microscopic examination of the liver shows multiple epithelium-lined cysts and a proliferation of bile ducts. Which of the following best describes the appearance of the kidneys in this fetus? □ (A) Bilaterally enlarged kidneys replaced by 1- to 4-cm, fluid-filled cysts □ (B) Bilaterally shrunken kidneys with uniformly finely granular cortical surfaces □ (C) Decreased overall size of the right kidney and normal-sized left kidney □ (D) Irregular cortical scars in asymmetrically shrunken kidneys with marked calyceal dilation □ (E) Marked bilateral renal pelvic and calyceal dilation with thinning of the cortices □ (F) Normal-sized kidneys with smooth cortical surfaces □ (G) Symmetrically enlarged kidneys composed of small, radially arranged cysts(G) Autosomal-recessive polycystic kidney disease (ARPKD) most often occurs in children and may involve the liver; most cases have mutations in the PKHD1 gene encoding for fibrocystin expressed in kidney, liver, and pancreas. By contrast, autosomal-dominant polycystic kidney disease (ADPKD) manifests with renal failure in adults and involves PKD1 and PKD2 gene mutations encoding for polycystin proteins found in renal tubules. Some less common forms of ARPKD are accompanied by survival beyond infancy, and these patients develop congenital hepatic fibrosis. Enlarged kidneys with 1- to 4-cm cysts are characteristic of ADPKD in adults. Perhaps the most common renal cystic disease seen in fetuses and infants is multicystic renal dysplasia (multicystic dysplastic kidney), in which the cysts and kidneys are variably sized. This disease can be focal, unilateral, or bilateral; however, congenital hepatic fibrosis is not present. Small, shrunken, granular kidneys typify end-stage renal diseases in adults. For oligohydramnios to be present, both kidneys must be affected, not just one. Irregular cortical scars with pelvicaliceal dilation may represent hydronephrosis complicated by infection in chronic pyelonephritis, a process that occurs in adults. Dilation with calyceal thinning can occur with obstructions in utero, such as posterior urethral valves in males or urethral atresia in males or females; liver lesions are not present in these cases. A cause of oligohydramnios other than abnormalities of the urinary tract (e.g., leakage of amniotic fluid with premature and prolonged rupture of membranes) could be present if the kidneys appear normal, but in this case the distinctive finding of congenital hepatic fibrosis points to ARPKD.A 61-year-old woman sees the physician because she has experienced increasing malaise for the past 5 years. On physical examination, there are no abnormalities other than a blood pressure of 150/95 mm Hg. One week later, she dies suddenly. At autopsy, both kidneys have the external (left panel) and bisected (right panel) appearance as shown in the figure. Which of the following conditions was the most probable cause of death? □ (A) Metastatic Wilms tumor □ (B) Ruptured berry aneurysm □ (C) Acute tubular necrosis □ (D) Disseminated intravascular coagulation □ (E) Pneumothorax(B) These findings are characteristic of autosomal-dominant polycystic kidney disease (ADPKD). As seen in the figure, several large cysts have completely replaced the kidney. In autosomal-recessive polycystic kidney disease, which typically manifests in fetal and neonatal life, the kidneys have a smooth external appearance. On cut section, many small cysts give the kidney a spongelike appearance. About 10% to 30% of affected patients with ADPKD have an intracranial berry aneurysm, and some of these can rupture without warning. Wilms tumor does not arise in a polycystic kidney. Acute tubular necrosis is the result of ischemic or toxic renal injuries. Disseminated intravascular coagulation may complicate hemolytic-uremic syndrome. Pulmonary disease does not accompany adult polycystic kidney disease.A 35-year-old, previously healthy man is found dead in his home. At autopsy, the medical examiner notices bilaterally enlarged kidneys that contain multiple, irregularly arranged cysts of different shapes and sizes. There is a 0.5-cm nonruptured intracerebral berry aneurysm of the anterior communicating artery. There are scattered 1- to 2-cm, fluid-filled liver cysts involving 10% of the parenchymal volume. Postmortem laboratory testing of the urine and blood shows markedly elevated levels of cocaine and its metabolite, benzoylecgonine. Which of the following is the most appropriate conclusion to be drawn from these findings? □ (A) He had lesions related to chronic use of cocaine □ (B) He had autosomal-recessive polycystic kidney disease, but survived to adulthood □ (C) His surviving family (children, siblings, and parents) should be evaluated for a similar condition □ (D) The immediate cause of death is berry aneurysm □ (E) The underlying cause of death is autosomal-dominant polycystic kidney disease(C) The combination of cysts in the kidney and berry aneurysms in the brain is characteristic of adult autosomal- dominant polycystic kidney disease (ADPKD). The cysts also may appear in the liver and pancreas. Because of the autosomal dominant pattern of inheritance, with high penetrance of the gene, first-degree relatives are at risk of having the same disorder, and should be evaluated by ultrasound or other imaging techniques. This evaluation is particularly important because many patients remain asymptomatic until the onset of renal failure as adults. Cocaine use can increase the risk of hemorrhages, but no hemorrhage was found in this case. The cause of death was cocaine intoxication. Autosomal-recessive polycystic kidney disease is unlikely to remain asymptomatic from birth. Because the berry aneurysm had not ruptured, it was not the cause of death. About 1% of all individuals have a berry aneurysm, whereas at least 10% of individuals with ADPKD have such an aneurysm. Most berry aneurysms do not rupture, however. The patient did not die as a consequence of ADPKD; had he lived, he might have developed complications from renal failure, leading to death decades laterAn 8-month-old male infant presents with progressive renal and hepatic failure. Despite intensive medical therapy, the infant dies. At the time of autopsy, the external surfaces of his kidneys are found to be smooth, but cut section reveals numerous cysts that are lined up in a row. Which of the following is the mode of inheritance of this renal abnormality? a. Autosomal dominant b. Autosomal recessive c. X-linked dominant d. X-linked recessive e. MitochondrialThe answer is b. (Kumar, pp 962-966. Rubin, pp 866-868.) Cystic diseases of the kidney, which may be congenital, acquired, or inherited, have characteristic gross appearances. In two types of cystic renal disease, the numerous cysts are found in both the cortex and medulla. These two types of polycystic disease of the kidney are the infantile type and the adult type. Adult polycystic kidney disease typically presents in adulthood and has an autosomal dominant inheritance pattern. Histologically, the cysts are lined by tubular epithelium, while the stroma between the cysts is nor- mal. Adult polycystic renal disease is associated with liver cysts and berry aneurysms, which may rupture and cause a subarachnoid hemorrhage. About one-half of patients with adult polycystic renal disease eventually develop uremia. Infantile polycystic kidney disease typically presents in newborns, has an autosomal recessive pattern of inheritance, and is associ- ated with hepatic cysts (microhamartomas) and congenital hepatic fibrosis. Grossly, these renal cysts have a radial spoke arrangement. In two types of cystic renal disease, the cysts are limited to the medulla. Medullary sponge kidney is usually asymptomatic, is not familial, and is characterized by normal-sized kidneys with small cysts in the renal papillae. In medullary cystic disease complex (nephronophthisis), kidneys are small and sclerotic with multiple cysts at the corticomedullary junction. Individuals with this abnormality present in the first two decades of life with salt-wasting polyuria and progressive renal failure. Most cases are familial and display both recessive and dominant inheritance patterns. Two other types of cysts that are not limited to the medulla are simple cysts and acquired cysts. Simple cortical cysts are single, unilateral cysts, found in adults, that are benign. Patients are usually asymptomatic, but they may present with microscopic hematuria. Acquired polycystic renal disease is associated with chronic renal dialysis. These kidneys are shrunken and have multiple cysts and an irregular surfaceA 52-year-old woman has noticed increasing thirst and urine output for the past 6 months. She has become more lethargic and has had decreased mental agility during that time. She has had flank pain on the right during the past month. On physical examination, her temperature is 37°C, pulse is 77/min, respirations are 14/min, and blood pressure is 150/95 mm Hg. There are bilateral palpable masses in the abdomen. The figure shows an abdominal CT scan. Urinalysis shows specific gravity of 1.010, pH 6.5, 2+ proteinuria, 2+ hematuria, and no glucose or ketones. Laboratory findings show hemoglobin of 10.4 g/dL, hematocrit of 31.3%, glucose of 102 mg/dL, AST of 30 U/L, ALT of 21 U/L, creatinine of 5.5 mg/dL, and urea nitrogen of 53 mg/dL. One year later, she develops a sudden, severe headache. CT scan of the head shows a subarachnoid hemorrhage at the base of the brain. What is the most likely diagnosis? □ (A) Adult-onset medullary cystic disease □ (B) Cystinosis □ (C) Diabetes mellitus type 2 □ (D) Autosoma-dominant polycystic kidney disease □ (E) Polyarteritis nodosa □ (F) Wegener granulomatosis □ (G) Wilson disease(D) About 10% of individuals with autosomal-dominant polycystic kidney disease (ADPKD) have a berry aneurysm of the circle of Willis, which may be complicated by rupture and hemorrhage into the subarachnoid space. The cysts of ADPKD may appear in the liver, and rarely in the pancreas. The cysts in adult-onset medullary cystic disease are centrally located in the kidney. Although renal failure does occur in middle age, similar to ADPKD, the kidneys are small and shrunken, and there are no cysts in other organs. Abnormal renal resorption of amino acids, including cystine, may lead to formation of cystine crystals and stones in the urine; maple syrup urine disease and severe liver disease may cause such a finding. Diabetic nephropathy includes nephrosclerosis, glomerulosclerosis, pyelonephritis, and papillary necrosis, but not cystic disease. Polyarteritis nodosa may produce small microaneurysms of arteries, typically in the kidneys, and may affect multiple organs, but cystic disease is not seen. Wegener granulomatosis is a form of vasculitis that can affect multiple organs, principally the kidneys and lungs, but it does not produce cystic disease. Wilson disease, or hepatolenticular degeneration, leads to chronic liver disease and putaminal degeneration, not cystic disease.A 68-year-old man has experienced increasing malaise for 3 years. Physical examination shows no remarkable findings. Laboratory findings include a serum creatinine level of 4.9 mg/dL and urea nitrogen level of 45 mg/dL. Abdominal CT scan shows bilaterally enlarged cystic kidneys. DNA analysis shows a polycystin-1 gene mutation. Which of the following lesions is the most likely complication of this man's disease? □ (A) Multinodular goiter □ (B) Islet cell hyperplasia □ (C) Adrenal atrophy □ (D) Parathyroid hyperplasia □ (E) Pituitary microadenoma(D) This patient has autosomal-dominant polycystic kidney disease with secondary hyperparathyroidism resulting from decreased phosphate excretion by the kidneys. The resultant hyperphosphatemia depresses the serum calcium level and stimulates parathyroid gland activity. Because of reduced renal parenchymal function, there also is less active vitamin D, which leads to decreased dietary calcium absorption. Renal failure does not lead to any other endocrine lesions.nephrotic syndrome- 3.5g protein/day in urine - Hypoalbumunemia, Hypoglammaglocbulinemia - Hypercoaguable state (loss of antitherombin 3) - Hyperlipemia, Hypercholesterolismminimal change nephrotic syndrome- Common in kids Type 1- Idiopathic --> trigger--> infection, immunization Type 2- Hodgkins lymphoma (massive cytokine production0 - change is minimal - albumin is lost - Prodocyte foot process 2-6 years of age - complete remission in 8 weeksThe parents of a 6-year-old girl notice that she has become increasingly lethargic over the past 2 weeks. On examination by the physician, she has puffiness around the eyes. Her temperature is 36.9°C, and blood pressure is 100/60 mm Hg. Laboratory findings show a serum creatinine level of 0.7 mg/dL and urea nitrogen level of 12 mg/dL. Urinalysis shows a pH of 6.5; specific gravity 1.011; 4+ proteinuria; and no blood or glucose. The 24-hour urine protein level is 3.8 g. The child's condition improves after glucocorticoid therapy. Which of the following findings by electron microscopy is most likely to characterize this disease process? □ (A) Subepithelial electron-dense humps □ (B) Reduplication of glomerular basement membrane □ (C) Areas of thickened and thinned basement membrane □ (D) Increased mesangial matrix □ (E) Effacement of podocyte foot processesE) A child with nephrotic syndrome and no other clinical findings is most likely to have lipoid nephrosis, also called minimal change disease. The term minimal change disease reflects the paucity of pathologic findings. There is fusion of foot processes, which can be seen only by electron microscopy. Subepithelial electron-dense humps represent immune complexes and are seen in postinfectious glomerulonephritis. Variability of basement membrane thickening may be seen in Alport syndrome. The mesangial matrix is expanded in some forms of glomerulonephritis (e.g., IgA nephropathy) and other diseases, such as diabetes mellitus, but not in minimal change disease.A 7-year-old boy is brought to the physician by his mother, who is concerned because he has become less active over the past 10 days. On physical examination, the boy has facial puffiness. Urinalysis shows no blood, glucose, or ketones, and microscopic examination shows no casts or crystals. The serum creatinine level is normal. A 24-hour urine collection yields 3.8 g of protein. He improves after corticosteroid therapy. He has two more episodes of proteinuria over the next few years, both of which respond to corticosteroid therapy. A renal biopsy is done. What is the most likely mechanism causing his disease? □ (A) Immune complex-mediated glomerular injury □ (B) Verocytotoxin-induced endothelial cell injury □ (C) Cytotoxic T cell-mediated tubular epithelial cell injury □ (D) Cytokine-mediated visceral epithelial cell injury □ (E) IgA-mediated mesangial cell injuryD) Steroid-responsive proteinuria in a child is typical of minimal change disease, in which the kidney looks normal by light microscopy, but there is foot process fusion by electron microscopy. The most likely cause of foot process fusion is a primary injury to visceral epithelial cells caused by T cell-derived cytokines. Immune complex deposition in membranous glomerulopathy can cause nephrotic syndrome, but is less common in children than adults and is not steroid-responsive. Certain verocytotoxin-producing Escherichia coli strains can cause hemolytic-uremic syndrome by injury to capillary endothelium. Acute cellular renal transplant rejection is mediated by T cell injury with tubulitis. IgA nephropathy with mesangial IgA deposition and consequent glomerular injury causes recurrent gross or microscopic hematuria and, far less commonly, nephrotic syndrome.A 2-year-old boy is being evaluated for the development of progres- sive peripheral edema. Physical examination finds that he is afebrile, and his blood pressure is within normal limits. Laboratory examination finds decreased serum albumin, increased serum cholesterol, and normal BUN and creatinine levels. Examination of his urine finds massive proteinuria and lipiduria, but no red blood cells are seen. The loss of albumin in the urine is much greater than the loss of globulins. A histologic section from a renal biopsy examined with a routine H&E stain is unremarkable, but elec- tron microscopic examination finds flattening and fusion of the foot processes of the podocytes. The basement membrane is not fragmented and electron dense deposits are not found. What is the best diagnosis? a. Diffuse proliferative glomerulonephritis (DPGN) b. Heymann glomerulonephritis (HGN) c. Membranoproliferative glomerulonephritis (MPGN) d. Membranous glomerulopathy (MGN) e. Minimal change disease (MCD)The answer is e. (Damjanov, pp 2089-2090. Kumar, pp 981-982.) There are numerous causes of nephrotic syndrome (NS), including immune complex diseases, diabetes, amyloidosis, toxemia of pregnancy, and such circulating disturbances as bilateral renal vein thrombosis, but the most common cause of the nephrotic syndrome children is minimal change disease (MCD), which is synonymous with foot process disease or nil disease. MCD presents clinically as the nephrotic syndrome, character- istically occurring in younger children but also seen in adults (rarely), with hypoalbuminemia, edema, hyperlipidemia, massive selective proteinuria, and lipiduria (lipoid nephrosis). MCD is a selective proteinuria because it results from decreased amounts of polyanions (mainly heparan sulfate) in the glomerular basement membrane. These polyanions normally block the filtration of the small but negatively charged albumin molecules. The glomeruli in patients with MCD are known for their rather normal appear- ance on light microscopy. Electron microscopy is necessary for demon- strating the characteristic flattening and fusion of the foot processes of the podocytes attached to the Bowman's space side of the glomerular basement membrane. The podocytes may revert to normal (with steroid immuno- suppressive therapy), or the foot process attenuation may persist to some extent, in which case the proteinuria also persists. The glomeruli in patients with MCD lack electron-dense deposits, and immunofluorescence (IF) tests are negative. In contrast, subepithelial deposits are seen in diffuse proliferative glomerulonephritis (GN), such as poststreptococcal glomerulonephritis (GN). Epimembranous deposits (similar to subepithelial deposits) are found in patients with membranous GN or in the experimental disease Heymann GN. Note that the deposits in MGN are rela- tively small and are deposited in a very uniform fashion, while the deposits in poststreptococcal GN are comparably large (subepithelial humps) and are not uniformly distributed. Subendothelial deposits are seen with systemic lupus erythematosus, while ribbon-like electron-dense deposits in the basement membrane are seen with type 2 membranoproliferative GN (dense deposit dis- ease). Finally, diffuse thinning with fragmentation of the glomerular basement membrane can be seen with Alport's syndrome (hereditary nephritis).Focal segmental glomerulosclerosis- increased in black people Type 1- Idiopathing --> may lead to end stage renal Type 2- other --> HIV/AIDS, Heroin, Sickle sell diseases - Focally segmented glomulerulus - Hyalinosis - Proteinuria (hematuria on microscope seen) - Patchy fushion of feet processes and effacement - Focal deposits - IGM, C3, C1Focal segmental glomerulosclerosis genes involved- IGM -C3 -C1 - NPHS2 Gene mutation Normal protin product of teh gene is? PodocinA 45-year-old Hispanic man has had increasing malaise with headaches and easy fatigability for the past 3 months. Physical examination reveals his blood pressure is 200/100 mm Hg. There are no palpable abdominal masses and no costovertebral tenderness. Laboratory studies show hemoglobin, 9.5 g/dL; hematocrit, 28.3%; MCV, 92 μm3; creatinine, 4.5 mg/dL; and urea nitrogen, 42 mg/dL. Urinalysis reveals 3+ hematuria and 3+ proteinuria, but no glucose or leukocytes. A renal biopsy is done; light microscopic examination of the biopsy specimen shows that approximately 50% of the glomeruli appear normal, but the rest show that a portion of the capillary tuft is sclerotic. Immunofluorescence staining shows IgM and C3 deposition in these sclerotic areas. Past history is significant for repeated episodes of passing dark brown urine, which failed to respond to corticosteroid therapy. Which of the following mechanisms is most likely responsible for his disease? □ (A) Deposition of immune complexes containing microbial antigens □ (B) Dysfunction of the podocyte slit diaphragm apparatus □ (C) Deposition of anti-glomerular basement membrane antibodies □ (D) Inherited defect in the basement membrane collagen □ (E) Deposition of C3 nephritic factor (C3NeF)(B) Corticosteroid-resistant hematuria and proteinuria in a Hispanic man leading to hypertension and renal failure is typical for focal segmental glomerulosclerosis (FSGS). FSGS is now the most common cause of nephrotic syndrome in adults in the United States. Specialized extracellular areas overlying the glomerular basement membrane between adjacent foot processes of podocytes are called slit diaphragms, and these exert control over glomerular permeability. Mutations in genes affecting several proteins, including nephrin and podocin, have been found in inherited cases of FSGS, and their dysfunction, possibly caused by cytokines or unknown toxic factors, is believed to be responsible for acquired cases of FSGS. FSGS also is seen in patients with HIV-associated nephropathy. Immune complexes containing microbial antigens cause postinfectious glomerulonephritis. Anti-glomerular basement membrane antibodies are responsible for Goodpasture syndrome. Inherited defects in basement membrane collagen cause Alport syndrome, also characterized by hematuria, but other congenital abnormalities, such as deafness, are often present, and nephrotic syndrome is uncommon. C3NeF is an autoantibody directed against C3 convertase, and it is seen in membranoproliferative glomerulonephritis type II.A 28-year-old man presents with moderate proteinuria and hyperten- sion. Histologic sections of a kidney biopsy reveal the combination of normal- appearing glomeruli and occasional glomeruli that have deposits of hyaline material. No increased cellularity or necrosis is noted in the abnormal glomeruli. Additionally, there is cystic dilation of the renal tubules, some of which are filled with proteinaceous material. Electron microscopy reveals focal fusion of podocytes, and immunofluorescence examination finds granu- lar IgM/C3 deposits. Further workup finds a mutation involving the NPHS2 gene, the product of which is found within the slit diaphragm of the glomeru- lus. What is the normal protein product of this gene? a. Cubilin b. Megalin c. Nephrin d. Podocin e. PolycystinThe answer is d. (Kumar, pp 962-965, 982-984. Rubin, pp 874-875.) The protein podocin is a component of the slit diaphragm of the glomerulus that is abnormal in a minority of cases of focal segmental glomerulosclerosis (FSGS), a type of glomerular disease that accounts for about 10% of the cases of nephrotic syndrome. FSGS, which affects children and adults, begins as a focal process, affecting only some glomeruli. In the earliest stage, only some of the juxtamedullary glomeruli show changes. Eventually, some glomeruli in other parts of the cortex are affected. In the late stages of the disease, the process may become diffuse, affecting most or all glomeruli. Initially, the process is also segmental, involving some but not all of the lobules within an individual glomerular tuft. The involved area shows sclerosis and may show hyalinosis lesions. Eventually some glomeruli show sclerosis of the entire tuft (global sclerosis). Electron microscopy shows increased mesangial matrix and dense granular mesangial deposits. Immunofluorescence typically shows granular mesangial fluorescence for IgM and C3. Because of the focal nature of FSGS, early cases can be difficult to distinguish from minimal change dis- ease (MCD). Clinically, the nephrotic syndrome of FSGS is more severe than that of MCD and is nonselective. The process is much less responsive to steroids and is much more prone to progress to chronic renal failure. It tends to recur in transplanted kidneys. Although FSGS can be associated with several disorders such as HIV infection, heroin use, and sickle cell disease, it can also be primary (idio- pathic) disorder. Some of these primary cases in fact have a genetic basis and are related to mutations of genes coding for protein products of the slit diaphragm of the glomerulus. One of these is the protein podocin, which is coded for by the NPHS2 gene. Mutations involving this gene have been found in an autosomal recessive form of FSGS and a steroid-resistant nephrotic syndrome of childhood. Nephrin, which is coded for by the NPHS1 gene, is also an important component of the slit diaphragm. Muta- tions of this gene have been found in the congenital nephrotic syndrome of the Finnish type. In contrast, megalin and cubilin are two receptors on the luminal side of proximal tubular epithelial cells that are important for the reabsorption of albumin and low molecular weight proteins that have been filtered in the glomerulus. Finally, defects in polycystin-1 and polycystin-2 are seen with the autosomal dominant (adult) form of polycystic kidney disease (PKD), while defects in fibrocystin are seen with the autosomal recessive (childhood) form of PKD.Membranous glomeropathy (2 types)- immune complex mediated - IgG and C3 - Adult (elderly) Type 1 - Antibodies to phospate A Type 2- to drugs- Nsaids, penicillin - due to infection (HBV, HCV, syphilis, SLE or solid tumor) - Increased risk thromboembilism - Diffuse thickening of glomeruli capillary walls - EM--> spike and domeA 49-year-old man saw his physician because he had increased swelling in the extremities for 2 months. Physical examination showed generalized edema. A 24-hour urine collection yielded 4.1 g of protein and albumin and globulins. Extensive testing did not indicate the presence of a systemic disease, such as diabetes mellitus or systemic lupus erythematosus. He did not respond to a course of corticosteroid therapy. A renal biopsy was done, and microscopic examination showed diffuse thickening of the basement membrane. Immunofluorescence staining with antibody to the C3 component of complement was positive in a granular pattern in the glomerular capillary loops. Two years later, he experiences increasing malaise. Laboratory studies now show serum creatinine level of 4.5 mg/dL and urea nitrogen level of 44 mg/dL. Which of the following immunological mechanisms was most likely responsible for the glomerular changes observed in the biopsy specimen? □ (A) Antibodies that react with basement membrane collagen □ (B) Antibodies against streptococci that cross-react with the basement membrane □ (C) Release of cytokines by inflammatory cells □ (D) Cytotoxic T cells directed against renal antigens □ (E) Deposition of immune complexes on the basement membraneE) This patient has idiopathic membranous glomerulopathy, producing nephrotic syndrome. Diffuse basement membrane thickening, in the absence of proliferative changes, and granular deposits of IgG and C3 are typical of this condition. It is caused by the deposition of immune complexes on the basement membrane, which activates complement. Antibodies that react with basement membrane give rise to a linear immunofluorescence pattern, as in Goodpasture syndrome. Membranous glomerulopathy has no association with streptococcal infections. There also is no evidence of cytokine-mediated or T cell-mediated damage in this disease. In 85% of patients with membranous glomerulopathy, the cause of immune complex deposition is unknown. In the remaining 15%, an associated systemic disease (e.g., systemic lupus erythematosus) or some known cause of immune complex formation (e.g., drug reaction) exists.35 A 42-year-old man has experienced increasing malaise for the past month. He is bothered by increasing swelling in the hands and legs. On physical examination, there is generalized edema. He is afebrile, and his blood pressure is 140/90 mm Hg. Urinalysis shows a pH of 6.5; specific gravity 1.017; 4+ proteinuria; and no blood, glucose, or ketones. Microscopic examination of the urine shows no casts or RBCs and 2 WBCs per high-power field. The 24-hour urine protein level is 4.2 g. A renal biopsy specimen is obtained, and immunofluorescence staining with antibody to the C3 component of complement produces the pattern shown in the figure. Which of the following underlying disease processes is most likely to be present? □ (A) Chronic hepatitis B □ (B) AIDS □ (C) Multiple myeloma □ (D) Recurrent urinary tract infection □ (E) Nephrolithiasis(A) One of the most common causes of nephrotic syndrome in adults is membranous glomerulopathy, caused by immune complex deposition, shown here as granular deposits with C3. About 85% of cases are idiopathic, but some cases follow infections (e.g., hepatitis, malaria), or are associated with causes such as malignancies or autoimmune diseases. In some cases of AIDS, a nephropathy resembling focal segmental glomerulosclerosis occurs. Multiple myeloma can be complicated by systemic amyloidosis, which can involve the kidney. Recurrent urinary tract infection can cause chronic pyelonephritis. Nephrolithiasis may lead to interstitial nephritis, but it does not cause glomerular injuryA 26-year-old woman presents with increasing fatigue and malaise. She states that recently she develops a red facial rash whenever she goes out- side on a sunny day. Physical examination finds that she is afebrile, but her blood pressure is slightly increased and slight peripheral edema is found. Laboratory evaluation finds slightly elevated BUN and creatinine, while dip- stick examination of her urine reveals slight proteinuria with microscopic hematuria. Very rare granular and red cell casts are seen. Laboratory exami- nation is also positive for serum antinuclear antibodies, one of which is anti- double-stranded DNA. A renal biopsy reveals changes of diffuse proliferative glomerulonephritis, and the diagnosis of class IV lupus nephritis is made. Which of the following histologic changes is most characteristic of class IV lupus nephritis? a. Mesangial deposits form a "holly leaf" pattern b. Positive immunofluorescence staining forms a "string of popcorn" pattern c. Splitting of the basement membrane forms a "tram-track" pattern d. Thickening of the basement membrane forms a "spike and dome" appearance e. Thickening of the glomerular capillaries forms a "wire-loop" appearanceThe answer is e. (Kumar, pp 227-235, 990. Rubin, pp 887-889.) The glomerular diseases of patients with systemic lupus erythematosus (SLE) are many and include mesangial lupus glomerulonephritis (GN), focal or diffuse proliferative GN, and membranous GN. The World Health Organization (WHO) classifies SLE renal disease into five classes as follows: class I = no changes; class II = mesangial GN; class III = focal proliferative GN; class IV = diffuse proliferative GN (the most common class); class V = diffuse membra- nous GN. All of these glomerular diseases are the result of the deposition of immune complexes (DNA-anti-DNA complexes) that may be in a mesangial, intramembranous, subepithelial, or subendothelial location. In membranous lupus GN, the deposits are in a subepithelial location, while in diffuse prolif- erative lupus GN (WHO class IV) the deposits are mainly in a subendothelial location and produce a characteristic "wire-loop" appearance due to thicken- ing of the capillary wall. None of these changes are specific for lupus. In contrast to the "wire-loop" appearance of the glomerular capillaries with lupus nephritis, "holly leaf" mesangial deposits are seen with focal seg- mental GN (IgA deposits suggests Berger disease), a "string of popcorn" immunofluorescence pattern is also seen with membranous glomerulo- nephropathy, "tram-track" splitting of the basement membrane is seen with both types of membranoproliferative GN, and a "spike and dome" appearance of the basement membrane is seen with membranous glomerulonephropathy.List the 4 Rapidly progressive glomerulonephritis- Cresentric changes - Good pastures - PSGN - Wegners GCresentric changes to glomeruli- crescents in bowman's capsule - made of fibrin and macrophagesGood pastures- nephritis + pulmonary (linear anti GBM) - pulmonary hemorrage - Linear anti basement membrane - Hematuria and HemoptysisProgressive glomerulonephritis- immuno-complex depositsWegners G- Hematuria - Hemoptysis - Sinus problems - C-ANCA/ P-ANCA - Churg-Strauss (P-ANCA, glomeruloma, Eosin, asthma)Churg-Straussp-ANCA vasculitis + eosinophilia + asthma53 A 45-year-old man has experienced increasing malaise, nausea, and reduced urine output for the past 3 days. On physical examination, he is afebrile and normotensive. Laboratory findings show a serum creatinine level of 2.5 mg/dL. Urinalysis shows hematuria, but no pyuria or glucosuria. A renal biopsy is done; the immunofluorescence pattern with antifibrinogen is shown in the figure. Which of the following additional studies is most useful for classification and treatment of this disease? □ (A) ANA titer □ (B) Anti-glomerular basement membrane antibody test □ (C) HIV titer □ (D) Quantitative serum immunoglobulins □ (E) Rheumatoid factor □ (F) Urine immunoelectrophoresis(B) The renal biopsy specimen shows glomerular crescents, which indicate rapidly progressive glomerulonephritis. Crescentic glomerulonephritis is divided into three groups on the basis of immunofluorescence: type I (anti-glomerular basement membrane [GBM] disease), type II (immune complex disease), and type III (characterized by absence of anti- GBM antibodies or immune complexes). Each type has a different cause and treatment. The presence of anti-GBM antibodies suggests Goodpasture's syndrome; patients with this disorder require plasmapheresis. Type II crescentic glomerulonephritis can occur in systemic lupus erythematosus, in Henoch-Schönlein purpura, and after infections. Causes of type III crescentic glomerulonephritis include Wegener's granulomatosis and microscopic polyangiitis. Immunofluorescence studies are crucial for the classification and treatment of crescentic glomerulonephritis. A positive ANA test result may be reported in patients with lupus nephritis, which uncommonly manifests with glomerular crescents. HIV nephropathy has features similar to those of focal segmental glomerulosclerosis, which is not rapidly progressive. Quantitative serum immunoglobulins are not helpful because the important consideration is the pattern of immune deposits in the kidney. Rheumatoid factor is present in rheumatoid arthritis, which is not associated with renal complications. Urine immunoelectrophoresis is useful in categorizing a monoclonal gammopathy.A 28-year-old man is diagnosed with acute myelogenous leukemia (M2). After induction with a multiagent chemotherapy protocol, he has an episode of lower abdominal pain accompanied by passage of red-colored urine. He has no fever, dysuria, or urinary frequency. On physical examination, there are no remarkable findings. Urinalysis shows a pH of 5.5; specific gravity 1.021; 2+ hematuria; and no protein, ketones, or glucose. There are no remarkable findings on an abdominal radiograph. Which of the following additional urinalysis findings is most likely to be reported for this patient? □ (A) Bence Jones protein □ (B) Eosinophils □ (C) Myoglobin □ (D) Oval fat bodies □ (E) RBC casts □ (F) Triple phosphate crystals □ (G) Uric acid crystals □ (H) Waxy casts □ (I) WBC casts (this is the second time u are seeing this question)(G) The rapid cell turnover in acute leukemias and cell death from treatment cause the release of purines from the cellular DNA breakdown. The resulting hyperuricemia can predispose to the formation of uric acid stones. Renal stones can produce colicky pain when they pass down the ureter and through the urethra, and the local trauma to the urothelium can produce hematuria. Uric acid stones form in acidic urine. In contrast to stones containing calcium, uric acid stones are radiolucent and are not visible on a plain radiograph. The urine dipstick is sensitive to albumin, but not to globulins; a separate test for Bence Jones protein may be positive, although the dipstick protein result is negative. Bence Jones proteinuria is characteristic of multiple myeloma, however, not of leukemias or lymphomas. Eosinophils may appear in the urine in drug-induced interstitial nephritis. Myoglobin can cause the dipstick reagent for blood to become positive in the absence of RBCs or hemoglobin. Myoglobinuria results most often from rhabdomyolysis, which can occur after severe crush injuries. Oval fat bodies are sloughed tubular cells containing abundant lipid; they are characteristic of nephrotic syndromes. RBC casts appear in nephritic syndromes as a result of glomerular injury. Triple phosphate crystals are typical of infections with urease-positive bacteria, such as Proteus. Waxy casts form in dilated, damaged tubules. WBC casts alone are most indicative of acute pyelonephritis, but they can appear in conjunction with other cellular elements in severe glomerular injury.In a patient with vasculitis, the finding of serum antineutrophil cyto- plasmic autoantibodies (ANCAs) that react by immunofluorescence stain- ing in a perinuclear pattern (P-ANCAs) is most suggestive of which one of the following diseases? a. Giant cell arteritis b. Classic polyarteritis nodosa c. Wegener's granulomatosis d. Churg-Strauss syndrome e. Microscopic polyangiitisThe answer is e. (Kumar, pp 536-541. Rubin, pp 515-516. Damjanov, pp 1429-1431.) Antineutrophil cytoplasmic antibodies (ANCAs) may be found in patients with certain inflammatory vascular diseases or glomeru- lar diseases, and their presence is of clinical importance for diagnosing these diseases. Immunofluorescence reveals ANCAs to have two different patterns. One is directed toward myeloperoxidase of neutrophils and is found in a perinuclear location (P-ANCAs). This pattern is seen in patients with microscopic PAN or idiopathic crescentic glomerulonephritis without systemic disease. Microscopic PAN commonly involves glomerular and pulmonary capillaries and may produce hematuria, hemoptysis, and renal failure. Histologic sections reveal segmental fibrinoid necrosis. The other ANCA pattern reveals the antibodies to be directed against neutral leuko- cyte protease (proteinase 3) and results in a cytoplasmic staining pattern (C-ANCAs). This pattern is seen in patients with Wegener's granulomatosis or Churg-Strauss syndrome.A 38-year-old woman presents with the new onset of multiple pur- puric skin lesions. Two years ago she developed late-onset asthma and mild hypertension. Laboratory examination reveals an increase in the number of eosinophils in the peripheral blood (peripheral eosinophilia), and a biopsy from one of the purpuric skin lesions reveals leukocytoclas- tic vasculitis. No perivascular IgA deposits are found, and no antineu- trophil cytoplasm autoantibodies are present. Which of the following is the most likely diagnosis? a. Churg-Strauss syndrome b. Henoch-Schönlein purpura c. Macroscopic polyarteritis nodosa d. Microscopic polyangiitis e. Wegener's granulomatosisThe answer is a. (Kumar, pp 536-541. Rubin, pp 515-516. Dam- janov, pp 1429-1431.) Leukocytoclastic angiitis refers to the histologic finding of fragmented neutrophils surrounding small blood vessels. The differential diagnosis of leukocytoclastic vasculitis includes microscopic PAN and three other disorders: Henoch-Schönlein purpura, Wegener's granulomatosis, and Churg-Strauss syndrome. Henoch-Schönlein pur- pura is a disorder of children who present with hemorrhagic urticaria and hematuria following an upper respiratory infection. The pathology of this disease involves the deposition of immunoglobulin A (IgA) immune com- plexes in small vessels of the skin. Because the antibody is IgA, the alter- nate complement pathway is activated in these patients. Wegener's granulomatosis (WG) is characterized by acute necrotizing granulomas of the upper and lower respiratory tract, focal necrotizing vasculitis affecting small- to medium-sized vessels, and renal disease. Histologically there is fibrinoid necrosis of small arteries, early infiltration by neutrophils, and granuloma formation with giant cells. The peak incidence is in the fifth decade, and many patients have C-ANCAs. The disease is highly fatal, with death occurring within 1 year, unless recognized and treated with immunosuppressive agents. Churg-Strauss syndrome (allergic vasculitis) is a form of necrotizing vasculitis with granulomas of the respiratory tract and asthma. The disorder is associated with increased serum IgE and peripheral eosinophilia.Benign Prostate Hyperplasia (BPH)- Smooth, elastic firm nodular enlargement of transition zone - Compresses the urethra into vertical slits - Dihydrotestosterone - increased urinary frequency - Hypertrophy of bladder wall - Increased risk of diverticula - Increased PSA - Increased Fraction of free PSADihydrotestosterone- 5-alpha reductase In stromal cells - Acts as adrogen receptor on stomal and epithelial69-year-old man presents with urinary frequency, nocturia, drib- bling, and difficulty in starting and stopping urination. Rectal examination reveals the prostate to be enlarged, firm, and rubbery. A needle biopsy reveals increased numbers of glandular elements and stromal tissue. The glands are found to have a double layer of epithelial cells. Prominent nuclei or back-to-back glands are not seen. Which of the following is the most likely diagnosis? a. Atrophic prostatitis b. Atypical small acinar proliferation c. High-grade prostatic intraepithelial neoplasia d. Benign prostatic hyperplasia e. Prostatic adenocarcinomaThe answer is d. (Kumar, pp 1052-1053. Rubin, pp 953-956.) Benign enlargement of the prostate is caused by benign prostatic hyperplasia (BPH) and produces clinical symptoms of urinary frequency, nocturia, dif- ficulty in starting and stopping urination, dribbling, and dysuria. Histolog- ically, the hyperplastic nodules are composed of a variable mixture of hyperplastic glands and hyperplastic stromal cells. Histologic signs of malignancy are not present. The development of BPH is associated with increased age and higher testosterone levels. BPH results from androgen- induced glandular proliferation, but estrogen also sensitizes the tissue to androgens. Urinary obstruction results because the inner, periurethral por- tions of the prostate (the middle and lateral lobes) are affected most com- monly. BPH does not predispose the individual to cancer. In contrast to the benign histology of BPH, the histologic signs characteristic of prostatic ade- nocarcinoma include small glands that appear "back to back" without intervening stroma or that appear to be infiltrating beyond the normal prostate lobules. Histologically, these malignant glands are composed of a single layer of cuboidal epithelial cells, because the outer basal layer of epithelial cells, seen in normal and hyperplastic glands, is not present. These malignant cells often contain one or more enlarged nucleoli.Prostatic adenocarcinoma- posterior lobe of prostate gland - Increased PSA - NEEDLE CORE BIOPSY - no urinary symptoms - Gleasons scoring - osteoblastic metastase may develop later (lower back pain, ALP, PSA)Osteoblastic metastasesproliferative bony lesions of increased density (LOWER BACK PAIN) alkaline phosphatase and Prostate specific antigen are INCREASEDA 67-year-old man is found on rectal examination to have a single, hard, irregular nodule within his prostate. A biopsy of this lesion reveals the presence of small glands lined by a single layer of cells with enlarged, prominent nucleoli. From what portion of the prostate did this lesion most likely originate? a. Anterior zone b. Central zone c. Peripheral zone d. Periurethral glands e. Transition zoneThe answer is c. (Kumar, pp 1050-1056.) Knowledge of the anatomic division of the prostate is important in understanding the locations of the major pathologic diseases of the prostate. Most adenocarcinomas of the prostate originate in the peripheral zone, while hyperplastic nodules originate in the transition zone. This anatomic differentiation is the result of the physi- ologic fact that the transition zone is particularly estrogen-sensitive, while the peripheral zone is particularly androgen-sensitive. Dihydrotestosterone (DHT), which is formed from testosterone by the action of 5-α-reductase, is responsible for the development of the prostate during fetal growth and also at the time of puberty. With aging, DHT levels are increased in the prostate, where DHT binds to nuclear DNA and causes prostatic hyperplasia. This hyperplastic effect by DHT is augmented by estrogen, which appears to func- tion by induction of androgen receptors, and therefore this hyperplasia occurs in the portion of the prostate that is particularly estrogen-sensitive.FEMAL/MALE AND GITIS LEFT