Biochemistry Problem Set

Jack Blazyk3/9/04

Case #1

Lamont

Presenting Complaint

“I’ve felt so weak lately. Sometimes, I can hardly stand up, and when I do, I feel like I’ll fall,” muttered Lamont.

History of Chief Complaint

Lamont, a 15-year-old boy, presents in the emergency department with general weakness that has increased progressively over the past three weeks. He states that he thinks he has had the flu. He admits nausea, fever, and abdominal pain as part of his flu symptoms. He also states that although he often feels hungry, he has had trouble eating. He has had some diarrhea and flatus. He denies any vomiting. He denies any history of head injury . Mom says she’s noticed that Lamont is making frequent trips to the bathroom to urinate.

Medication

Lamont takes no prescription or over-the-counter medication on a regular basis, except for an occasional Advil for sports-related aches and pains.

Habits

Lamont denies recreational drug use. He does not use tobacco or alcohol. He had been exercising regularly in high school athletics until about 3 months ago, when he began to feel worn out and decided to take a break.

Social History

Lamont lives at home with his parents and younger brother and attends high school. Until recently, he was active in wrestling and track.

Past Medical History

Lamont has had no major medical problems in the past, except for a case of pneumonia when he was six years old.

Family Medical History

Lamont’s father, 45 years old, has hypertension as does his paternal grandfather. The father, a local landscaper, says that his only sibling, a brother, had “a wasting type sickness” as a young boy and that he died at age 10. Except for fibrocystic breast disease, the mother is in good health. Her parents died in a plane crash in 1969. There is no family history of heart disease, high blood pressure, stroke, renal disease, tuberculosis, cancer, psychiatric or neurological disorders, migraine headaches, blood diseases, rheumatic disease or gout.

Systems Review

• Respiratory

Lamont’s mother states that he had pneumonia when he was 6 years old and that he has had a fever off and on for the last couple of weeks, but she doesn't know how high.

• Gastrointestinal

Lamont complains of some abdominal pain and has had nausea and diarrhea with his “flu.”

Systems Review

• Endocrine

Lamont admits to frequent trips to the bathroom during the day and having to get up during the night as many as five or six times to urinate. He states that he has been drinking quite a bit of water for the past few months now, and that he has lost about 25 pounds in the last 6 months, which he attributed to not eating right and loss of appetite.

Physical Exam

• General Appearance

Height: 71 inches

Weight: 132 pounds

Alert, but disoriented and unbalanced

Thin with poor skin turgor, skin is very dry

Physical Exam

• Vital Signs

Temperature: 101.2°F

Pulse: 115/min supine, 140/min upright

Respirations: 32/min

Blood Pressure: 106/76 supine, 88/60 upright

Physical Exam

• Head / Neck

Mucous membranes red and very dry

Slight superficial cervical and paratracheal lymphadenopathy

• Abdomen

Bowel sounds are hyperactive in all quadrants

Physical Exam

• Neurological

Lethargic, disoriented, and weak, but able to verbalize and communicate

Muscles are very weak

Lab Tests

Acetone Positive

Arterial Blood Gases

P O2 100 mm Hg

P CO2 25 mm Hg

pH 7.18

HCO3- 9 meq/L

Lab Tests

Electrolytes

Na+ 148 meq/L

K+ 5.4 meq/L

Cl- 103 meq/L

HCO3- 9 meq/L

Anion gap 41 meq/L

Lab Tests

Glucose

Random 625 mg/dL

HbA1c 18%

Lab Tests

Lipid Profile

Total Cholesterol 190 mg/dL

HDL Cholesterol 40 mg/dL

LDL Cholesterol 135 mg/dL

Triglycerides 150 mg/dL

Lab Tests

Liver Profile

SGOT (AST) 25 U/L

SGPT (ALT) 39 U/L

Bilirubin 0.8 mg/dL

Lab Tests

Urinalysis

Acetone Positive

Glucose Positive

Questions

1. What is Lamont’s acid-base situation? How did this arise?

2. What is happening in adipose cells? How is this regulated?

3. Since glucose can enter liver cells by facilitated diffusion, why is the liver NOT capable of reducing the blood glucose concentration?

4. What is happening in skeletal muscle? Why?

5. What is HbA1c and what is its significance? Is hemoglobin the only protein that can react with glucose?

HyperglycemicConditions

Gly

coly

sis

Glycogenesis

PentoseShunt

Fatty AcidSynthesis

CholesterolSynthesis

TriglycerideSynthesis

Hyperglycemic Liver

Gly

coly

sis Pentose

Shunt

Fatty AcidSynthesis

CholesterolSynthesis

TriglycerideSynthesis

Hyperglycemic Adipose

Hyperglycemic Muscle

Glycogenesis

Insulin-deficientConditions

Liver Glu

con

eog

enes

is

Fatty AcidOxidation

Ketone Body Synthesis

Glycogenolysis

Adipose Fatty AcidOxidation

TriglycerideBreakdown

No Uptake

Muscle Fatty AcidOxidation

Ketone BodyUtilization

No Uptake

Case #2

Mazie

Presenting Complaint

Mazie visits her family practitioner complaining of another yeast infection.

History of Chief Complaint

Over the years, Mazie, a 58-year-old female, has experienced recurring yeast infections. This is her fourth this year. She states she has been thirsty lately and urinates frequently. She says that she is hungry all the time. Recently, she has noticed that she gets dizzy when she stands up quickly.

Medication

Mazie takes no prescription or over-the-counter medication on a regular basis.

Habits

Mazie has smoked two packs of cigarettes a day for over 30 years. She admits to an occasional beer. Her lifestyle is totally sedentary.

Social History

Mazie is a housewife with six children, ages 28 to 42. She lives in Nelsonville with her husband, who is unemployed. She has never been outside of Athens County in her life, and has only been to Athens twice. She worries whether Medicaid will cover her doctor bills.

Past Medical History

Mazie had gall bladder problems 23 years ago.

Past Surgical History

Mazie had her gall bladder removed at age 35.

Family Medical History

Mazie’s maternal grandmother had “sugar” and died at age 64. Her mother, age 73, also has “sugar” and has had two heart attacks, the most recent last year. Her father died in an accident at the coal mine when she was 2. Her only sibling, a 57-year-old sister, has sugar and kidney problems.

Systems Review

• Cardiovascular

Mazie admits dyspnea on exertion, but denies any recurrent chest discomfort, palpitations, orthopnea, paroxysmal nocturnal dyspnea, hypertension, edema, cyanosis, cardiac murmurs, phlebitis, varicosities or claudication.

Systems Review

• Respiratory

Mazie often has “coughing spells” upon waking in the morning, but denies any history of pain in or unusual drainage from the ears, nose or throat. She does not suffer frequent nosebleeds. She denies recurrent chest pain, wheezing, hemoptysis, pneumonia, tuberculosis, fever or night sweats.

Systems Review

• Gastrointestinal

Mazie admits to increased appetite recently. She denies any history of recurrent abdominal pain, chronic indigestion, pyrosis, food dyscrasias, anorexia, recurrent nausea, vomiting, diarrhea, constipation, hematemesis, abnormal stools, jaundice, hemorrhoids or recent change in bowel habits.

Systems Review

• Urinary

Mazie admits to a burning sensation on the “outside” while urinating. She admits to polyuria, and has to get up three or four times at night to urinate. She denies any problems with urinary urgency, dysuria, hematuria, facial edema, oliguria, recurrent kidney or bladder infections, difficulty starting urinary stream, change in size or force of urinary stream, kidney stones, incontinence or urinary retention.

Systems Review

• Genital / Reproductive

Mazie has experienced repeated yeast infections accompanied by cheesy white discharge.

• Endocrine

Mazie admits to dry skin and increased thirst and urination recently. Over the past two years, she has gained about 20 pounds.

Physical Exam

• General Appearance

Height: 64 inches

Weight: 180 pounds

Alert

Oriented to time, person and place

BMI

Physical Exam

• Vital Signs

Temperature: 98.6°F

Pulse: 80/min supine, 95/min upright

Respirations: 15/min

Blood Pressure: 120/80 supine, 100/60 upright

Physical Exam

• Head / Neck

Mucous membranes dry and pink

Dentition is poor, with numerous caries noted

Gingiva are inflamed

• Genitals

White cheesy discharge (KOH positive) noted

Lab Tests

Acetone Moderate

Arterial Blood Gases

P O2 100 mm Hg

P CO2 32 mm Hg

pH 7.34

HCO3- 17 meq/L

Lab Tests

Electrolytes

Na+ 140 meq/L

K+ 4.2 meq/L

Cl- 100 meq/L

HCO3- 14 meq/L

Anion gap 30 meq/L

Lab Tests

Cardiac Monitor Sinus tachycardia

Lab Tests

Glucose

Random 325 mg/dL

2-hr Postprandial 560 mg/dL

HbA1c 13%

Lab Tests

Lipid Profile

Total Cholesterol 250 mg/dL

HDL Cholesterol 38 mg/dL

LDL Cholesterol 205 mg/dL

Triglycerides 160 mg/dL

Lab Tests

Liver Profile

SGOT (AST) 12 U/L

SGPT (ALT) 15 U/L

Bilirubin 0.4 mg/dL

Lab Tests

Urinalysis

Acetone Negative

Glucose Positive

Questions

1. How does Mazie’s acid-base situation compare to that of Lamont’s? Is Mazie likely to experience full-blown ketoacidosis?

2. How does the root cause of Mazie’s condition compare to that of Lamont’s?

3. Is Mazie producing insulin? If so, how much?

4. From the diagnostic studies, estimate how long Mazie has been experiencing these symptoms.

5. How will the long-term treatment differ for Mazie compared to Lamont?

Zimmet et al., Nature 414 (2001) 782

Zimmet et al., Nature 414 (2001) 782

Saltiel & Kahn, Nature 414 (2001) 799

Saltiel & Kahn, Nature 414 (2001) 799

Saltiel & Kahn, Nature 414 (2001) 799

Saltiel & Kahn, Nature 414 (2001) 799

Moller, Nature 414 (2001) 821

Moller, Nature 414 (2001) 821

Statins for the Masses?

Pravachol = pravastatin

Lipitor = atorvastatin

               

            

Christopher Cannon, MDBrigham and Women's HospitalBoston, ME

Disclosure: Research grant support: Bristol Myers Squibb, Merck, Sanofi-Synthelabo Consultant: AstraZeneca, GlaxoSmithKline, Guildford Pharmaceuticals, Vertex

Pravastatin or Atorvastatin Evaluation and Infection Therapy-Thrombolysis in Myocardial Infarction 22 (PROVE IT-TIMI 22) Lipid-lowering therapy with statins has been problem to reduce the risk of cardiovascular events, but the optimal degree of low-density lipoprotein (LDL) cholesterol lowering isa unclear.

PROVE IT was designed to answer to assess whether 1) statins are effective in reducing cardiac events when started early after acute coronary syndromes, and 2) intensive lowering of LDL cholesterol confers added benefit compared with LDL cholesterol lowering to <100 mg/dL as recommended by current national guidelines.

PROVE IT was conducted at 349 sites worldwide and included 4,162 patients who had been hospitalized for an acute coronary syndrome (ACS) within the previous 10 days. They were randomized to intensive lipid-lowering therapy with atorvastatin, 80 mg/day, or a moderate-intensive strategy with pravastatin, 40 mg/day. The primary endpoint was the composite of all-cause mortality, myocardial infarction, documented unstable angina requiring hospitalization, revascularization, and stroke. The mean duration of treatment and follow-up was 2.5 years, at which time 1,001 total events were recorded. To be eligible, patients had to be in stable condition and had to have a total cholesterol =240 mg/dL, measured within the first 24 hours after the onset of ACS (or up to 6 months earlier if no sample had been obtained during the first 24 hours). Sixty-nine percent of the study patients had a percutaneous coronary intervention in response to their ACS. Ninety three percent of the patients received aspirin during the treatment period, 69% received ACE inhibitors, 85% were treated with beta blockers, and 72% received clopidogrel or ticlopidine initially (20% at 1 year).

The median baseline LDL cholesterol was 106 mg/dL in each group at the time of randomization, which was a median of 7 days after the onset of the index event. The mean achieved LDL cholesterol was 62 mg/dL in the patients assigned to atorvastatin vs. 95 mg/dL in those assigned to pravastatin.

The primary endpoint occurred in 22.4% of patients randomized to atorvastatin and 26.3% of patients assigned to pravastatin, which corresponds to a 16% risk reduction (p =0.005) in the atorvastatin recipients. The benefit of the intensive lipid-lowering strategy emerged as soon as 30 days and was maintained over time. There was a trend toward a reduction in all-cause mortality with the aggressive lipid-lowering strategy (28% relative risk reduction; p =0.07). The benefit of the aggressive strategy was consistent across all endpoints, except for stroke, and all subgroups. The benefit of intensive lipid lowering was greater in patients with a baseline LDL cholesterol =125 mg/dl compared with patients with a baseline LDL cholesterol <125 mg/dL.

In conclusion, PROVE IT demonstrated a benefit to aggressive LDL cholesterol reduction on top of optimal management when initiated at discharge in patients hospitalized for ACS. The results suggest that after an ACS, the target LDL cholesterol may be lower than current guidelines, especially in those patients with higher baseline LDL cholesterol levels.