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Environmental &Nutritional Pathology

นายแพทย ดร.ณตพล ศภุณฐัเศรษฐกุลภาควิชาพยาธิวิทยาและนติิเวชศาสตร คณะแพทยศาสตร มหาวทิยาลัยนเรศวร

Topics• Environmental pathology

– General mechanism of Toxicity– Environmental pollution– Effects of Tobacco– Effects of Alcohol– Injury by Physical agent

• Nutritional deficiencies– Protein – Energy Malnutrition– Anorexia Nervosa and Bulimia– Vitamin Deficiencies– Mineral Deficiencies– Obesity

Environmental Pathology

• General mechanism of Toxicity• Environmental pollution• Effects of Tobacco• Effects of Alcohol• Injury by Physical agent

Environment Diseases

= Conditions caused by exposure to chemical or physical agents in the environment

[outdoor, indoor, occupational, personal (tobacco, alcohol, drug) environment]

Figure 8-1 Human exposure to pollutants. Pollutants contained in air, water, and soil are absorbed through the lungs, GI tract, and skin.In the body they may act at the site of absorption but are generally transported through the bloodstream to various organs, where they

may be stored or metabolized. Metabolism of xenobiotics may result in the formation of water-soluble compounds that are excreted or in activation of the agent, creating a toxic metabolite.

General Mechanisms of Toxicity

• “Toxicology” = The science of poison

• “Poison” basically depends on dosage

• “All substances are poisons”(Paracelsus 16th century)

• “Xenobiotics” = Exogenous chemicals

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Figure 8-2 Xenobiotic metabolism. Xenobiotics can be metabolized to nontoxic metabolites and eliminated from the body (detoxification). However, their metabolism may also result in activation of the chemical leading to formation of a reactive metabolite that is toxic to cellular components. If repair is not effective, short- and long-term effects develop. (Based on Hodgson E: A Textbook of Modern

Toxicology, 3rd ed. Fig. 1-1. Hoboken, New Jersey, John Wiley & Sons, 2004.)

Metabolism of Xenobiotics

• Cytochrome P-450 system in liver

• Detoxification and excretion

• Toxic metabolites reactive oxygen species (ROS) Cellular injury and cell death

Environmental Pollution

• Air pollution(Ozone, Nitrogen dioxide, Sulfur dioxide, Carbon monoxide)

• Metals as Environmental Pollutants(Lead, Mercury, Arsenic, Cadmium)

Carbon monoxide (CO)

• An air pollutants and important cause of death from accidents and suicide

• Imperfect oxidation of cabonaceous material: car exhaustion, wood furnace, etc.

• Binds hemoglobin with high affinity (Carboxyhemoglobin) and cause systemic asphyxiation with CNS depression, lethal coma

in 5 minutes

Heavy Metal• Lead: paint, Encephalopathy and Mental

deterioration in children, bone defect, anemia

• Mercury: Contaminated fish, CNS defect (cerebral palsy, deafness, blindness)

• Arsenic: soil and water, GI, cardio and CNS disturbance with hyperpigmentation of skin

• Cadmium: soil, batteries, obstructive lung disease and kidney damage

Effects of Tobacco

• Tobacco smoke contains >2,000 compounds

• Nicotine Tobacco addiction

• Strong carcinogen: Polycyclic aromatic hydrocarbon, nitrosamine, aromatic amines, especially Lung Cancer

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Figure 8-6 Adverse effects of smoking: the more common are in bold face.Figure 8-7 The risk of lung cancer is determined by the number of cigarettes smoked. (Modified from Stewart BW, Kleihues P [eds]:

World Cancer Report, Lyon, IARC Press, 2003.)

Smoking cessation

“Greatly reduces the risk of death from

Lung cancer”

Effects of Alcohol

• Drawsiness at blood level 200 mg/dl

• Alcohol is oxidized to acetaldehyde in the liver by alcohol dehydrogenase and acetate used in respiratory chain in mitochondria

• Acute effects: CNS depression, Fatty liver, gastritis, diuresis, dehydration, metabolic acidosis, hyperventilation

Effects of Alcohol

• Chronic alcoholism: alcoholic hepatitis, cirrhosis, portal hypertension, esophageal varice, gastric ulcer, cardiomyopathy, pancreatitis, Thiamine deficiency, hepatocellular carcinoma, and oral cancer

• Fetal alcohol syndrome: microcephaly, growth retardation, unusual facial feature, reduction in mental functions

Fetal Alcohol Syndrome

http://www.nlm.nih.gov/medlineplus/ency/images/ency/fullsize/21723.jpg

Growth retardation, Mental retardation, Unusual facial feature

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Drugs or Medications

• Adverse drug reaction(NSAIDs, paracetamol, Antibiotics, etc.)

• Drug abuse (Cocaine, Heroin, Marijuana, LSD, Ectasy,

Ice, Sedatives, Anxiolytics, Antitussive)

Injury by Physical Agents• Mechanical trauma (Abrasion, Laceration, Contusion, Cut wound,

Puncture wound)

• Thermal injury(Burns, Heat stroke, Hypothermia)

• Electrical injury (burns, cardiac failure)

• Radiation injury

Radiation Injury• Direct injury to DNA mutation

neoplastic transformation

• Indirect injury by generating free radicals from water or molecular oxygen in the body

• Rapidly dividing cells are very sensitive (germ cells, bone marrow, GI tract)

• Vascular damage and sclerosis ischemic necrosis and replacement by fibrous tissue

Figure 8-13 Effects of ionizing radiation on DNA and their consequences. The effects on DNA can be direct or, most importantly, indirect,through free-radical formation.

Figure 8-15 Overview of the major morphologic consequences of radiation injury. Early changes occur in hours to weeks; late changes occur in months to years. ARDS, acute respiratory distress syndrome.

Topics• Environmental pathology• Nutritional deficiencies

– Protein – Energy Malnutrition– Anorexia Nervosa and Bulimia– Vitamin Deficiencies– Mineral Deficiencies– Obesity

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Nutritional RequirementAn aequate diet should provide:1. Energy, in the form of carbohydrates,fats, proteins

2. Essential (as well as nonessential) aminoacids and fatty acids as building blocks

3. Vitamins and minerals function ascoenzymes and hormones in vital metabolic pathways

http://www.easy-weightloss-tips.com/images/diabetic-food-pyramid.jpg

Primary malnutrition : missing from the diet

Secondary malnutrition : adequate nutrientssupply, but malnutrition may result from

- Malabsorption- Impaired nutrient use or storage- Excess nutrient losses- Increased need for nutrients

ภาวะทุพโภชนาการ (Malnutrition) Common Causes

• Ignorance and poverty• Chronic alcoholism• Acute and chronic illnesses• Self-imposed dietary restriction

Protein - Energy malnutrition (PEM)

-PEM refers to a range of clinical syndrome characterized by an inadequate dietary intake of protein and calories to meet the body’s needs.

- Primary (children) and Secondary (illness) PEM

-Two polar forms: - Marasmus, - Kwashiorkor

1. Marasmus.

- Severe reduction in caloric intake (ขาดพลังงาน)- Reduction in body weight > 60%- Most common during the first year of life- Use somatic protein component &

subcutaneous fat as a source of energy- Serum albumin levels are either normal or only

slightly reduced- Growth retardation, multivitamin deficiencies,

anemia, immune deficiency

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2. Kwashiorkor

- More severe form of malnutrition than marasmus- Mainly occur in children 6 months to 3 years of age- Occurs when protein deprivation is relatively greater

than the reduction in total calories (ขาดโปรตีน)- Loss of visceral protein component- Hypoalbuminemia → generalized edema- Fatty change of liver- Skin lesion : hypo-and hyperpigmentation, desquamation- Hair change : overall loss of color or alternating band

(flag sign), straightening, loss of firm attachment tothe scalp

- Multivitamin deficiencies, anemia, immune deficiency

Secondary PEM.

poorSerumalbumin< 2.8 gm/dl

Normal fat andmuscle , edema,easily pluckablehair

WeeksAcute,catabolicillness (e.g.,severetrauma, burn,sepsis)

2. kwashiorkor-like PEM

Variable;dependsonunderlyingdisease

Normal ormildlyreducedserumproteins

History of weightloss, musclewasting, absentsubcutaneous fat

MonthsChronicillness (e.g.,cancer,chronic lungdisease,)

1. marasmus-likePEM

PrognosisLaboratoryfindings

Clinical featuresTimecourse

Clinicalsetting

SyndromeAnorexia Nervosa

• Self-induced starvation, resulting in marked weight loss

• Manifested as severe PEM with endocrine abnormalities– Amenorrhea (GnRH, LH, FSH)– Decreased bone density (Estrogen)– Decreased thyroid hormone release (cold

intolerance, bradycardia, constipation)

• Increased susceptibility to cardiacarrhythmia and sudden death

http://www.womenshealthzone.net/eating-disorders/anorexia-nervosa/effects/img/1287.gif

Bulimia

• A condition in which the patient binges on food and then induces vomiting

• Amenorrhea occurs in less than 50% of Pt., Endocrine hormone usually NOT affected

• Major medical complications:– Electrolyte imbalances (Hypokalemia) and cardiac

arrhythmia– Pulmonary aspiration of gastric content– Esophageal and cardiac rupture

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http://www.netscool.com/elrio/daniela/bulimia.jpg

Vitamin deficiencies• A (Retinoic acid) B1 (Thiamine)• D (Calciferol) B2 (Riboflavin)

B3 (Niacin)B12 (Cobalamin)C (Ascorbic acid)Folate

Vitamin A Deficiency: night blindness

: Bitot’s spot (small plaques of keratin debris),keratomalacia (corneal ulcer and destruction),xerophthalmia (dry eye), total blindness

: Squamous metaplasia→ 2o pulmonary infection,KUB stone (keratin debris)

Vitamin D1, 25 (OH)2 D is the active form of vitamin D

(synthesis from kidney by α1-hydroxylase)

Function : stimulate intestinal absorption of Ca and P.

: collaborates with parathyroid hormone (PTH)in the mobilization of Ca from bone, and reabsorption of Ca in the distal renal tubules

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Vitamin D deficiency• Rickets : is a softening of bones in children

potentially leading to fracture and deformity

• Vitamin D and calcium deficiencies from severe malnutrition

• Osteomalacia : same condition occurred in adult

Vitamin B1 (thiamine)Function : maintains neural membranes and

normal nerve conduction, especially peripheral nerve

Deficiency : most common in chronic alcoholism, result in syndromes of

- dry beriberi (polyneuropathy)- wet beriberi (heart failure, peripheral edema)- Wernicke – Korsakoff Syndrome

(Encephalopathy and psychosis)

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Vitamin B2 (Riboflovin) - cheilosis (cheilitis, angular stomatitis):

first + most characteristic sign (crack + fissure at the angles)

- Glossitis : tongue atrophy, red-blue discoloration

- Eye change : interstitial keratitis, cornealvascularization, corneal ulcer

- Scaling dermatitis : nasolabial folds and cheek (butterfly distribution), scrotal, vulva

Vitamin B3 (Niacin) - an essential component of NAD+ and NADP- Pellagra (3 D’s):

- Dermatitis sharply demarcated scaling and desquamation of exposure area, bilaterally symmetry

- Diarrhea caused by atrophy of the gastrointestinal epithelium

- Dementia results from neuron degeneration in the brain, and in the spinal cord

Vitamin B12 (Cobalamin) - Coenzyme in the DNA synthetic pathway

(as well as folic acid)

- Vit.B12 + R-binder(saliva) → protease (pancreas)↓

vit.B12 + intrinsic factor(gastric parietal cell)

↓absorb at ileum

Vitamin B12 Deficiency 1)Megaloblastic anemia

- hypochromic macrocytic anemia- hypersegmented neutrophils

2) Atrophic glossitis

3) Myelin degeneration of the spinal cord

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Folate- Coenzyme in the DNA synthetic pathway

- Absorb at proximal jejunum

- Deficiency: Neural tube defects in the

developing fetus (first few weeks post-conception)

Vitamin C (Ascorbic acid)

-Function : hydroxylation of procollagen, antioxidant

-Deficiency : impaired synthesis of collagen (bone and vessel)

Morphology- Scurvy in growing child

- Hemorrhagic diathesis

- Cartilagenous overgrowth widening of epiphysis and inadequate synthesis of osteoid

- Impaired wound healing and local infection

- Skin lesions : perifollicular hemorrhage, hyperkeratotic, papular rash

Figure 8-22 Major consequences of vitamin C deficiency caused by impaired formation of collagen. They include bleeding tendency because of poor vascular support, inadequate formation of osteoid matrix, and impaired wound

healing.

Mineral deficiencies• Iron : Hypochromic microcytic anemia • Zinc : Acrodermatitis enteropathica, growth

retardation, infertility • Iodine : Goiter and hypothyroidism • Selenium : Myopathy, rarely cardiomyopathy• Manganese : Muscle weakness, neurologic

defects, hypopigmentation, abnormal collagen cross-linking

Iron

-Absorbtion at duodenum

-Functional iron (80%) : hemoglobin, myoglobin, iron-containing enzymes

-Storage pool (20%) : hemosiderin, ferritin-bound iron ( liver, spleen, bone marrow, skeletal muscle )

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Iron Deficiency: dietary lack, increased requirement, chronic

blood loss: koilonychia (spoon nail), alopecia: atrophic changes in the tongue and gastric

mucosa, intestinal malabsorption: hypochromic microcytic anemia, poikilocytosis

# Plummer – Vinson syndrome: 1.) microcytic hypochromic anemia2.) Atrophic glossitis3.) Esophageal webs (dysphagia)

Hypochromic microcytic anemia with poikilocytosis

Obesity

Mesurement : Body mass index (BMI) = Wt (kg)/Ht(m) 2: Body–fat percentage (skin fold measurement) and lean body weight

BMI : normal = 18.5 – 24.9 kg./m2

: overweight = 25.0 – 29.9 kg./m2

: obesity > 30.0 kg./m2

Neurohumoral mechanism

• เปนกลไกการควบคมุการเผาผลาญพลังงาน• Afferent (humoral) signals : leptin(adipose

tissue), insulin, ghrelin(stomach)

• Hypothalamus

• Efferent : feeding behavior + energyexpenditure (TRH and autonomic pathway)

Food–derived energy > energy expenditure

Storage as triglycerides in adipose tissue (insulin effect)

- Daily requirement : 2000 – 3000 kcal/d.- Daily energy expenditure = Basal energy expenditure (BEE)

+Activities.

BEE man = 66 + (13.7 x Wt.) + (5 x Ht.) – (6.8 x age)BEE woman = 655 + (9.5 x Wt.) + (1.8 x Ht.) – (4.7 x age)

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Exercise more than 3 times per week

1. Aerobic exercise = moderate intensity+ long duration (20 – 45 min.)

→ use oxegen to burn fat→ Cardiovascular protection

2. Anaerobic exercise = high intensity +short duration.

→ glycogenolysis + muscular hypertrophy

Factors contributing to obesity :

1. Genetic predisposition2. Decreased lipid utitization : aging,

defective thermogenesis, inactivity, underexcercising

3. Sociocultural environment : stress, emotional, disturbances

4. Diseases : hypothalamic disorder.: hypothyroidism.: Cushing’s syndrome.: Polycystic ovary syndrome.

Complication of obesity

Metabolic syndrome, insulin resistance,impaired glucose tolerance, type 2diabetes mellitus, dyslipidemia,polycystic ovary syndrome

Endocrine/Metabolic

Gallstones, pancreatitis, abdominalhernia, nonalcoholic fatty liverdiseases (steatosis, steatohepatitis,and cirrhosis), and possiblygastroesophgeal reflux

Gastrointestnaltract

Urinary stress incontinenceGenitourinary

Abnormal menses, infertilityGynecologic

Osteoarthritis, gout, low back painMusculoskeletal

Abnormal pulmonary function, obstrucive sleepapnea, obesity hypoventilationsyndrome(pickwickian syndrome)

Respiratory

Hypertension, coronary artery disease, congestiveheart failure, arrhythmias, pulmonary hypertension,ischemic stroke, venous stasis, deep veinthrombosis, pulmonary embolus

Cardiovascular

Atelectasis, pneumonia, deep veinthrombosis, pulmonary embolus

Postoperativeevents

Esophagus, colon, gallbladder, prostate,breast, uterus, cervix, kidney

Cancer

Idiopathic intracranial hypertension(pseudotumor cerebri)

Neurologic

CataractsOphthalmologicReferences

• สุภรณ พงศะบุตร, บรรณาธิการ, “ตําราพยาธิวิทยาทั่วไป.”, ภาควิชาพยาธิวิทยาและนิติเวชศาสตร, โกลบอลพริ้นท, 2551, หนา 357-381, 417-438.

• Kumar V., Abbas A. K., Fausto N., “Robbins and Cotran Pathologic Basis of Disease, 7th edition.”, Elsevier Saunders, 2005, p.415-446, 446-466.