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Case Studies

A 35 –year-old woman became severely depressed after the sudden death of her husband. Two months later,she was brought to emergency room by her friend because of  extreme weakness and lethargy. She appeared thin and pale. Questioning revealed that she had not eaten for several weeks. 

Analysis of a plasma sample indicated elevated levels of Alanine, Acetoacetate, β hydroxy butyrate, and blood urea nitrogen(BUN). However her plasma glucose concentration was low (55mg/dL) . She was hospitalized, given intravenous feeding,  antidepressant medications and subsequently shifted to an 1800 Cal (7500 kJ) diet. Her recovery was uneventful. 

How was the patient obtaining energy during the time when she was not eating?

How could patient  maintain her plasma glucose within normal limits even though she was not eating?

What  is the significance of  elevated  plasma Alanine level?

Why is BUN elevated?

What is indicated by the fact that the plasma Acetoacetate and β– hydroxy butyrate levels are elevated?

It is a case of starvation. The high blood Alanine level signifies the catabolic state. Alanine in excess is released during starvation from muscle to serve as a substrate for glucose production in liver. Acetoacetate and β hydroxy butyrate are ketone bodies which are used as alternative fuel during conditions of glucose deprivation . High BUN signifies protein degradation; the carbon skeletons of amino acids are utilized for glucose production while amino groups are converted to urea.

Starvation

Prolonged fasting may result from an inability to obtain food, from the desire to lose weight rapidly, or in clinical situations in which an individual can not eat because of trauma,surgery, neoplasms, burns etc or even in depression (As in the given case) . In the absence of food the plasma levels of glucose, amino acids and triacylglycerols fall, triggering a decline in insulin secretion and an increase in glucagon release. The decreased insulin to glucagon ratio, and the decreased availability of circulating substrates, make this period of nutritional deprivation a catabolic state, characterized by degradation of glycogen, triacylglycerol and protein. This sets in to motion an exchange of substrates between liver,adipose tissue, muscle and brain that is guided by two priorities (i) the need to maintain glucose level to sustain the energy metabolism of brain ,red blood cells and other glucose requiring cells and (ii) to supply energy to other tissues by mobilizing fatty acids from adipose tissues and converting them to ketone bodies to supply energy to other cells of the body.

Fuel Stores

A typical well-nourished 70-kg man has fuel reserves totaling about 161,000 kcal (670,000 kJ).  The energy need for a 24-hour period ranges from about 1600 kcal (6700 kJ) to 6000 kcal (25,000 kJ), depending on the extent of activity. Thus, stored fuels suffice to meet caloric needs in starvation for 1 to 3 months. However, the carbohydrate reserves are exhausted in only a day.

Energy supply during starvation

During starvation the energy needs are  fulfilled by three types of fuels, glucose, fatty acids and ketone bodies.

a) Glucose supply during starvation (Gluconeogenesis)

Energy needs of brain and RBCs

Even under  conditions of starvation, the blood-glucose level has been maintained above 2.2 mM (40 mg/dl). The first priority of metabolism in starvation is to provide sufficient glucose to the brain and other tissues(such as red blood cells) that are absolutely dependent on this fuel.However, precursors of glucose are not abundant. Most energy is stored in the fatty acyl moieties of triacylglycerols. Fatty acids cannot be converted into glucose, because acetyl CoA cannot be transformed into pyruvate. The glycerol moiety of triacylglycerol can be converted into glucose, but only a limited amount is available. The only other potential source of glucose is amino acids derived from the breakdown of proteins. However, proteins are not stored,and so any breakdown will necessitate a loss of function.

Thus, the second priority of metabolism in starvation is to preserve protein,which is accomplished by shifting the fuel being used from glucose to fatty acids and ketone bodies by cells  other than brain cells and the cells lacking mitochondria.

It is a biological compromise to provide glucose to these cells as a priority. During prolonged starvation , when the gluconeogenic precursors are not available, proteins are however  broken down to use carbon skeleton of  glucogenic amino acids for glucose production.

b) Fatty acid oxidation

Energy need of liver

The low blood-sugar level leads to decreased secretion of insulin and increased secretion of glucagon. Glucagon stimulates the mobilization of triacylglycerols in adipose tissue and gluconeogenesis in the liver. The liver obtains energy for its own needs by oxidizing fatty acids released from adipose tissue. The concentrations of acetyl Co A and citrate consequently increase, which switch off glycolysis. Thus glucose utilization is stopped in liver cells to preserve glucose for priority cells

Energy need of muscles

The uptake of glucose by muscle is markedly diminished because of the low insulin level, whereas fatty acids enter freely.Consequently, muscle shifts almost entirely from glucose to fatty acids for fuel.The beta-oxidation of fatty acids by muscle halts the conversion of pyruvate into acetyl CoA, because acetyl CoA stimulates the phosphorylation of the pyruvate dehydrogenase complex, which renders it inactive. Most of the pyruvate is transaminated to alanine, at the expense of amino acids arising from breakdown of “labile” protein reserves synthesized in the fed state. The alanine, lactate and much of the keto-acids resulting from this transamination are exported from muscle, and taken up by the liver, where the alanine is transaminated to yield pyruvate. Pyruvate is a major substrate for gluconeogenesis in the liver.(Figure-1)

Figure- 1-showing Glucose Alanine and Cori’s cycle

In adipose tissue the decrease in insulin and increase in glucagon results in activation of intracellular hormone-sensitive lipase.This leads to release from adipose tissue of increased amounts of glycerol(which is a substrate for gluconeogenesis in the liver) and free fatty acids,which are used by liver, heart, and skeletal muscle as their preferred metabolic fuel, therefore sparing glucose.

Loss of muscle mass

During starvation, degraded proteins are not replenished and serve as carbon sources for glucose synthesis. Initial sources of protein are those that turn over rapidly, such as proteins of the intestinal epithelium and the secretions of the pancreas. Proteolysis of muscle protein provides some of three-carbon precursors of glucose. The nitrogen part of the amino acids is converted to urea (BUN)

c) Ketosis

Energy need of peripheral tissues

After about 3 days of starvation, the liver forms large amounts of acetoacetate and beta- hydroxybutyrate. Their synthesis from acetyl CoA increases markedly because the citric acid cycle is unable to oxidize all the acetyl units generated by the degradation of fatty acids. Gluconeogenesis depletes the supply of oxaloacetate, which is essential for the entry of acetyl CoA into the citric acid cycle. (Figure-2) Consequently, the liver produces large quantities of ketone bodies, which are released into the blood. At this time, the brain begins to consume appreciable amounts of acetoacetate in place of glucose. After 3 days of starvation, about a third of the energy needs of the brain are met by ketone bodies. The heart also uses ketone bodies as fuel. After several weeks of starvation, ketone bodies become the major fuel of the brain.

Figure- 2-fatty acid oxidation and ketosis during starvation.

In essence, ketone bodies are equivalents of fatty acids that can pass through the blood-brain barrier. Only 40 g of glucose is then needed per day for the brain, compared with about 120 g in the first day of starvation. The effective conversion of fatty acids into ketone bodies by the liver and their use by the brain markedly diminishes the need for glucose. Hence, less muscle is degraded than in the first days of starvation. The breakdown of 20 g of muscle daily compared with 75 g early in starvation is most important for survival.

A person’s survival time is mainly determined by the size of the triacylglycerol depot.

What happens after depletion of the triacylglycerol stores? The only source of fuel that remains is proteins. Protein degradation accelerates, and death inevitably results from a loss of heart, liver, or kidney function.

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Case details –

The patient is obese and is also suffering from “Metabolic syndrome”. She has a history of obesity dating to early child hood and also has a  positive family history. Her symptoms are suggestive of metabolic syndrome, a common complication of Obesity. Some of her features can be discussed as –

1) Obesity –She has an apple (android) pattern of fat distribution. Her waist to hip ratio is 41/39=1.05. Apple shape is defined as a waist to hip ratio of more than 0.8 in women, and more than 1.0 in men. She has therefore apple pattern of fat distribution which is common in males. Compared with other women of same body weight who have gynoid fat pattern, the presence of increased visceral or intra abdominal adipose tissue places her at greater risk for diabetes, hypertension,dyslipidemia and coronary heart disease. (The gynoid, “pear- shaped” or lower body obesity is defined as a waist to hip ratio of less than 0.8 for women and less than 1.0 for men. The pear shape is relatively benign health wise and is commonly found in females).

2) BMI (Body Mass Index)

BMI=Weight (kg)/height (m2).

For this patient

188 Pounds=85.5 kg (Approximately)

5 feet 1 inch height=1.55 meters (154.94 cm)

 =85.5/(1.55) 2

= 35.6 kg/ m2

World Health Organization (WHO) criteria based on BMI

Under this convention for adults,

Grade 1 overweight (commonly and simply called overweight) is a BMI of 25-29.9 kg/m2.

Grade 2 overweight (commonly called obesity) is a BMI of 30-39.9 kg/m2.

Grade 3 overweight (commonly called severe or morbid obesity) is a BMI greater than or equal to 40 kg/m2.

From the result calculated for the given patient, it is indicated that the patient is obese (Grade 2 overweight).

3)  Metabolic syndrome The patient is also suffering from ‘Insulin resistance syndrome’.She has hypertension, dyslipidemia, Hyperinsulinemia and impaired glucose tolerance.

Metabolic syndrome also referred to as Syndrome X or insulin resistance syndrome consists of a number of metabolic risk factors that increase the risk for atherosclerotic cardiovascular disease (CVD) and other cardiovascular complications such as cardiac arrhythmias, heart failure, and thrombotic events.

a) Criteria for diagnosis According to the National Cholesterol Education Program (NCEP) Adult Treatment Panel III (ATP III) report, there are six major components of metabolic syndrome relating to the development of CVD:

1) abdominal obesity

2) atherogenic dyslipidemia

3) elevated blood pressure

4) insulin resistance (with or without the presence of glucose intolerance)

5) proinflammatory state, and

6) prothrombotic state.

Note- A prothrombotic state is characterized by abnormalities,specifically elevations, in procoagulant factors, anti fibrinolytic factors,platelet alterations, and endothelial dysfunction. A proinflammatory state is characterized by elevations of circulating inflammatory molecules such as C-reactive protein (CRP), tumor necrosis factor-alpha, plasma resistin, interleukin (IL)-6, and IL-18. CRP is a general marker of inflammation that has been linked to CVD in patients with metabolic syndrome.

b)Associated diseases– Cardiovascular diseases and type 2 diabetes mellitus can be present in association with metabolic syndrome. The relative risk for new-onset CVD in patients with the metabolic syndrome, in the absence of diabetes, averages between 1.5- and threefold. Overall, the risk for type 2 diabetes in patients with the metabolic syndrome is increased three to fivefold. Patients with metabolic syndrome are also at increased risk for peripheral vascular disease. In addition to the features specifically associated with metabolic syndrome,insulin resistance is accompanied by other metabolic alterations. These include increases in uric acid,microalbuminuria, nonalcoholic fatty liver disease (NAFLD) and/or polycystic ovarian disease (PCOS), and obstructive sleep apnea (OSA).

A person suspected of having this syndrome should have a through history taken especially with regard to family history and presence of other cardiovascular risk factors.

c) An examination should include:-

 a) Recording the body weight

 b) Calculating the BMI

 c) Measurement of the waist circumference in inches

 d) Calculating the hip-waist ratio

 e) Measurement of the subcutaneous fat at 4 sites-biceps, triceps, sub scapular and supra-iliac

 f) Blood pressure measurement.

d) Laboratory Tests

1) Fasting lipids and glucose estimations are needed to determine if the metabolic syndrome is present.

2) The measurement of additional biomarkers associated with insulin resistance must be individualized. Such tests might include apo B, high-sensitivity CRP,fibrinogen, uric acid, urinary microalbumin, and liver function tests.

3) A sleep study should be performed if symptoms of OSA are present.

4) If  PCOS is suspected based on clinical features and an ovulation, testosterone, luteinizing hormone, and follicle-stimulating hormone should be measured.

 e) Management of metabolic syndrome – is highly dependent on the control of all of the contributing factors. This includes both underlying risk factors as well as metabolic risk factors. Lifestyle modifications should be implemented immediately for all patients diagnosed with metabolic syndrome. Lifestyle modifications include weight reduction, increased physical activity and nutritional therapy. Additional risk assessments should be performed in patients to assure appropriate goals of therapy throughout the course of the syndrome.

The key to preventing metabolic syndrome, however,remains diet and exercise. Any person with a strong family history of metabolic syndrome or type 2 diabetes should be especially careful to maintain a healthy lifestyle.
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A 40 –year- old woman, 5 feet 1 inch tall and weighing 188 pounds came for consultation to a physician complaining of frequent episodes of dizziness and numbness in her legs. She was too worried for her weight. Her waist measured 41 inches and hip measured 39 inches. Her only child who was 15-year-old, her sister and both of the parents were overweight. The patient recalled that she had been obese throughout her childhood and adolescence. Over the past 6 years she had been on seven different diets for periods of two weeks to three months, losing from 5 to 25 pounds. On discontinuation of each diet, she regained weight returning to 185 to 190 pounds.

During routine physical examination the patient was observed to be hypertensive (blood pressure of 200/120 mm Hg) but no abnormality was detected upon examination  of Chest, CNS and Abdomen .

The patient was asked to return to the clinic a week later in the fasting state,during which time a blood specimen was obtained. Blood Biochemistry revealed fasting hyperglycemia, hyperinsulinemia, dyslipidemia, and glucose intolerance.

What is the probable diagnosis?

What other investigations should be carried out to confirm the diagnosis?

Calculate the BMI for this woman and comment on the grade of obesity.

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