UNIMAS Faculty of Medicine and Health Sciences

PATHOGENESIS Similarities between the eating disorders Both eating disorders typically begin after a period of dieting by people who are fearful of becoming obese Become thin Preoccupied with food, weight, and appearance Struggling with feelings of depression, anxiety, and the need to be perfect Marked by disturbed attitudes towards eating Onset: Weight: Menstruation: Binge eating: Mortality: Cardiovascular: Skin / extremities: Glucose levels: Sex hormones level: LH and FSH level: Thyroxine levels: Cortisol levels:

Block 5 Endocrine, Metabolism and Nutrition

PATHOPHYSIOLOGY OF SIGNS AND SYMPTOMS ANEROXIA VS BULIMIA Anorexia Nervosa mid adolescence Markedly reduced Absent 25-50% ~5% per decade low BP, decreased heart rate Bulimia Nervosa late adolescence usually normal usually normal required for diagnosis low usually normal INVESTIGATIONS/OTHERS

PBL Summary

Causes of Obesity Environmental factors and social forces play a significant role in the development of obesity. The technological evolution of the physical environment has perpetuated the decline of physical activity and energy expenditure. A diet high in calories and/or fat appears to be an important factor in obesity (imbalanced diet and nutrition). Sedentary lifestyle and lack of physical activity. Followed a significant disturbance stress. Genetic factors may affect the many signaling molecules and receptors used by parts of the hypothalamus and GI tract to regulate food intake. Rarely, obesity results from abnormal levels of peptides that regulate food intake (eg, leptin) or abnormalities in their receptors (eg, melanocortin-4 receptor). Prenatal maternal obesity, prenatal maternal smoking, intrauterine growth restriction, and insufficient sleep can disturb weight regulation. Drugs, including corticosteroids, lithium, traditional antidepressants (tricyclics, tetracyclics, and monoamine oxidase inhibitors [MAOIs]), benzodiazepines, and antipsychotic drugs, often cause weight gain. Eating Disorder

dry skin, lanugo hair usually normal

Complications (cont) Insulin resistance, dyslipidemias, and hypertension (the metabolic syndrome) develop, often leading to diabetes mellitus and coronary artery disease. These complications are more likely in patients with fat that is concentrated abdominally, a high plasma triglyceride level, a family history of type 2 diabetes mellitus or premature cardiovascular disease, or a combination of these risk factors. Obesity is also a risk factor for nonalcoholic steatohepatitis (which may lead to cirrhosis) and for reproductive system disorders, such as a low plasma testosterone level in men and polycystic ovary syndrome in women. Obstructive sleep apnea can result if excess fat in the neck compresses the airway during sleep. Breathing stops for moments, as often as hundreds of times a night. This disorder, often undiagnosed, can cause loud snoring and excessive daytime sleepiness and increases the risk of hypertension, cardiac arrhythmias, and metabolic syndrome. Obesity may cause the obesity-hypoventilation syndrome (Pickwickian syndrome). Impaired breathing leads to hypercapnia, reduced sensitivity to CO2 in stimulating respiration, hypoxia, cor pulmonale, and risk of premature death.

Hypoglycemia Low estrogen or testosterone low

usually normal

usually normal

usually normal

low normal increased

usually normal usually normal

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Complications Osteoarthritis and tendon and fascial disorders may result from obesity. Skin disorders are common; increased sweat and skin secretions, trapped in thick folds of skin, are conducive to fungal and bacterial growth, making intertriginous infections especially common. Being overweight probably predisposes to cholelithiasis, gout, deep venous thrombosis and pulmonary embolism, and many cancers (especially colon and breast cancers).

UNIMAS Faculty of Medicine and Health Sciences

D: Metabolic disorders result from the absence or abnormality of an enzyme or its cofactor, leading to either accumulation or deficiency of a specific metabolite. PATHOGENESIS metabolic disorders can be caused by several mechanisms. Most metabolic disorders are caused by a single enzyme deficiency that disrupts one step of a metabolic pathway. This disruption may lead to the accumulation of metabolites preceding the interrupted step, as in alkaptonuria, or the inability to make certain intermediates or end- products of a specific metabolic pathway, such as ketoacids during fasting in patients with medium chain acyl-CoA dehydrogenase (MCAD) deficiency In most cases, metabolic disorders result from single mutations, deletions, or other genetic changes. However, a single enzyme, such as mitochondrial trifunctional protein, can be composed of multiple subunits encoded by different genes and catalyze more than one metabolic reaction. CLASSIFICATION Amino acid disorders Amino acids are important for the synthesis of numerous compounds, including structural proteins, peptide hormones, and enzymes needed for gluconeogenesis or in the generation of energy via acetyl-CoA formation. Organic acidemias Organic acidemias, also known as organic acidurias, are characterized by accumulation of abnormal (and usually toxic) organic acid metabolites and increased excretion of organic acids in the urine. A variety of disorders may result in abnormal urine organic acid profiles, including organic acidemias, phenylketonuria, maple syrup urine disease, certain fatty acid oxidation disorders, disorders of ketogenesis, and mitochondrial disorders. Urea cycle disorders The urea cycle is the metabolic pathway that transforms nitrogen to urea for excretion from the body (show figure 1). Deficiency of any of the enzymes in the pathway causes a urea cycle disorder (UCD). Examples of UCD include ornithine transcarbamylase deficiency and citrullinemia. Carbohydrate disorders Disorders of carbohydrate metabolism can lead to hypoglycemia, liver dysfunction, myopathy and/or cardiomyopathy. These disorders include deficiencies of enzymes in the pathways of the metabolism of glycogen, galactose, and fructose. Examples of carbohydrate disorders include galactosemia and the glycogen storage diseases.

Block 5 Endocrine, Metabolism and Nutrition

INBORN ERROR METABOLISM Mitochondrial disorders The frequency of recognition of disorders of mitochondrial metabolism is increasing. Within the mitochondria, organic acids, fatty acids, and amino acids are metabolized to acetyl-CoA, which condenses with oxaloacetate to form citric acid, which is oxidized in the Krebs cycle. Mitochondrial disorders can affect muscle alone, muscle and brain, or multiple systems with variable involvement of the heart, kidney, liver, skeletal muscle, or brain. The genetics and clinical manifestations of defects of the respiratory chain are discussed separately. Peroxisomal disorders Numerous catabolic and anabolic functions in cellular metabolism occur in peroxisomes. Catalytic functions include beta-oxidation of very long chain fatty acids (VLCFA); oxidation of pipecolic, phytanic, pristanic, and many dicarboxylic acids; and degradation of hydrogen peroxide by catalase. Anabolic functions include synthesis of bile acids and plasmalogen (an important component of cell membranes and myelin). Lysosomal storage disorders Lysosomes are cytoplasmic, single membrane-bound organelles that contain enzymes responsible for the degradation of a variety of compounds including mucopolysaccharides, sphingolipids, and glycoproteins. Deficient activity of specific enzymes leads to progressive accumulation of partially degraded material, leading to distention of the cell, disruption of cellular function, and, sometimes, failure of active transport of small molecules from the lysosomes. Purine and pyrimidine disorders Purine and pyrimidine nucleotides are important constituents of RNA, DNA, nucleotide sugars and other high-energy compounds, and cofactors, such as adenosine triphosphate (ATP) and nicotinamide adenine dinucleotide (NAD). The clinical presentation of disorders of purine and pyrimidine metabolism varies widely and may include renal calculi, neurologic dysfunction, delayed physical and mental development, selfmutilation, hemolytic anemia, and immune deficiency. Examples include Lesch-Nyhan disease, gout, and adenosine deaminase deficiency. Porphyrias The porphyrias are genetic or acquired deficiencies in the activity of enzymes in the heme biosynthetic pathway. They are discussed separately.

PBL Summary
What cause hyperammonic episode? Anything which places increased stress on the patient can trigger an episode. Viral infections are probably the most common cause, but episodes can be triggered by physical or emotional stress, dehydration, trauma, broken bones, the menstrual cycle, certain medications (like valproic acid), and changes in the diet.

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UNIMAS Faculty of Medicine and Health Sciences

Pituitary tumor (GH-secreting tumors) : 1. Densely granulated (monomorphic & acidophilic cells) 2. Sparsely granulated (chromophobe cells + considerable nuclear and cytologic pleomorphism, and retain focal and weak GH reactivity) Persistent hypersecretion of GH stimulates hepatic secretion on insulin-like growth factor I (IGF-I or Somatomedin C)

Block 5 Endocrine, Metabolism and Nutrition

ACROMEGALY [children] Before epiphyses closed, elevated of GH result in GIGANTISM body sizes, disproportionately long arms and legs After epiphyses closed acromegaly (1) skin and soft tissues (viscera such as thyroid, heart, liver, and adrenals); and bones of the face, hands, and feet (2) bone density (hyperostosis) in spine & hip (3) enlarged jaw d/t protrusion (prognathism) + broadening of the lower face (4) hands & feet s are enlarged + broad, sausage-like fingers IGF-1 is released more evenly than GH, and IGF-1 levels remain higher longer Somatostatin control the amount of GH in the body Symptoms Arthralgia (75%) Amenorrhea in women Hyperhidrosis Sleep apnea (60%) Headaches (55%) Paresthesia or carpal tunnel syndrome (40%) Loss of libido or impotence Hypertension (28%) Goiter (21%) Visual field defects Signs Gradual enlargement of the hands and feet (may be indicated by increased ring size or shoe size) Rapid growth Swelling of soft tissue Skin tags Thyroid disorders Muscle weakness/fatigue Skin changes, including thickening, oiliness, acne Hirsutism Coarsening of facial features, including forehead, nose, lips, tongue, jaw -

PBL Summary
Documentation of elevated serum GH and IGF-1 levels Tumor can be removed surgically or destroyed by radiation therapy GH secretion can be reduced by drug therapy MRI, CT scan, ECG

Goals of treatment Restore GH levels to normal symptoms referable to a pituitary mass lesion while not causing hypopituitarism

Diseases ass. + excess GH Gonadal dysfunction Diabetes mellitus Generalized muscle weakness Hypertension Arthritis Congestive heart failure Gastrointestinal cancers ( risk) Multiple Endocrine Neoplasia Type 1 (MEN 1) rare heritable disorder, abnormalities of parathyroid, pancreas, and pituitary glands (3Ps) Pituitary - some patients develop acromegaly from somatotrophin-secreting tumors

GH is produced by the pituitary IGF-1 is produced primarily by the liver in response to GH Somatostatin is produced by the hypothalamus, a part of the brain that influences the pituitary

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UNIMAS Faculty of Medicine and Health Sciences

Dietary iodine deficiency impaired synthesis of thyroid hormone Diffuse and multinodular goiters Impairment of thyroid hormone synthesis compensatory in serum TSH level causes hypertrophy & hyperplasia of thyroid follicular cells (gross enlargement of the thyroid gland) Compensatory in functional mass (gland) is able to overcome the hormone deficiency ensuring an euthyroid (state of having normal thyroid gland function) metabolic state (majority) If the underlying disorder is sufficiently severe compensatory responses may be inadequate to overcome the impairment in hormone synthesis goitrous hypothyroidism Degree of thyroid enlargement is proportional to the level and duration of thyroid hormone deficiency. DIFFUSE NONTOXIC (SIMPLE) GOITER Lack of iodine leads to synthesis of thyroid hormone & compensatory in TSH follicular cell hypertrophy, hyperplasia, goitrous enlargement Goiter may result from hereditary enzymatic defects interfere with thyroid hormone synthesis, all transmitted as autosomal-recessive conditions (dyshormonogenetic goiter)

Block 5 Endocrine, Metabolism and Nutrition

MULTINODULAR GOITER DIFFUSE NONTOXIC (SIMPLE) GOITER Simple goiter + euthyroid Serum T3 and T4 levels are normal Serum TSH is usually elevated In children, dyshormonogenetic goiter, caused by a congenital biosynthetic defect, may induce cretinism MULTINODULAR GOITER Multilobulated, asymmetrically enlarged glands produce lateral pressure in midline structure (trachea, esophagus) Airway obstruction Dysphagia Compression of large vessels in the neck and upper thorax ** Primary hyperthyroidism toxic multinodular goiter -

PBL Summary
TSH level is the most sensitive index of thyroid function Low TSH suggests hyperthyroidism. High TSH suggests primary hypothyroidism

MULTINODULAR GOITER Produce a more irregular thyroid enlargement May be nontoxic or may induce thyrotoxicosis (toxic multinodular goiter) Occur in both sporadic and endemic forms because it derives from simple goiter

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UNIMAS Faculty of Medicine and Health Sciences

DIABETES MELLITUS TYPE I

Block 5 Endocrine, Metabolism and Nutrition

DM Association of DM Arteriolosclerosis The effects of hyperglycemia (DM) on the lens and iris Thickening of the basement membrane of the epithelium of the pars plicata of the ciliary body. Retinal vasculopathy of diabetes mellitus may be classified into background (preproliferative) diabetic retinopathy and proliferative diabetic retinopathy. [pg.1437] Vulva diseases Pancreatic endocrine neoplasm (rare) Periodontitis (inflammation of supporting structure of teeth periodontal ligaments, alveolar bone, and cementum) [pg.775] Oral candidiasis (thrush) [pg.777] Manifestations in the skin Peripheral neuropathy (adult-onset) [pg.1335] Causes of steatosis (fatty change) abnormal accumulations of triglycerides within parenchymal cells (often seen in the liver because it is the major organ involved in fat metabolism, but it also occurs in heart, muscle, and kidney) [pg.36] Metabolic status can change wound healing [pg.114] Enhance development of infection, which manifests as small white surface patches similar to monilial lesions elsewhere. It is accompanied by leukorrhea and pruritus [pg.907] Hemochromatosis is characterized by the excessive accumulation of body iron, most of which is deposited in parenchymal organs such as the liver and pancreas [pg.908] Urinary tract infection Acute pyelonephritis (DM predisposing factor) Affect on glomerulus

PBL Summary
Diagnostic criteria: Fasting plasma glucose > 126 mg/dL Symptoms of diabetes + random plasma glucose > 200 mg/dL Plasma glucose level > 200 mg/dL after oral dose of 75g of glucose

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UNIMAS Faculty of Medicine and Health Sciences

Block 5 Endocrine, Metabolism and Nutrition

PBL Summary

DIABETES MELLITUS TYPE 2

Metabolic staging of DM 2

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UNIMAS Faculty of Medicine and Health Sciences

Due to elevation of glucocorticoid level Most causes of Cushing syndrome are the result of the administration of exogenous glucocorticoids Other three sources of the hypercortisolism can be categorized as endogenous Cushing syndrome:

Block 5 Endocrine, Metabolism and Nutrition

CUSHINGS SYNDROME (HYPERCORTISOLISM) Morphology. The adrenals have one of the following abnormalities: (1) cortical atrophy (2) diffuse hyperplasia (3) nodular hyperplasia (4) an adenoma, rarely a carcinoma Results from exogenous glucocorticoids suppression of endogenous ACTH results in bilateral cortical atrophy, d/t lack of stimulation of the zonae fasciculata and reticularis by ACTH Diffuse hyperplasia diffusely thickened and yellow in the size and number of lipid-rich cells in the zonae fasciculata and reticularis Central obesity (about trunk and upper back) 8590% Moon facies Weakness and fatigability Hirsutism Hypertension Plethora Glucose intolerance Osteoporosis Neuropsychiatric abnormalities Menstrual abnormalities Skin striae (sides of lower abdomen)

PBL Summary

Primary hypothalamic-pituitary diseases associated with hypersecretion of ACTH Hypersecretion of cortisol by an adrenal adenoma, carcinoma, or nodular hyperplasia - ACTH-independent Cushing syndrome (autonomous adrenal functions) The secretion of ectopic ACTH by a nonendocrine neoplasm (eg: small cell carcinoma of lung)

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