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CLINICAL APPLICATION EXERCISE CARBOHYDRATE METABOLISM LIST OF CASES CASE: DISEASE: 1 Hereditary fructose intolerance Fructose-1-phosphate aldolase (Aldolase b) deficiency Topic: Fructose metabolism 2 Galactosemia (severe form) Hexose-1-phosphate uridylyl transferase deficiency Topic: Galactose metabolism 3 Von Gierke disease (Glycogen storage disease type I) Glucose-6-phosphatase deficiency Topic: Liver glycogen metabolism 4 Glucose-6-phosphate dehydrogenase deficiency With primaquine-induced hemolytic anemia Topic: Pentose phosphate pathway 5 Hypoglycemia secondary to ethanol intoxication Topic: Gluconeogenesis 6 Tarui disease (Glycogen storage disease type VII) Muscle phosphofructokinase-1 deficiency Topic: Glycolysis CLINICAL APPLICATION EXERCISE CARBOHYDRATE METABOLISM LIST OF CASES BY CHIEF COMPLAINT CASE: CHIEF COMPLAINT: 1 Patient IF was a 7 month-old baby boy who was brought to the emergency room by his parents after suffering a "seizure". 2 Patient SG was an eight day-old female infant who was admitted to the neonatal intensive care unit with unexplained vomiting, diarrhea and jaundice. 3 Patient GV was a 12-year-old girl who gave a long history of episodes of weakness, sweating and "turning pale". 4 Patient DG was a 26-year-old medical student who was hospitalized with weakness, dyspnea on exertion and jaundice. 5 Patient JD was a homeless white male about 40-year-old who was brought unconscious to the emergency room. 6 Patient FP was a 7-year-old boy who complained of muscle weakness and pain after exercise. Glossary of clinical terms HPI: History of Present Illness FH: Family History PE: Physical Exam DX: Diagnosis EMT: Emergency Medical Technician CARBOHYDRATE METABOLISM CLINICAL APPLICATION EXERCISE CASE 1: PATIENT IF HPI: Patient IF was a 7 month-old baby boy who was brought to the emergency room by his parents after suffering a "seizure". He was born after a normal full-term pregnancy and was the first child. He was described as "healthy" and had grown normally during the first 6 months of life. His mother said that she breast-fed him exclusively until 6 months of age when she added cereal to his diet along with milk formula sweetened with sugar. Upon this change in feeding, the child began to feed poorly, vomited frequently and began to lose weight. The mother tried various formulas but the problem did not improve. The night before admission the child had become irritable after eating. About one hour after eating, the baby lost consciousness and became rigid which lasted about two minutes after which muscle jerking was observed and the child was rushed to the hospital. FH: The parents said that they were unrelated. This was their first child. The parents denied having any inherited diseases in their family. PE: The exam showed a thin, pale baby who was somnolent and difficult to arouse. He was sweating profusely but was afebrile. Deep tendon reflexes were absent. The liver was enlarged and the patient appeared jaundiced. LAB: Lab studies revealed hypoglycemia, hyperbilirubinemia, mostly unconjugated, and hypophosphatemia. Serum calcium was normal. Studies also showed hyperammonemia and elevated liver enzymes. Fructosuria was present on urinalysis. COURSE: The child was hospitalized and glucose was administered intravenously. After a few minutes the child became alert and reflexes returned to normal. Lab studies drawn the next morning before feeding were normal except for mildly elevated unconjugated bilirubin. A fructose tolerance test was started but was discontinued after one hour when blood samples drawn at that time showed hypoglycemia and hypophosphatemia. DX: HEREDITARY FRUCTOSE INTOLERANCE FRUCTOSE-1-PHOSPHATE ALDOLASE (ALDOLASE B) DEFICIENCY Some of the questions that you should address include: 1. 2. 3. 4. 5. 6. What is the diagnosis? What is the function of the enzyme whose deficiency produces this condition? What metabolite was accumulating inside the liver cells of this patient? Why was this patient hypoglycemic? What caused the drop in serum phosphate upon administration of fructose? Why was the patient in liver failure? CARBOHYDRATE METABOLISM CLINICAL APPLICATION EXERCISE CASE 2: PATIENT SG HPI: Patient SG was an eight day-old female infant who was admitted to the neonatal intensive care unit with unexplained vomiting, diarrhea and jaundice. The patient was born of an uncomplicated vaginal delivery. She appeared healthy and she breast fed well for the first day. On her second day, she began to refuse to breast feed and she vomited several times. The next day she developed diarrhea and began to lose weight. She continued to be restless and fussy, taking her meals reluctantly and vomiting frequently. On the eighth day, jaundice was noticed and she was transferred to the NICU. FH: Both parents described themselves as healthy. They were not known to be related to each other but they said that they were both born in the same small village in Ireland. PE: On admission to the NICU the patient was afebrile with normal vital signs. The patient appeared jaundiced. The liver was enlarged. Opthlamoscopic exam revealed small cataracts in both lenses. LAB: Blood chemistry revealed low serum glucose at 2.9mM (52mg/dl). [Normal female child: 3.3mM – 5.6mM (60 - 100mg/dl)] and hyperbilirubinemia both unconjugated and conjugated. Liver enzymes were elevated. Serum galactose levels were elevated. Urinalysis showed galactosuria. COURSE: The patient improved on a low-lactose diet. Within two days on this diet, the vomiting and diarrhea stopped and the patient began to gain weight. The galactose disappeared from her blood and urine. After one week the jaundice was gone and her liver had returned to normal size, but the cataracts remained. DX: GALACTOSEMIA (SEVERE FORM) HEXOSE-1-PHOSPHATE URIDYLYL TRANSFERASE DEFICIENCY Some of the questions that you should address include: 1. 2. 3. 4. 5. 6. What is the diagnosis? What is the function of the enzyme whose deficiency produces this condition? What metabolite was accumulating inside the liver cells of this patient and causing liver cell damage? Why was the patient hypoglycemic? Why was the patient treated with a low lactose diet? What caused the cataracts in this patient? CARBOHYDRATE METABOLISM CLINICAL APPLICATION EXERCISE CASE 3: PATIENT GV HPI: Patient GV was a 12-year-old girl who gave a long history of episodes of weakness, sweating and "turning pale". These episodes were relieved by drinking juice or by eating. She also complained of pain in the right upper quadrant of her abdomen. The girl's parents said that at her birth the pediatrician had told them that "her liver was big". The parents also said that her development had been slower than normal. FH: Both parents described themselves as "healthy". They said that they shared the same great-greatgrandfather. This was their second child. The other child was healthy. There was no family history of inherited disease. PE: Physical examination revealed a very thin girl. She displayed poor musculature and very little adipose tissue. Her height and weight were both below the third percentile for her age. Her abdomen was protuberant. Slight venous distension was noted over the abdomen. Her liver was enlarged, firm and smooth, and descended into the pelvic area. Her spleen was not enlarged. The remainder of the exam was within normal limits. LAB: Routine laboratory values were normal except for a low overnight fasting blood glucose level of 40mg/dl. [Normal female child: 60 - 100mg/dl]. Intramuscular injection of 0.5mg epinephrine did not produce an increase in blood glucose. The serum uric acid level was elevated at 0.6mM [Normal child: 0.12 – 0.30mM]. A liver biopsy showed an excessive number of cytoplasmic glycogen granules within the hepatocytes. Biochemical analysis revealed that the glycogen was normal in structure. COURSE: The patient was discharged on frequent feedings to counter the hypoglycemia. The parents were offered genetic counseling. DX: VON GIERKE DISEASE (GLYCOGEN STORAGE DISEASE TYPE I) GLUCOSE-6-PHOSPHATASE DEFICIENCY Some of the questions that you should address include: 1. 2. 3. 4. 5. 6. What is the diagnosis? What is the main function of the enzyme whose deficiency produces this condition? Why was the patient hypoglycemic? Why did the serum glucose not rise after injection of epinephrine? Why was the liver enlarged? Why was the serum uric acid level elevated? CARBOHYDRATE METABOLISM CLINICAL APPLICATION EXERCISE CASE 4: PATIENT DG HPI: Patient DG was a 26-year-old male medical student who was hospitalized with weakness, dyspnea on exertion and jaundice. He said that he had been short-of-breath on mild exertion for several days. Two days ago he observed that his urine was very dark. One day before admission he noticed yellowish coloration of his skin and eyes. The patient said that 2 weeks earlier he had returned to the U.S. from a two-month-long medical missionary service in Papua New Guinea. Shortly after his return, he had suffered severe general malaise with fever and chills. He had been diagnosed as having malaria due to Plasmodium vivax and had been treated with primaquine for the past 8 days. Although the fever and chills had resolved, he continued to feel very weak. FH: The patient said that both his parents were alive and in apparent good health. The patient said that both his parents had emigrated to the U.S. from Lebanon in 1985. The patient had 2 male siblings and 2 female siblings who were all in good health. The patient did not recall any history of inherited disease in his family. PE: The patient appeared acutely ill. Dyspnea was observed when the patient walked into the examination room. Heart rate and respiration rate were both accelerated. Other vital signs were normal. Both sclerae were yellow. The skin was pale with a yellowish coloration. The spleen was felt below the left rib cage. No other physical abnormalities were noted. LAB: CBC revealed anemia with reduced hemoglobin at 8.1g/dl [Normal male: 11 – 18g/dl] and reduced RBC count at 2.9 X 106/L [Normal male: 4 - 6 X 106/L]. Reticulocyte count was 12% [Normal 0.5 – 1.5%]. Peripheral smear revealed normochromic, normocytic erythrocytes; no malarial parasites were seen but the erythrocytes contained numerous Heinz bodies. Hyperbilirubinemia was present with 95% of the bilirubin unconjugated. The RBC glucose-6-phosphate dehydrogenase level was about one-tenth of the normal value. Urinalysis revealed dark urine which tested positive for hemoglobin. COURSE: The patient was given a transfusion of packed red cells. After 24 hours the patient hemoglobin and RBC count were within normal limits and the reticulocyte count had fallen to normal levels. Primaquine treatment was discontinued and the patient started on mefloquine. The jaundice cleared after 3 days and the patient was discharged on antimalarial therapy. DX: GLUCOSE-6-PHOSPHATE DEHYDROGENASE DEFICIENCY WITH PRIMAQUINE-INDUCED HEMOLYTIC ANEMIA Some of the questions that you should address include: 1. 2. 3. 4. 5. 6. What is the diagnosis? What is the main role that the affected metabolic pathway normally plays in erythrocytes? What important redox coenzyme is decreased in this patient's erythrocytes? What are Heinz bodies & how do they form in this condition? Why was the unconjugated bilirubin elevated in this patient? What are the probabilities that the patient's male and female siblings have this same condition? CARBOHYDRATE METABOLISM CLINICAL APPLICATION EXERCISE CASE 5: PATIENT JD HPI: Patient JD was a homeless white male about 40 years old who was brought unconscious to the emergency room. The EMT’s who brought him in said that when they first found him he was still conscious but was incoherent and speaking unintelligibly. He lost consciousness on the way to the hospital. He was found with an empty rum bottle in his possession. He carried no identification on his person. FH: Not available. PE: The patient was comatose and unresponsive to painful stimuli. His face was flushed and his breath had the odor of alcohol. His heart and respiration rates were both increased. Blood pressure was 100/50. He was afebrile. Optical light reflexes were present bilaterally but deep tendon reflexes were absent. The patient appeared thin and wasted as if he had not eaten for several days. Skin was pale and cold to the touch and he was sweating profusely. Skin turgor was reduced. LAB: Arterial blood gases revealed metabolic acidosis: pO2 95mm Hg, pCO2 30 mm Hg, pH 7.2. The patient was markedly hypoglycemic: blood glucose was 35mg/dL (Normal: 70 – 100mg/dL). Lactic acid concentration was elevated at 23.4mg/dL (Normal: 4.2 – 7.0mg/dL). Liver aspartate aminotransferase (SGOT) and alanine amino transferase (SGPT) were both elevated. Other routine lab studies were within normal limits. Blood alcohol content was 0.10% (0.10g/dL or 21.7mM). COURSE: IV fluids containing 10% glucose supplemented with vitamins were started. Within a few minutes the patient was awake and able to converse with his examiners. After three hours the patient was able to consume a light meal. About 6 hours after regaining consciousness, the patient complained of feeling "shaky" and sick to his stomach. He shouted that he felt like "bugs were crawling" on his skin. On exam the patient was trembling and appeared anxious and agitated and was uncooperative. Blood pressure was 220/120. Patient was hyperreflexive. A bolus of benzodiazepam was given IV and the patient was soon calm and cooperative. Periodic benzodiazepam injections were given over the next 48 hours. Three days after admission the patient left the hospital against medical advice and was lost to follow-up. DX: HYPOGLYCEMIA SECONDARY TO ETHANOL INTOXICATION Some of the questions that you should address include: 1. 2. 3. 4. 5. 6. What is the diagnosis? What redox cofactor is generated in large amounts by the metabolism of ethanol? Why did this patient develop hypoglycemia? Why was the patient's liver unable to use the carbon from glucogenic amino acids to make glucose? Why was the patient's liver unable to use glycogenolysis to release glucose? What was causing the metabolic acidosis in this patient? CARBOHYDRATE METABOLISM CLINICAL APPLICATION EXERCISE CASE 6: PATIENT FP HPI: Patient FP was a 7 year-old boy who complained of muscle weakness and pain after exercise. He said that after strenuous exercise he felt painful cramps in his leg muscles. Sometimes the pain was accompanied by nausea and vomiting. The patient said that sometimes after exercising his urine turned reddish purple. The patient stated that the weakness & muscle pain were more severe when he exercised right after eating. FH: The patient was of Japanese descent. The parents said that they were from the same small town in Japan and were distantly related. The patient had one older brother & one younger sister who were both apparently healthy. There was no history of inherited disease in the family. PE: The patient appeared thin and mildly jaundiced. Muscle strength was reduced in both arms & in both legs. Otherwise the exam revealed no abnormalities. The liver was not enlarged. LAB: Total hemoglobin content was within normal limits but RBC count was slightly reduced at 3.7 X 106/L [Normal male: 4-6 X 106/L]. The reticulocyte count was elevated at 5% [Normal 0.5 – 1.5%]. Peripheral smear showed normochromic, normocytic erythrocytes. Fasting blood glucose was normal and a glucose tolerance test gave normal results. An epinephrine response test gave a normal increase in blood glucose. Mild hyperbilirubinemia, mostly unconjugated, was present. Liver function studies were within normal limits. Creatine kinase MM isozyme was elevated. Serum lactate concentration at rest was 5.9mg/dL [Normal: 4.2-7.0mg/dL]. The urine tested positive for myoglobin. An ischemic forearm test was performed. Venous blood was drawn from the left arm at rest for baseline levels. Then a blood pressure cuff on the patient's upper left arm was inflated above systolic pressure and the patient was asked to rapidly contract and relax his left hand for 2 minutes. After 5 minutes a second sample of blood was drawn & the cuff was removed. The second blood sample showed an increase in serum ammonia of 135g/dL [Normal: serum ammonia increase of at least100g/dL] but serum lactate did not change [Normal: serum lactate increase of at least 5mg/dL]. The patient was admitted to the hospital for skeletal muscle and liver biopsies. A skeletal muscle biopsy showed increased glycogen deposits in muscle fibers. Biochemically the muscle glycogen could be digested by amylase indicating unusually long branches that resembled amylopectin. A liver biopsy displayed a normal amount of glycogen which was biochemically resistant to amylase digestion. COURSE: The patient was discharged in the care of his parents. He was instructed to avoid carbohydrate-rich food before playing and to avoid vigorous exercise. The parents were given genetic counseling. DX: TARUI DISEASE (GLYCOGEN STORAGE DISEASE TYPE VII) MUSCLE PHOSPHOFRUCTOKINASE-1 DEFICIENCY Some of the questions that you should address include: 1. 2. 3. 4. 5. 6. What is the diagnosis? What is the enzyme deficiency in this patient & in what tissue is the enzyme located? Why did the serum lactate level not increase after ischemia was induced by a blood pressure cuff? Why were the muscle symptoms more severe when he exercised right after eating? Why does the glycogen accumulating in the muscle resemble amylopectin? What made the patient's urine turn purple after strenuous exercise?