Y2PATHOB9L4 - Environmental and Nutritional Diseases.pdf

Y2PATHOB9L4 LECTURER: DR. JOENER B. BANGERO, MD, DPSP PATHOLOGY SEPTEMBER 12, 2...

Y2PATHOB9L4 LECTURER: DR. JOENER B. BANGERO, MD, DPSP PATHOLOGY SEPTEMBER 12, 2024 | 3:00-5:00 ENVIRONMENTAL AND NUTRITIONAL DISEASES 7 PATHOGENESIS TABLE OF CONTENTS Most of the absorbed lead is taken up to bone and I. Environmental Disease F. Marijuana developing teeth (80-85%) II. Metals as Environmental IV. Injury Produced by Ionizing ○ Competes with calcium for binding to phosphates Pollutants Radiation ○ Incorporated in the hydroxyapatite molecule during bone A. Lead A. Morphology formation instead of calcium B. Mercury B. Acute and Chronic 5-10% of absorbed lead remains in the blood C. Tobacco Effects ○ Remainder is distributed throughout soft tissues D. Alcohol V. Nutritional Diseases Lead binds sulfhydryl groups III. Injury by Therapeutic Drugs A. Malnutrition ○ Interferes with activity of several enzymes required for A. Adverse Drug Effect B. Severe Malnutrition heme synthesis, leading to anemia B. Menopausal Hormone C. So-Called Secondary ○ ALA dehydratase enzyme Therapy (MHT) Malnutrition → Destruction of heme synthesis C. Oral Contraceptives D. Vitamin Deficiencies Lead that binds as cofactor D. Opioids E. Obesity Lead competes with calcium for binding to proteins E. Cocaine ○ Interferes with the proteins that participate in mitochondrial and neural functions (neurotoxicity) I. ENVIRONMENTAL DISEASE Lead interferes with membrane ion transporters ○ Which may contribute to renal toxicity Environmental factors - can cause/influence many diseases → Proximal tubule of the kidney is affected ○ Indoor and Outdoor factors ○ Occupational factors MORPHOLOGY Exposure is largely determined by public health measures ○ Governmental laws that ensure water and air quality Major targets: ○ Provide protections from physical dangers ○ Bone marrow → Engineering control ○ Nervous system → Administrative control ○ Kidneys ○ Toxins in the workplace and community Earliest sign of lead accumulation: Matters of personal choice ○ Found in the peripheral blood ○ Tobacco use, alcohol ingestion, recreational drug → When suspecting lead toxicity, the primary laboratory consumption, diet, exercise, etc test ordered is peripheral blood smear Threats become more pronounced due to alterations in ○ Look for: ○ Weather patterns → Microcytic, hypochromic anemia associated with ○ Sea levels punctate basophilic stippling of red cells ○ Food production Stippled dots in the mature RBC ○ Distribution of infectious diseases RBCs are small and spherical Brain damage tends to occur in children II. METALS AS ENVIRONMENTAL POLLUTANTS ○ Severe form leads to → Brain edema A. LEAD → Demyelination of white matter Can lead to multiple toxicities → Neuronal necrosis ○ Hematologic - Hematopoiesis → Astrocytic proliferation ○ Skeletal - Maturation of the skeleton Adults: ○ Neurological - Changes related to cognition ○ Peripheral demyelinating neuropathy (motor neurons) ○ Gastrointestinal - GI problems leading to wrist drop and foot drop ○ Renal Children are more susceptible for CNS damage In current practice, the prevalence is lesser since its largely ○ More permeable blood brain barrier been eliminated from paints and gasoline → Adults are more prone to PNS damage ○ But persists in mines, foundries, and batteries Kidneys Highest risk is seen in children living in older houses with ○ Develop proximal tubular damage associated with flaking lead paint intranuclear lead inclusions ○ Settlements from the 1960s and earlier → The proximal tubule tends to reabsorb these metals ○ Tend to taste sweet thus making it attractive to toddlers because they think it’s calcium Ingested lead is particularly harmful to children ○ Chronic renal damage: ○ Absorb more than 50% of lead from food → Interstitial fibrosis → Adults absorb only 15% → Gout ○ Children have more permeable blood-brain barrier → Renal failure → Increased susceptibility to brain damage 🔊🗃️ MG 3 | MG 10 1 of 17  Y2PATHOB9L4: ENVIRONMENTAL DISEASES CLINICAL FEATURES About Figure 3: ○ In lead poisoning, impaired calcification of the cartilage, Dependent on exposure levels especially in growing individuals is usually found. ○ Signs and symptoms depend on the levels of exposure. → Seen as radiodensity or opacities in the epiphysis → Not always constant. → Cortical bones appear radiopaque and denser than → Depends on serum lead levels. the surrounding medulla - clue of lead toxicity Lead-induced peripheral neuropathies in adults ○ Generally resolve with elimination of exposure B. MERCURY Neurologic abnormalities in children are usually irreversible Lead poisoning may be suspected on the basis of Damages CNS ○ Neurologic changes, or ○ Particularly the developing fetus and other organs: ○ Presence of unexplained anemia → GI tract - when ingested, it often damages the lining → Blood smear = important diagnostics for lead toxicity epithelium since it's the first to contact it Treatment: → Kidneys - during excretion ○ Prevention of further exposure Main source of exposure: Eating contaminated fish ○ Administration of chelating agents that enhance excretion ○ Common in areas w/ factories releasing mercury into water of lead in urine Inorganic mercury ○ Eliminate lead found within the household substances ○ Environmental sources or from industrial contamination ○ Converted to organic compounds such as methyl mercury by bacteria → Enters food chain and is concentrated in carnivorous fish (swordfish, shark, bluefish and tuna) Avoid consumption due to increased risk of intoxication Ingested methyl mercury is efficiently absorbed and distributed widely in the body Developing brain is extremely sensitive to methyl mercury CDC recommended that pregnant women avoid the consumption of fish known to contain mercury ○ Sardines are relatively safer since they feed on plants ○ Avoid tuna and other carnivorous fishes Ingested mercury injures gut and cause: ○ Ulcerations ○ Bloody diarrhea Figure 1. Effects of Lead Poisoning in Children Related to Blood In Kidneys: Levels ○ Acute tubular necrosis → Mercury is excreted in the lumen ○ Renal failure C. TOBACCO Various media campaigns portray tobacco to contain numerous carcinogens and toxins that cause several cancers and contribute to cardiovascular disease Main culprit is cigarette smoking ○ Most common form of tobacco consumption. ○ Americans were once famous for their cigars Smokeless tobacco in various forms is an important cause of oral cancer ○ Snuff ○ Chewing tobacco → Most commonly observed among indigenous people Responsible for 400,000 deaths per year (⅓ from lung cancer) Second-hand smokers ○ Nonsmokers inhale smoke from the environment Figure 2. Effects of Lead Poisoning in Children in Various Organs → Can cause lung cancer ○ Deadlier – Doesn’t have a filter to protect from the smoke Increases risk of: ○ Coronary atherosclerosis ○ Fatal myocardial infarction Children living in households with adult smokers: ○ Increases frequency of respiratory illness and asthma ○ Caused by the damage to the respiratory epithelium ○ Among females, it causes frequent COPD and asthma Risk of cancer from tobacco depends on way of consumption Figure 3. Impaired Calcification of the Cartilage on the Wrist ○ Cigars and smokeless tobacco MG 3 | MG 10 2 of 17  Y2PATHOB9L4: ENVIRONMENTAL DISEASES → Commonly associated with squamous cell carcinoma Risk is multiplied by exposure to other carcinogens of the tongue and oral mucosa ○ Asbestos, radiation Puffing of smoke is concentrated in the mouth Tobacco smoke is linked to development of cancers of: → There is no inhalation ○ Oral cavity ○ For cigarette smoking ○ Esophagus (Squamous cell carcinoma) → Lungs are affected due to deep inhalation for the ○ Pancreas (Ductal carcinoma) nicotine to take its effect ○ Bladder (Uterine carcinoma) → Associated with lung cancer from bronchi ○ Other tissues MYOCARDIAL INFARCTION Various factors in tobacco smoke: ○ Increase platelet aggregation - reduces blood flow ○ Decrease myocardial oxygen supply ○ Decrease the threshold for ventricular fibrillation Almost 1/3 of heart attacks are associated with cigarette smoking Smoking has multiplicative effect on risk when combined with hypertension and hypercholesterolemia ○ Polycyclic hydrocarbons can also damage the endothelium, → Could form fatty streaks and atherosclerosis E-cigarettes and vaping ○ Uncertain if they share these risks and to what degree are they correlated Figure 4. Smoking and Other Diseases ○ Researchers are still on the lookout for prospective studies About Figure 4: regarding vaping and e-cigs ○ Fatal malignancies associated with smoking include lung ○ Tobacco is avoided in pregnant women cancer, myocardial infarction, systemic atherosclerosis → Spontaneous abortions → Preterm births → Intrauterine Growth Restrictions PATHOGENESIS Addictive nature of tobacco is attributable to nicotine SPONTANEOUS ABORTIONS, PRETERM BIRTHS, AND ○ Binds nicotinic receptors in brain and peripheral tissues INTRAUTERINE GROWTH RETARDATION → Changes in alertness, blood pressure, and heart rate. Effects partly result from carbon monoxide in cigarette smoke Most common diseases involve the lung: reducing oxygen delivery to the fetus. ○ COPD ○ Reduces the effect of the oxygen binding for the RBC’s → Emphysema which are delivered via the placenta → Chronic bronchitis ○ Lung cancer Virtually no organ is spared even the pancreas and the bladder (urothelium) can be damaged MAJOR DISORDERS CHRONIC OBSTRUCTIVE PULMONARY DISEASE Agents in smoke have a direct irritant effect on the tracheobronchial mucosa Results in: ○ Inflammation ○ Increase mucus production (bronchitis) → Acts like chemokine attracting neutrophils in endothelium Figure 5. Graph on Age and Death of Smokers and Non-Smokers → Present in chronic bronchitis About Figure 5: Smoke causes recruitment of leukocytes to the lung ○ A person that have never smoked a cigarette will have Local production of elastase and injury to lung tissue leads to better chances of being alive than those who are pregnant emphysema and cigarette smokers ○ Elastase - released during chronic tobacco smoking Table 1. Effects of Selected Tobacco Smoke Constituents CARCINOGENESIS SUBSTANCE EFFECT Polycyclic hydrocarbons and nitrosamines are potent Tar Carcinogenesis carcinogens Polycyclic aromatic Risk of lung cancer is related to Carcinogenesis hydrocarbons ○ Intensity of exposure (pack years) → E.g. 1 pack/day for 20 years = 20 pack years Nicotine Ganglionic stimulation and depression; ○ In cigarettes smoked per day Tumor promotion → If quantification of pack years is not available MG 3 | MG 10 3 of 17  Y2PATHOB9L4: ENVIRONMENTAL DISEASES Phenol Tumor promotion Mucosal irritation Benzopyrene Carcinogenesis Carbon monoxide Impaired oxygen transport and utilization Formaldehyde Toxicity to cilia Mucosal irritation Nitrogen Oxides Toxicity to cilia Mucosal irritation Nitrosamine Carcinogenesis Table 2. Suspected Organ-Specific Carcinogens in Tobacco Smoke ORGAN CARCINOGEN Polycyclic aromatic hydrocarbons ○ 4-(Methylnitrosamino)-1-(3-pyridyl)-1-bu Lung Figure 8. Updated Health Consequences Causally Linked to tanone ( NNK) Larynx Smoking (Surgeon General's report 2016) ○ Polonium 210 Esophagus N’ - Nitrosonornicotine (NNN) Lecturer notes: Pancreas NNK Some people, though with smoking as a lifestyle, are A-Aminobiphenyl genetically protected from cancer by polymorphisms Bladder 2-naphthylamine Polycyclic aromatic hydrocarbons Oral Cavity D. ALCOHOL ○ NNK (smoking) ○ NNN Excessive acute or chronic use of ethyl alcohol NNK ○ May cause marked physical and psychological damage Oral Cavity NNN ○ The alcohol that can be consumed orally. (snuff) Polonium 210 Alcohol ingestion is responsible for >100,000 deaths annually ○ 50% - alcohol related accidents, homicides, and suicides ○ 15% - cirrhosis of the liver Consumption by pregnant women especially during the first trimester may cause fetal alcohol syndrome: ○ Microcephaly ○ Growth retardation ○ Facial abnormalities in newborn ○ Reduction of mental functions in older children PATHOGENESIS Ethanol is absorbed in the stomach and small intestine ○ Distributed throughout the body in direct proportion to Figure 6. Graph on Relative Risk to Cigarettes Smoked per Day the blood level About Figure 6: ○ First-pass effect in the liver and into the systemic ○ ↑ pack years = ↑ relative risk of getting lung cancer circulation via zero-order kinetics in cytochrome pathway Less than 10% is excreted in urine, sweat, and breath Remainder is metabolized to acetaldehyde in the liver by the alcohol dehydrogenase In chronic alcoholics: ○ Cytochrome P-450 isoenzymes are induced → May greatly enhance the rate of alcohol metabolism ○ Responsible for the priming effect of a person that have previously consumed a lot of alcohol → You will have more immediate effect after consumption Small amounts of alcohol are metabolized by catalase ○ Present in the lysosome Acetaldehyde produced is converted to acetate by acetaldehyde dehydrogenase ○ Acetate is responsible for the hungover effects after binge-drinking episode Figure 7. Multiplicative Increase in the Risk of Laryngeal Cancer From the Interaction between Cigarette Smoking and Alcohol Consumption MG 3 | MG 10 4 of 17  Y2PATHOB9L4: ENVIRONMENTAL DISEASES Injury to myocardium ○ Dilated congestive cardiomyopathy Increases risk of pancreatitis Mechanisms of carcinogenic effect are uncertain although chronic injury and inflammation likely contribute. III. INJURY BY THERAPEUTIC DRUGS A. ADVERSE DRUG EFFECT Untoward effects of drugs administered in conventional therapeutic settings Extremely common: may affect 7-8% of admitted patients 10% of reactions are fatal Older adults (>65 yo) more likely to suffer from adverse drug Figure 9. Metabolism of Ethanol reactions More common: Drug reactions caused by direct actions of the CLINICAL FEATURES drug or to immunologically based hypersensitive reactions Common manifestations: ACUTE ALCOHOLISM ○ Skin rashes Exerts effects primarily on the CNS, stomach, and liver ○ Mimic autoimmune disorders (SLE) Alcohol directly depresses neural activity in CNS ○ Hemolytic anemia ○ Impaired motor, sensory, and cognitive dysfunction ○ Immune thrombocytopenia ○ High doses may lead to stupor, coma, potentially death Gastric damage B. MENOPAUSAL HORMONE THERAPY (MHT) ○ Acute gastritis and ulceration (multiple ulcerations in gastric mucosa) Most common type: administration of estrogens alone or Liver together with a progesterone in ages beyond 45 years old ○ Multiple fat droplets accumulate in the cytoplasm of with symptoms of menopause hepatocytes (fatty change/steatosis) → Used primarily to counteract “hot flashes” and other → Acetaldehyde and acetate would coalesce and found symptoms of menopause in multiple fat droplets Risk-to-benefit consensus: ○ Needed because MHT is a double-edged sword CHRONIC ALCOHOLISM ○ Combination estrogen-progesterone increases risk of breast cancer after median time of 5-6 years in Leads to significant morbidity and shortened lifespan (damage menopausal patients to liver, GIT, CNS, CVS, and pancreas) ○ MHT may have a protective effect on the development of Liver atherosclerosis and coronary artery diseases in women ○ Main site of chronic injury younger than 60 y/o, but there is no protection in women ○ Steatohepatitis, alcoholic hepatitis, or cirrhosis who started MHT at an older age ○ Obstruction of blood flow by cirrhosis leads to portal → One must weigh potential risks and benefits individually hypertension (portal vein obstruction) → E.g.: Therapy may be protective in one age group while ○ Chronic injury increases risk of hepatocellular carcinoma also being a risk for malignancy in another organ site → Malignant transformation ○ MHT increases risk of stroke and venous GI Tract thromboembolism, ○ Can cause bleeding from gastritis, gastric ulcer, → Including deep venous thrombosis and pulmonary esophageal varices (portal hypertension) which may be embolism massive and prove fatal ○ Increased risk of venous thromboembolism - more → Esophageal varices is a sequelae of portal pronounced in women who have other risk factors such as hypertension immobilization and hypercoagulable states. Massive and fatal upper GI bleeding MHT is currently viewed to have a role in the management of Balloon tamponade is needed for the repair of the menopausal symptoms in early menopause but shouldn’t be varices because they bleed profusely used over the long term prevention of cardiovascular disease Thiamine deficiency ○ Common in chronic alcoholic patients C. ORAL CONTRACEPTIVES (OCs) ○ Principal lesions include peripheral neuropathies and Wernicke-korsakoff syndrome Usually contain synthetic estradiol and variable amount of a → Wernicke-Korsakoff Syndrome progestin Caused by damage in thalamus & mammillary bodies ○ However, some preparations contain only progestins Manifestations: because it minimizes the risk of developing cancer ⎻ Memory deficits → Means doing away with estrogen in oral contraceptives ⎻ Confabulations formulations ⎻ Cognitive defects Oral contraceptives carry risks and benefits upon therapeutic CNS damage may occur: use listed in Table 3. ○ Cerebral atrophy ○ Cerebellar degeneration ○ Optic neuropathy MG 3 | MG 10 5 of 17  Y2PATHOB9L4: ENVIRONMENTAL DISEASES Table 3. Oral Contraceptives Risk and Benefits PULMONARY DISEASE DISEASE RISKS AND BENEFITS OF OCs Complications include: Associated with small increased risk ○ Edema of breast cancer (1-2 fold) ○ Septic embolism Since breast cancer is rare in young ○ Lung abscess Breast Carcinoma women, overall number of excess ○ Opportunistic infections cancers attributed to OCs is small ○ Foreign body granulomas Granulomas result from inhalation of talc and other Endometrial Cancer OCs have protective effect against adulterants mixed with opioid substance and Ovarian Cancers these tumors ○ Inhaled talc has potential to remain in lung parenchyma OCs may be associated w/ increased → Elicit macrophages to aggregate locally thus forming risk of cervical carcinomas in clusters like granulomas women affected w/ HPV Cervical cancer In general, risk for cervical cancer is INFECTIONS more associated with sexual Common complication of opioid use particularly in injectable activity and consequent risk of HPV forms of delivery infection rather than effects of OCs Possible sites of infection: Associated with 3-6 fold increased ○ Skin and subcutaneous tissue risk of venous thrombosis & ○ Heart valves pulmonary thromboembolism ○ Liver resulting from increased hepatic → Hepatitis infection due to sharing of needles synthesis of coagulation factors ○ Lungs ○ Estrogen is an important stimuli for → Bronchial pneumonia due to contamination w/ S. aureus the synthesis of these factors Endocarditis: can be sequelae with contaminated needles ○ Women at reproductive ages are ○ More often reported in the right side of the heart less likely to experience → Injectables are administered through peripheral veins thromboembolism due to higher and reach right side of the heart via venous circulation levels of proteins C and S ○ Most reported cases are caused by S. aureus but fungi (inhibitors to thrombus formation) and other organisms are implicated Uncertain risk of atherosclerosis and → Most common skin contaminant in skin breeches Thromboembolism myocardial infarction in users of OCs → Increased risk of infection if skin is not sterilized OCs do not increase the risk of Sharing of needles has led to a high incidence of infections in coronary artery disease in women intravenous drug users younger than 30 years or in older ○ Infections may either bacterial or viral in nature like HIV women who are nonsmokers Risk is ~2x in women older than 35 SKIN LESIONS years who smoke Most frequent telltale sign of heroin addiction Related to local effects of contamination from needle injection Well-defined association between OC Accompanying acute changes: use and this rare benign hepatic ○ Abscess Hepatic Adenoma tumor, especially in older women who ○ Cellulitis have used OCs for prolonged periods ○ Ulcerations resulting from subcutaneous injections → Severe lesions may progress into panniculitis D. OPIOIDS Scarring at injection sites and thrombosed veins are the usual Opioid overdoses sequelae of repeated intravenous inoculation ○ Current leading cause of death in US in adults under 50 y/o → Highly sensationalized in the news RENAL DISEASE → Common in middle age and young adult populations Common hazard in those with chronic heroin addiction Opioid use has a wide range of adverse physical effects that Two forms: can be categorized according to: ○ Amyloidosis ○ Pharmacologic action of the agent ○ Focal glomerulosclerosis ○ Reactions to the cutting agents or contaminants ○ Both will result in membranous-type nephrotic syndrome, ○ Hypersensitivity reactions to the drug or its adulterants with heavy proteinuria as most important presentation ○ Diseases contracted through the sharing of needles E. COCAINE ADVERSE EFFECTS OF HEROIN AND OTHER OPIOIDS Extracted from the leaves of the coca plant SUDDEN DEATH (RELATED TO OVERDOSE) Sold as powder and colloquially known as “crack” or crystals Example: use of illegal drug Heroin of cocaine hydrochloride ○ Risk of sudden death is associated with overdose May be snorted, smoked, or injected intravenously → Ever present among usage of synthetic opioids Drug effects: Chief mechanism of death: Profound respiratory depression ○ Intense euphoria Opioid overdoses can be quickly reversed with an opioid ○ Mental alertness antagonist (i.e. Naloxone) if administered promptly ○ Profound psychological dependence = highly addictive MG 3 | MG 10 6 of 17  Y2PATHOB9L4: ENVIRONMENTAL DISEASES MANIFESTATIONS Contains psychoactive substance Δ9-tetrahydrocannabinol (THC) made from leaves of: CARDIOVASCULAR EFFECTS ○ Cannabis sativa Most dangerous acute physical effect to cardiovascular system ○ Cannabis indica Sympathomimetic agent ○ Hybrid of the species ○ CNS: Blocks uptake of dopamine Beneficial effects: ○ Adrenergic nerve endings: Blocks reuptake of epinephrine ○ Capacity to decrease intraocular pressure in glaucoma and norepinephrine ○ Combat intractable nausea secondary to cancer chemo Neurotransmitters accumulate in synapses and → Apart from serotonin inhibitors prescribed to counteract hyperstimulation results in: nausea, medical marijuana can also be used ○ Tachycardia ○ Hypertension Lecturer notes: ○ Peripheral vasoconstriction Marijuana and Cocaine - included in routine drug testing kit Cocaine causes coronary artery vasoconstriction and promotes thrombus formation by facilitating platelet aggregation ACUTE AND CHRONIC EFFECTS ○ Depending on site (referring to thrombus formation) → Heart: Multiple Infarction (MI) Table 4. Acute and Chronic Effects of Marijuana → Cerebral: Stroke ORGAN SYSTEM EFFECTS Net effect: Distorts sensory perception (time, speed, ○ Myocardial ischemia or infarction secondary to CNS distance) → Increased cardiac demand Impairs motor coordination Sympathomimetic effect Effects generally clear in 4 to 5 hours → Decreased cardiac blood flow Occluding effects in the blood vessel. Increases HR and sometimes BP May induce fatal cardiac arrhythmia Cardiovascular Can lead to angina in people with coronary ○ By causing myocardial ischemia and independent effects disease on cardiac ion transporters Chronic marijuana smoking is associated ○ Due to unperfused areas of heart & from massive release of with laryngitis, pharyngitis, bronchitis, neurotransmitters which disrupt rhythm from nodal system cough, asthma-like symptoms, and mild ○ Has dependent effect on the IM transporters airway obstruction Toxicities are only loosely dose-related Associations with more severe Fatal arrhythmias may occur in 1st time user taking typical dose Pulmonary complications of tobacco smoking (COPD, ○ One of the shocker drugs that we have lung cancer) have not been established ○ Even with small doses from first encounter and sympathomimetic effects because these are very potent IV. INJURY PRODUCED BY IONIZING RADIATION CNS EFFECTS Ionizing radiation has sufficient energy to remove tightly bound Most common neurological findings: electrons from molecules with which it interacts ○ Hyperpyrexia: Due to effects on pathways that control Ionization: body temperature ○ Reaction cascade caused by collision of free electrons with → Due to sympathomimetic effects in the hypothalamus other atoms which releases additional electrons and limbic system, which control body temperature Main sources: ○ Seizures: Due to hyperstimulation ○ X-rays and gamma rays → If CNS is deranged, it will lead to seizures → Dissipate energy over a longer course → Rule out the use of addictive agents (i.e., cocaine) and → Produce considerably less damage per unit of tissue as other drugs of abuse in seizures compared to alpha particles ○ Electromagnetic waves of very high frequencies EFFECTS ON THE FETUS ○ High-energy neutrons ○ Alpha particles Cocaine may decrease blood flow to placenta → Induce greater damage in restricted area ○ Resulting in fetal hypoxia and spontaneous abortion ○ Beta particles Pregnant women who are chronic drug users Ionizing radiation is used to treat some cancers ○ Neurologic development may be impaired in the fetuses ○ Therapeutic ionizing radiation is a double-edged sword (mutagenic, carcinogenic, and teratogenic) CHRONIC EFFECTS → Effective in causing DNA damage and apoptosis in Perforation/ulcerations of the nasal septum in snorters cancer cells Decreased lung diffusing capacity when inhaling the smoke DNA: ○ Lung fibrosis – decreases the diffusing capacity to oxygen ○ Most important cellular target of ionizing radiation in the lung parenchyma ○ Effects include DNA breakage and cross-linking of DNA Dilated cardiomyopathy with proteins ○ Interfere with gene expression and cellular proliferation F. MARIJUANA → Damaged DNA template ○ DNA damage Most widely used illegal drug → Can be repaired by cellular repair enzymes Most are consumed by smoking - gives out fragrant aroma ○ 5-10% of THC content is absorbed MG 3 | MG 10 7 of 17  Y2PATHOB9L4: ENVIRONMENTAL DISEASES Defects are targeted for regulation and repaired by ○ Neutropenia cellular mechanisms ○ Thrombocytopenia → Damages not repaired lead to mutations, which Very high doses of radiation kill marrow stem cells and induce manifest years later as cancer permanent aplasia (aplastic anemia) → Cells w/ damaged DNA still normally proceed in cell cycle ○ Often used in patients undergoing hematopoietic stem cell ○ Development of fibrosis in the irradiated field transplantation to kill defective resident stem cells for the → Due to vascular injury and ischemic damage to tissues new graft to proliferate → Limited motion in these areas Acute damage ○ To gut = result in bloody diarrhea A. MORPHOLOGY ○ To oropharynx = ulceration leading to development of infections exacerbated by neutropenia and lymphopenia Surviving cells have wide structural changes in chromosomes: ○ To oocytes and spermatogonia = may lead to sterility ○ Deletions ○ Breaks Lecturer’s notes: ○ Translocations Irradiation of blood - relevant in blood banking to avoid the ○ Fragmentation spread of blood borne diseases in blood transfusions Damage manifest as abnormal nuclear morphology that persists for years CHRONIC EFFECTS ○ Giant cells with pleomorphic nuclei or more than one nucleus that can mimic malignancy Related to vascular damage, fibrosis, carcinogenesis Fibrosis Radiation to the chest may lead to: ○ Important morphological feature ○ Myocardial fibrosis ○ May develop in irradiated field, weeks/months after irradiation ○ Coronary artery disease ○ Dead parenchymal cells are replaced by connective tissue ○ Pulmonary fibrosis ○ Contractures resulting in insufficient blood flow - happens ○ Increased risk of neoplasms (e.g. carcinoma of the breast) when fibrosis occurs in target areas such as the breast and Risk of cancer depends on site of exposure and type & dose other deep tissues in the body cavity of radiation received → Radiologists are careful in field planning for targeted Most common neoplasms related to radiation exposure: radiotherapy in cancer patients ○ Leukemias Ionizing radiation may damage endothelial cells ○ Carcinomas of the lung (uranium miners) ○ Leads to sclerosis of vessels due to deposition of ○ Thyroid carcinoma (radioactive iodine) compact collagen (hyalinization) & thickening of the media ○ Breast CA Vascular insufficiency contributes to fibrosis, scarring, and ○ Melanomas contractions. ○ Sarcomas Figure 10. Example of a salivary gland that underwent. (A) Normal salivary gland. (B) and (C) Irradiated salivary glands. About Figure 10: ○ (A) It is lobulated, more intense nuclei ○ (B) Less intense nuclei and more fibrosis ○ (C) Changes in the vascularity and epithelial cells ○ In general, morphologic features such as giant cell formation and nuclear pleomorphism are found B. ACUTE AND CHRONIC EFFECTS ACUTE EFFECTS Most striking in organs and tissues composed of rapidly Figure 11. Organs damaged by ionizing radiation dividing cells: ○ Gonads V. NUTRITIONAL DISEASES ○ Hematopoietic A. MALNUTRITION ○ Lymphoid systems ○ Lining of the GI tract Occurs when one or more of these components are missing Radiation directly destroys lymphocytes both in blood & tissues from the diet, or when they are present in inadequate amounts Hematopoietic precursors in bone marrow are sensitive, ○ Due to malabsorption, impaired use or storage, excess producing dose-dependent marrow aplasia w/in 1 to 2 weeks: losses, or increased requirements MG 3 | MG 10 8 of 17  Y2PATHOB9L4: ENVIRONMENTAL DISEASES ○ Sufficient calories for daily metabolic needs ○ Essential amino acids and fatty acids ○ Critical vitamins and minerals Poor/inadequate diet is prevalent in underdeveloped countries SETTINGS Infants, adolescents, and pregnant women ○ Increased nutritional needs that may go unrecognized ○ Ignorance about nutritional content of various foods also contributes to malnutrition Chronic alcoholics Figure 12. Child with Marasmus ○ Prone to deficiency of several vitamins (thiamine, pyridoxine, folate, and vitamin A) KWASHIORKOR ○ Causes dietary deficiency, defective GI absorption, Occurs when protein deprivation is relatively greater than abnormal nutrient utilization and storage, increased the reduction in total calories metabolic needs, and increased rate of loss Marked by loss of protein from the visceral compartment Acute and chronic illnesses Results in hypoalbuminemia ○ Raise basal metabolic rate resulting in increased daily ○ Gives rise to generalized or dependent edema requirements for all nutrients → Masks the true extent of weight loss Self-imposed dietary restriction → Described as clumped and thin ○ Comes in form of eating disorders such as anorexia Relative sparing of muscle mass and subcutaneous fat nervosa and bulimia which may lead to malnourishment Characteristic skin lesion: Other causes: ○ Alternating zones of hyperpigmentation, desquamation ○ GI disease, acquired and inherited malabsorption and hypopigmentation syndromes, drug therapies that block the uptake or use of → Used to be called as “Flag sign” particular nutrients and parenteral nutrition without Hair changes: supplemental vitamins ○ Loss of color or alternating bands of pale and darker color ○ Straightening B. SEVERE MALNUTRITION: ○ Fine texture ○ Loss of firm attachment to the scalp Previously called protein energy malnutrition May be associated with: ○ Serious, often lethal disease, that stems from inadequate ○ Fatty liver and apathy intake of protein and calories ○ Listlessness and loss of appetite Common in poor countries and war-torn areas where it Frequently present with: contributes to high death rates among the very young ○ Vitamin deficiencies Two extremes syndromes: Marasmus and Kwashiorkor ○ Defects in immunity ○ Stems from lack of protein and calories in the diet ○ Secondary infections ○ Marasmus Changes of the gut microbiome may impair nutrient absorption → Affects the somatic component more severely ○ Recovery of the malnourished child is hampered (proteins stored in skeletal muscles) ○ Kwashiorkor C. SO-CALLED SECONDARY MALNUTRITION → Depletes the viscera components more severely Not a diagnosis but a conglomeration of manifestations (proteins stored in the liver) Often develops in chronically ill, older, and bedridden patients Common in nursing home residents and in cancer patients MARASMUS ○ Cachexia - severe form of secondary malnutrition Develops when diet is severely lacking in calories leading to → Often develops in nursing home residents loss of protein from the somatic compartment Underlying mechanisms are complex, but appear to involve ○ Protein from the skeletal muscles and connective tissues “catechins” secreted by tumor cells, and cytokines Marasmic child suffers growth retardation & loss of muscle mass particularly tumor necrosis factor (TNF) Visceral protein compartment is initially largely unaffected ○ Both directly stimulate skeletal muscle protein degradation ○ Serum albumin levels are normal or only slightly reduced ○ Cytokines such as TNF causes loss of appetite and Subcutaneous fat is also mobilized and used as a fuel stimulates fat mobilization from lipid stores ○ Increases their thin appearance Due to losses of muscle and subcutaneous fat, the extremities D. VITAMIN DEFICIENCIES are emaciated and the head appears too large for the body Thirteen vitamins are necessary for health Anemia and manifestation of multi vitamin deficiencies are ○ Fat soluble (Vitamins A, D, E, K) present → More readily stored in the body except in those with GI Evidence of immune deficiency disorders of fat malabsorption ○ Particularly of T cell-mediated immunity ○ Water soluble → Often leading to concurrent infections Certain vitamins can be synthesized endogenously ○ Problems with antigen presentation and natural protection ○ Vitamin D from precursor steroids ○ Vitamin K and biotin by the intestinal microflora ○ Niacin from tryptophan MG 3 | MG 10 9 of 17  Y2PATHOB9L4: ENVIRONMENTAL DISEASES VITAMIN A VITAMIN A DEFICIENCY Generic name for related fat-soluble compounds including: Occurs worldwide as a consequence of poor nutrition or fat ○ Retinol - chemical name of vitamin A malabsorption ○ Retinal Bariatric surgery and continuous use of mineral oil laxatives ○ Retinoic acid may also lead to deficiency Sources: Visual effects ○ Animal-derived food - supply preformed vitamin A ○ Impaired vision particularly in reduced light (night blindness) → E.g. Liver, fish, eggs, milk, and butter → One of the earliest manifestations of vitamin A deficiency ○ Yellow and leafy green vegetables - supply carotenoids Effects on immune system: metabolized into active vitamin A ○ Increased morbidity from measles, pneumonia, and → E.g. Carrots, squash, and spinach infectious diarrhea Absorption requires: → Vit. A promotes normal cell differentiation and maintains ○ Bile the polarity of the epithelium for its maturation ○ Pancreatic enzymes Deficiency => less mature epithelium, mainly in gut, ○ Some level of antioxidant activity in the food lungs, and skin, making them more prone to Hepatic reserves infectious diseases ○ Sufficient to support needs for at least 6 months Epithelial changes - persistent deficiency gives rise to epithelial metaplasia and keratinization ○ Eyes: → Build up of keratin debris → Erosion of roughened corneal surface → Eventual softening and destruction of the cornea (keratomalacia) producing blindness ○ Squamous metaplasia: → Upper respiratory passages and urinary tract predisposes affected patients to: Pulmonary infections, renal and bladder stones → Plugging the ducts of the adnexal glands Skin changes Figure 13. Effects of Vitamin A deficiency Figure 12. Metabolism of Vitamin A About Figure 13: FUNCTIONS ○ Key features of Vit-A deficiency are related to neoplasia → Increased risk for cancer Vision - involves 4 forms of vitamin A-containing pigments: ○ Hematologic: Vit-A is needed for blood cell maturation ○ Rhodopsin - located in rods, involved in perception of light → Can predispose to acute promyelocytic leukemia ○ 3 forms of Iodopsin - located in cones, involved in perception of colors ○ Exposure to light changes pigment conformation, VITAMIN D triggering nerve impulses in the retina that are sent to the Required to maintain adequate plasma levels of calcium and brain's vision centers phosphorus Host Resistance to Infections Supports metabolic functions, bone mineralization, and ○ Due in part to its ability to stimulate the immune system neuromuscular transmission through unclear mechanisms Sources of vitamin D for humans: Regulation of Cell Growth and Differentiation ○ Majorly, in its endogenous synthesis ○ Vitamin A and related compounds regulate the → Requires UV light from the sun or artificial sources differentiation of mucous-secreting epithelium by binding → Production is less efficient in individuals with darker to retinoic acid receptors and regulating gene expression skin because of melanin pigmentation ○ Retinoid deficiency disrupts normal gene expression and ○ Remainder comes from dietary sources causes squamous metaplasia → Fish Regulation of Lipid Metabolism → Plants ○ Retinoic acid receptors form complexes w/ other nuclear → Grains receptors (e.g. peroxisome proliferator-activated Synthesis of active form of vitamin D occurs through receptors/ PPARs - key regulators of fatty acid sequential reactions that are carried out in the liver and kidney metabolism and other aspects of adipogenesis) MG 3 | MG 10 10 of 17  Y2PATHOB9L4: ENVIRONMENTAL DISEASES Last step: Renal production of dihydroxyvitamin D, regulated Skeletal diseases by three mechanisms: ○ Mainly caused by dietary deficiencies of calcium and ○ Hypocalcemia - stimulates secretion of parathyroid vitamin D along with limited exposure to sunlight hormone (PTH) Less common causes: → Increases the production of dihydroxyvitamin D by ○ Renal disorders activating α1-hydroxylase → Decrease the synthesis of dihydroxyvitamin D ○ Hypophosphatemia - directly activates α1-hydroxylase ○ Malabsorption disorder → Increasing dihydroxyvitamin D synthesis Mild forms: ○ High levels of dihydroxyvitamin D – suppresses its ○ Bone loss and hip fractures are common among elderly synthesis by inhibiting the action of α1-hydroxylase ↓ serum calcium -> stimulates PTH production, leading to: Renal failure results to deficiency by decreased Vitamin D ○ Release of calcium from bone hydroxylation ○ Decreased renal calcium excretion ○ Increased renal excretion of phosphate ○ This mechanism restores serum calcium levels to near normal but hyperphosphatemia persists leading to impaired bone mineralization Inadequate mineralization of bone in rickets ○ Exacerbated by ↓ calcification of epiphyseal cartilage ○ Results to enlarged and expanded osteochondral junctions Weakened bone ○ Prone to fractures & deformations by mechanical stress MORPHOLOGY Infants ○ Frontal bossing of skull and squared appearance of head ○ Overgrowth of costochondral junctions deforms the chest Figure 14. Normal metabolism of VItamin D (increased calcium (rachitic rosary) and phosphate absorption from bone and gut) → Characteristic finding in infants with Vit-D deficiency Ambulating child ○ Produces deformities of the spine and long bones ○ Lumbar lordosis and bowing of the legs → Characteristic of rickets Adults ○ Inadequately mineralized and weak bones that are vulnerable to fractures (osteomalacia) ○ Commonly involves the vertebrae and femoral neck Figure 15. Homeostasis in Vitamin D deficiency (decreased calcium and phosphate) About Figure 15: ○ Mobilization of calcium & phosphate from bone -> increase absorption from the gut and resorption by the kidney Figure 16. Vitamin D deficiency histology and gross effects ○ Morphologic features related to: About Figure 16: → Fractures A. Normal maturation of cartilage in costochondral junction → Brittle bones → (+) Palisading of chondrocytes → Rickets B. (-) Palisade in rickets → Osteomalacia → Chondrocytes appear darker; paler bone trabeculae Dihydroxyvitamin D acts by binding to nuclear receptors C. Bowing of the legs ○ Increase the transcription of specific genes Vitamin D ○ Maintains plasma levels of Ca2+ & phosphorus by stimulating VITAMIN C (ASCORBIC ACID) intestinal absorption of Ca2+ & resorption of Ca2+ in kidney Deficiency leads to scurvy characterized primarily by ○ Has effects on osteoclasts and osteoblasts that influence ○ Bone diseases in growing children bone resorption and calcification ○ Hemorrhages and healing defects in children and adults Ascorbic acid is not synthesized endogenously in humans PATHOGENESIS ○ Dependent on the diet: Causes hypocalcemia and a failure of bone mineralization → E.g. milk, liver, fish, fresh fruits and vegetables ○ Rickets in growing children Most clearly established function: Cofactor for prolyl and ○ Osteomalacia in adults lysyl hydroxylases ○ Required for hydroxylation of procollagen MG 3 | MG 10 11 of 17  Y2PATHOB9L4: ENVIRONMENTAL DISEASES Inadequate hydroxylation due vitamin C deficiency Hypothalamic neurons that control food ○ Leads to destabilization of procollagen and prevents it from intake and energy expenditure forming covalent cross-links Input from POMC/CART neurons → Production of loose aggregates Efferent System reduces food intake and activates neurons that enhance energy VITAMIN C DEFICIENCY expenditure and weight loss Decreases collagen secretion from fibroblasts and lowers its Input from NPY/AgRP neurons activates tensile strength while also increasing its solubility neurons that promote food intake and ○ Makes it more vulnerable to enzymatic degradation weight gain Clinical manifestations: ○ Bleeding in the skin, gums, joints, and muscle pain ○ Impaired wound healing Scurvy ○ Not common due to abundance of vit. C in food sources ○ Sometimes encountered as a secondary deficiency in: → Elderly persons → People who live alone → Chronic alcoholics → Those with erratic and inadequate eating patterns See Table 6 in the Appendix section for a list of vitamins, their major functions and deficiency syndromes E. OBESITY Figure 17. Neurohormonal Mechanism of Obesity (See Appendix) State of increased body weight caused by adipose tissue accumulation sufficient to produce adverse health effects Obesity and central obesity - associated with type 2 Excess adiposity and body weight - associated with diabetes, CVDs (atherosclerosis and hypertension), & cancers increased incidence of several important diseases of humans: Metabolic syndrome - Risks related to a constellation of ○ Diabetes findings often found in obese individuals ○ Cardiovascular disease ○ Characterized by glucose intolerance, hyperlipidemia, ○ Cancer hypertension, and systemic proinflammatory state Fat accumulation - assessed by measuring the body mass ○ Initiating events may be obesity-associated insulin index (BMI) with a normal range of 18.5 to 25 kg/m2 resistance and hyperinsulinemia ○ BMI between 25 and 30 - considered overweight ○ BMI greater than 30 - obese COMPLICATIONS Obesity reached epidemic proportions globally esp. in US Nonalcoholic fatty liver disease (associated with obesity and type 2 DM) PATHOGENESIS Hepatic fibrosis Etiology: Genetic, environmental, and psychological factors Hepatic cirrhosis Obesity - disorder of energy imbalance Cholelithiasis (gallstones) - 6x more common in obese than in ○ Regulated by neural & hormonal mechanisms that normally lean subjects maintain body weight w/in a narrow range for many years DISORDERS ASSOCIATED Table 5. Neurohormonal mechanisms COMPONENT DESCRIPTION Hypoventilation syndrome ○ Stems from respiratory compromise in very obese persons Generates signals in form of hormones ○ Hypersomnolence is characteristic Includes: ○ Associated with sleep apnea, polycythemia, and eventual ○ Leptin - by fat cells, reduces food right-sided heart failure (Corpulmonale) intake Degenerative joint disease (osteoarthritis) ○ Adiponectin - produced by fat cells Cancer Peripheral or ○ Insulin - from the pancreas ○ Men Afferent System ○ Ghrelin - from the stomach, → Associated with modest but measurable increase in stimulates appetite cancers of the esophagus, thyroid, colon, and kidney ○ Peptide YY - from the ileum and ○ Women colon, produced postprandially, a → Associated with modest but measurable increase in satiety signal cancers of the esophagus, endometrium, gallbladder, Integrates peripheral hormonal signals & and kidney generates neural signals transmitted by: ○ Underlying mechanisms are unknown and are likely to be ○ Proopiomelanocortin (POMC) multiple: Arcuate ○ Cocaine-and amphetamine - → Trophic effects of insulin Nucleus in the regulated transcript (CART) neurons → Increased peripheral production of estrogen Hypothalamus ○ Neuropeptide-Y (NPY) → Reduced secretion from adipose tissue of adiponectin ○ Agouti-related peptide (AgRP) → Proinflammatory state associated with obesity neurons MG 3 | MG 10 12 of 17  Y2PATHOB9L4: ENVIRONMENTAL DISEASES IV. SUMMARY → Ethanol is absorbed in the stomach and small intestine and distributes throughout the body in direct Environmental Disease proportion to the blood level ○ Many diseases are caused or influenced by environmental ○ Clinical features: factors (indoor, outdoor, and occupational settings) → Acute alcoholism ○ Exposure is largely determined by public health Exerts effects primarily on the CNS, stomach, and measures liver Metals as environmental pollutants → Chronic alcoholism ○ Lead Leads to significant morbidity and shortened → Lead had multiple effects that cause hematologic, lifespan (damage to liver, GIT, CNS, CVS, and skeletal, neurological, gastrointestinal, and renal pancreas) toxicities Injury By Therapeutic Drugs → Pathogenesis ○ Adverse drug effect Most absorbed lead is taken up to bone and → Untoward effects of drugs that are administered in developing teeth (80-85%) conventional therapeutic settings Lead binds sulfhydryl groups and interferes with → Extremely common in the practice of medicine and activity of several enzymes required for heme appear to affect 7% to 8% of admitted patients synthesis, leading to anemia ○ Menopausal Hormone Therapy (MHT) → Morphology → Most common type consists of administration of Major targets: estrogens together with a progestogen ⎻ Bone marrow → MHT increases the risk of stroke and venous ⎻ Nervous system thromboembolism ⎻ Kidneys ○ Oral Contraceptives Brain damage → OCs are associated with small increased risk of breast Peripheral demyelinating neuropathy in adults cancer (1-2 fold) Chronic renal damage → Endometrial Cancer and Ovarian Cancers → Clinical features → Cervical cancer Dependent on exposure levels → Thromboembolism Mercury → Cardiovascular disease ○ Damages CNS, particularly the developing fetus and other ○ Opioids organs such as GI tract and kidneys → Opioid overdoses are now the leading cause of death in ○ Source: eating contaminated fish the US in adults under the age of 50 ○ Inorganic mercury from environmental sources → Sudden death(related to overdose) ○ Methyl mercury enters food chain → Pulmonary disease ○ Kidneys: → Infections → Acute tubular necrosis → Skin lesions → Renal failure → Renal Disease Tobacco 2 forms: ○ Main culprit is cigarette smoking ⎻ Amyloids ○ Increases risk of: ⎻ Focal glomerulosclerosis → Coronary atherosclerosis ○ Cocaine → Fatal myocardial infarction → Extracted from the leaves of the coca plant ○ Pathogenesis → Drug produces intense euphoria, mental alertness, and → Addictive nature of tobacco is attributable to nicotine profound psychological dependence, making it highly → Most common diseases involve the lung: addictive Emphysema → Cardiovascular Effects Chronic bronchitis Myocardial ischemia or infarction (secondary to Lung cancer increased cardiac demand and decreased cardiac ○ Major Disorders blood flow) → Chronic Obstructive Pulmonary Disease May induce fatal cardiac arrhythmia → Carcinogenesis → CNS Effects → Myocardial Infarction Hyperpyrexia → Spontaneous abortions, preterm births, and Seizures intrauterine growth retardation → Effects on the Fetus Alcohol decrease blood flow to the placenta ○ Excessive acute or chronic use of ethyl alcohol may cause → Chronic Effects marked physical and psychological damage Perforation of the nasal septum in snorters ○ Consumption by pregnant women especially during the ○ Marijuana first trimester may cause fetal alcohol syndrome: → Most widely used illegal drug → Microcephaly → Δ9-tetrahydrocannabinol (THC) → Growth retardation → Capacity to decrease intraocular pressure in glaucoma → Facial abnormalities in newborn → CNS → Reduction of mental functions in older children Distorts sensory perception ○ Pathogenesis → Cardiovascular Increases heart rate & blood pressure MG 3 | MG 10 13 of 17  Y2PATHOB9L4: ENVIRONMENTAL DISEASES → Pulmonary Vision, immune function, epithelial maintenance Laryngitis, pharyngitis, bronchitis, cough, Animal-derived food & yellow and leafy green asthma-like symptoms, and mild airway obstruction vegetables Injury Produced by Ionizing Radiation Rhodopsin & 3 forms of Iodopsins ○ Sufficient energy to remove electrons from molecules Functions ○ Ionization ⎻ Vision → Reaction cascade caused by collision of free electrons ⎻ Host resistance to infections ○ Sources ⎻ Regulation of Cell Growth and Differentiation → X-rays, gamma rays, etc. ⎻ Regulation of Lipid Metabolism ○ Used to treat some cancers Deficiency ○ DNA ⎻ Visual Effects → Most important target of ionizing radiation ⎻ Immune Deficiency ○ Development of fibrosis in the irradiated field ⎻ Epithelial Changes → Morphology → Vitamin D Deletions, breaks, translocations, and fragmentation Calcium and phosphorus regulation Giant cells with pleomorphic nuclei Major source Dead parenchymal cells ⎻ endogenous synthesis ○ Acute and Chronic Effects ⎻ UV light → Neutropenia and thrombocytopenia Deficiency → Vascular damage, fibrosis, and carcinogenesis ⎻ rickets in children, → Common neoplasms ⎻ osteomalacia in adults Leukemias, Carcinomas of the lung, Thyroid → Vitamin C carcinoma, Breast carcinoma, Melanoma, Sarcomas Ascorbic acid Nutritional Diseases Cofactor for prolyl and lysyl hydroxylases ○ Malnutrition Collagen synthesis, antioxidant → Insufficient intake or absorption of calories, proteins, Deficiency vitamins, and minerals ⎻ Scurvy → Common in infants, adolescents, pregnant women, ○ Obesity alcoholics, and chronically ill patients → Excess adiposity leads to metabolic syndrome, type 2 → Acute and Chronic Illnesses diabetes, cardiovascular disease, and cancer Raised basal metabolic rate → Etiology → Self-imposed Dietary Restriction Genetic, environmental, psychological factors; ○ Severe Acute Malnutrition (SAM) neurohormonal control of energy balance → Protein energy malnutrition → Neurohormonal Mechanisms → Inadequate intake of protein and calories Afferent System → Marasmus ⎻ Generates signals in the form of hormones Calorie deficiency, affects somatic protein stores ⎻ Leptin reduces food intake (muscle wasting) ⎻ Ghrelin stimulates appetite Growth retardation and loss of muscle mass ⎻ Peptide YY is a satiety signal Anemia and manifestations of multivitamin Efferent System deficiencies ⎻ Input from POMC/CART neurons reduces food → Kwashiorkor intake Protein deficiency, affects visceral protein stores ⎻ Input from NPY/AgRP neurons promote food (edema, fatty liver) intake Relative sparing of the muscle mass as well as → Complications subcutaneous fat Nonalcoholic fatty liver disease Hair changes Hepatic fibrosis ⎻ loss of color Hepatic cirrhosis ⎻ loss of firm attachment to the scalp Cholelithiasis (gallstones) Skin lesions, fatty liver and apathy, listlessness, and → Disorders Associated loss of appetite Hypoventilation syndrome ○ So-called Secondary Malnutrition Degenerative joint disease (osteoarthritis) → Chronic illnesses, aging, and cancer-related cachexia Cancer (muscle wasting) → Cachexia V. REVIEW QUESTIONS Severe form of secondary malnutrition ○ Vitamin Deficiencies 1. What is a typical hematologic finding in patients with lead → 13 vitamins necessary for health: poisoning? 4 fat soluble (A, D, E, and K) A. Macrocytic anemia 9 are water soluble B. Microcytic hypochromic anemia → Vitamins synthesized endogenously C. Normocytic anemia D from precursor steroids D. Hemolytic anemia K and biotin by the intestinal microflora 2. Methylmercury exposure primarily results from the Niacin from tryptophan consumption of: → Vitamin A A. Contaminated water Retinol, retinal, and retinoic acid B. Contaminated air MG 3 | MG 10 14 of 17  Y2PATHOB9L4: ENVIRONMENTAL DISEASES C. Fish and seafood 14. What syndrome occurs in undernourished children due to a D. Vegetables protein-deficient diet? 3. Which vitamin deficiency is common in chronic alcoholics? A. Kwashiorkor A. Vitamin A B. Anorexia B. Vitamin C C. Marasmus C. Vitamin B1 D. Bulimia D. Vitamin B7 15. Which environmental exposure increases the risk of thyroid 4. Lead binds to which group, leading to enzyme inhibition? cancer? A. Hydroxyl groups A. Benzene B. Sulfhydryl groups B. Radioactive iodine C. Carbonyl groups C. Asbestos D. Amino groups D. Lead 16. Which of the following is a common side effect of ionizing 5. What is the primary carcinogen in tobacco that leads to lung radiation on rapidly dividing cells? cancer? A. Renal failure A. Nicotine B. Ulcer formation B. Tar C. Neutropenia C. Polycyclic hydrocarbons and nitrosamines D. Liver fibrosis D. Carbon monoxide 17. Vitamin D deficiency leads to what skeletal condition in adults? 6. Thiamine deficiency in chronic alcoholics can result in: A. Osteomalacia A. Korsakoff syndrome B. Scurvy B. Alzheimer?