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Environmental & Nutritional Pathology

นายแพทย ดร.ณตพล ศุภณัฐเศรษฐกุล

ภาควิชาพยาธิวิทยา

คณะแพทยศาสตร มหาวิทยาลัยนเรศวร 3 มีนาคม 2557

Topics • Environmental pathology

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

• Nutritional deficiencies – Protein – Energy Malnutrition – Vitamin Deficiencies – Mineral Deficiencies – Obesity

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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.

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General Mechanisms of Toxicity

• “Toxicology” = The science of poison

• “Poison” basically depends on dosage

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

• “Xenobiotics” = Exogenous chemicals

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.)

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Metabolism of Xenobiotics • Cytochrome P-450 system in liver (ER)

• Detoxification and excretion

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

• Chemicals, drugs, alcohol are primarily metabolized by this enzyme system

Environmental Pollution

• Air pollution : “smog” (Ozone, Nitrogen dioxide, Sulfur dioxide,

Carbon monoxide, particulate matter) • Metals as Environmental Pollutants (Lead, Mercury, Arsenic, Cadmium)

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Carbon monoxide (CO)

• An air pollutants and important cause of death from accidents and suicide (nonirritating, colorless, tasteless, odorless gas)

• 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

http://www.jems.com/Images/CO_Fig1_tcm16-186547.jpg

20-30% saturation = systemic hypoxia 60-70% saturation = unconsciousness and death

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Heavy Metal • Lead: paint, Encephalopathy and Mental

deterioration in children, bone defect, anemia

• Mercury: Contaminated fish and dental amalgams, CNS defect (cerebral palsy, deafness, blindness), “Minamata disease”

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

• Cadmium: soil, batteries, obstructive lung disease and kidney damage, itai-itai in postmenopausal

women (osteoporosis, osteomalacia associated with renal disease)

http://www.healthofchildren.com/images/gech_0001_0003_0_img0164.jpg

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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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Effects of Tobacco

• Important risk factor for atherosclerosis, MI, cerebrovascular accident (stroke)

• Predispose to emphysema, chronic bronchitis, chronic obstructive disease

• Maternal smoking increases the risk of abortion, premature birth, intrauterine

growth retardation

Figure 8-6 Adverse effects of smoking: the more common are in bold face.

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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”

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Effects of Alcohol

• Drawsiness at blood level 200 mg/dl ...เมา…

• 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

By law • เมาสุราตามกฎหมาย ปริมาณ alcohol ในกระแส

เลือดมากกวา 50 mg/dl (วัดโดยการเปาออกมาทางลมหายใจ)

• จําคุกไมเกิน 3 เดือน หรือปรับตั้งแต 2,000-10,000 บาท หรือ ทั้งจําทั้งปรับ (พรบ.จราจรทางบก พ.ศ. 2522)

• จําคุกไมเกิน 1 ป หรือปรับตั้งแต 5,000-20,000 บาท หรือทั้งจําทั้งปรับ และพักใชใบอนุญาตขับขี่ไมนอยกวา 6 เดือน หรือเพิกถอนใบอนุญาต (ฉบับที่ 7 พ.ศ. 2550) (รอลงอาญา+คุมประพฤติ)

• ไวน 2 แกว, เบียรปกติ 2 กระปอง, ไลทเบียร 4 กระปอง, สุรา 6 ฝา เปนตน

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• - ถาการกระทําความผิดตามวรรคหนึ่งเปนเหตใุหผูไดรับอนัตรายแกกายหรือ

จิตใจผูกระทําตองระวางโทษจําคุกตัง้แตหนึ่งปถึงหาป ปรับสองหมื่นบาทถึง หนึ่งแสนบาท และใหศาลสั่งพักใชใบอนุญาตขบัขี่ของผูน้ันมกีําหนดไมนอยกวา หนึ่งปหรือเพิกถอนใบอนุญาตขับขี ่

• - ถาการกระทําความผิดตามวรรคสองเปนเหตใุหผูอ่ืนไดรับอันตรายสาหัส ผูกระทําตองระวางโทษจําคกุตัง้แตสองปถึงหกป และปรับตั้งแตสี่หมืน่บาทถึงหนึ่งแสนสองหมื่นบาท และใหศาลสั่งพักใชใบอนุญาตขบัขี่ของผูน้ันมกีาํหนดไมนอยกวาสองป หรือเพิกถอนใบอนุญาตขับขี ่

• - ถาการกระทําความผิดตามวรรคสองเปนเหตใุหผูอ่ืนถงึแกความตาย ผูกระทําตองระวางโทษจําคุกตั้งแตสามปถึงสิบป และปรับตั้งแตหกหมืน่บาทถึงสองแสนบาท และใหศาลสั่งเพิกถอนใบอนุญาตขบัขี ่

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

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Fetal Alcohol Syndrome

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

Growth retardation, Mental retardation, Unusual facial feature

Drugs or Medications

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

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

Ice, Sedatives, Anxiolytics, Antitussive)

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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

Figure 8-12 A, Laceration of the scalp: the bridging strands of fibrous tissues are evident. B, Contusion resulting from blunt trauma. The skin is intact but there is hemorrhage of subcutaneous vessels, producing extensive discoloration. (From the teaching collection of the

Department of Pathology, University of Texas Southwestern Medical School, Dallas, Texas.)

Laceration wound Contusion

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Abrasion wound

Cut wound, Incised wound

Stab wound, Puncture wound

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

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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.

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Topics • Environmental pathology • Nutritional deficiencies

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

Nutritional Requirement

An aequate diet should provide: 1. Energy, in the form of carbohydrates,

fats, proteins

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

3. Vitamins and minerals function as coenzymes and hormones in vital metabolic pathways

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

Primary malnutrition : missing from the diet Secondary malnutrition : adequate nutrients

supply, but malnutrition may result from - Malabsorption - Impaired nutrient use or storage - Excess nutrient losses - Increased need for nutrients (GI diseases, chronic wasting diseases, acute critical illness)

ภาวะทุพโภชนาการ (Malnutrition)

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Common Causes • Poverty (homeless, aged, children) • Ignorance (infants, adolescents, pregnant women) • Chronic alcoholism • Acute and chronic illnesses (trauma, burn, cancer, etc.) • 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

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1. Marasmus.

- Severe reduction in caloric intake (ขาดพลังงานมากกวา) - Reduction in body weight > 60%

- Most common during the first year of life

- Use somatic protein component & subcutaneous fat as a source of energy very thin

- Serum albumin levels are either normal or only slightly reduced

- Growth retardation, multivitamin deficiencies, anemia, immune deficiency

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 (ขาดโปรตีนมากกวา)

- 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 to the scalp

- Multivitamin deficiencies, anemia, immune deficiency

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Secondary PEM.

Syndrome Clinical setting

Time course

Clinical features Laboratory findings

Prognosis

1. marasmus-like PEM

Chronic illness (e.g., cancer, chronic lung disease,)

Months History of weight loss, muscle wasting, absent subcutaneous fat

Normal or mildly reduced serum proteins

Variable; depends on underlying disease

2. kwashiorkor-like PEM

Acute, catabolic illness (e.g., severe trauma, burn, sepsis)

Weeks Normal fat and muscle , edema, easily pluckable hair

Serum albumin < 2.8 gm/dl

poor

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Vitamin Deficiencies and Toxicities

• Fat soluble vitamins – A, D, E, K – Deficiency due to abnormal fat

absorption – Accumulate and toxicity

• Water soluble vitamins

– B1, B2, B3, B6, B12, C, Folate

• Other names, diseases

Other names • Ascorbic acid • Niacin • Pyridoxine • Calciferol • Cobalamin • Retinoic acid • Thiamine • Riboflavin • Tocopherol • Phylloquinone • Folic acid

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Vitamin deficiencies Bitot’s spot, Keratomalacia Rickets, Osteomalacia Beri beri, Wernicke-Korsakoff syndrome Scurvy, impaired collagen synthesis Bleeding diathesis Neural tube defect Pellagra (3Ds) Angular stomatitis, cheilosis Megaloblasic anemia with neurologic symptoms

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)

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Vitamin D

1, 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, corneal vascularization, corneal ulcer

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

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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

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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

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Vitamin B12 • ผูปวยที่มีการผาตัดกระเพาะอาหาร • ผูปวย Chronic atrophic gastritis

(autoantibody to IF, parietal cell, IFR) • Strictly vegetarian • Megaloblastic anemia • Macrocytic RBC with Hypersegmented

neutrophil • Anemia with neurological changes

Folate

- Coenzyme in the DNA synthetic pathway

- Absorb at proximal jejunum

- Deficiency : Neural tube defects in the developing fetus (first few weeks post- conception)

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Vitamin C (Ascorbic acid)

-Function : hydroxylation of procollagen, antioxidant

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

Morphology

- Scurvy in growing child

- Hemorrhagic diathesis (bleeding tendency)

- Cartilagenous overgrowth widening of epiphysis and inadequate synthesis of osteoid

- Impaired wound healing and local infection

- Skin lesions : perifollicular hemorrhage, hyperkeratotic, papular rash

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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

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http://1.bp.blogspot.com/_uqBx13aymCE/TEfqeBHbq2I/AAAAAAAADNM/SylPjdnnHQs/s1600/anemia+symptoms.png

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

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Neurohumoral mechanism

• เปนกลไกการควบคุมการเผาผลาญพลังงาน

• Afferent (humoral) signals : leptin (adipose tissue), insulin, ghrelin(stomach)

• Hypothalamus

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

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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)

Factors contributing to obesity :

1. Genetic predisposition 2. 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.

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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

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ขอมูลเพิ่มเติม • สํานักงานกองทุนสนับสนุนการสรางเสริมสุขภาพ http://www.thaihealth.or.th/about • โครงการคนไทยไรพงุ กรมอนามัย กระทรวงสาธารณสุข http://nutrition.anamai.moph.go.th/web

/khonthairaipung.html • สํานักโภชนาการ กรมอนามัย กระทรวงสาธารณสุข http://nutrition.anamai.moph.go.th/

References • สุภรณ พงศะบุตร, บรรณาธิการ, “ตําราพยาธิวิทยาท่ัวไป.”, ภาควิชาพยาธิ

วิทยาและนิติเวชศาสตร, 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.