Diabetes PDF

○ Morphology of steatofibrosis / cirrhosis: Gross findings: nodular surface, greenish Microscopic findings: central vein sclerosis, perisinusoidal scarring, central portal fibrous septa, continual subdivision of nodules...

○ Morphology of steatofibrosis / cirrhosis: Gross findings: nodular surface, greenish Microscopic findings: central vein sclerosis, perisinusoidal scarring, central portal fibrous septa, continual subdivision of nodules (micronodular cirrhosis) With abstinence → regeneration (macronodules) ○ Clinical features of alcohol-related fatty liver disease: Steatosis: Asymptomatic if present with hepatomegaly Mild increase in serum bilirubin and alkaline phosphatase Resolves with abstinence Steatohepatitis: Weeks to months of heavy alcohol consumption Possible acute onset Malaise, anorexia, tender hepatomegaly, fever Hyperbilirubinemia, increased serum alkaline phosphatase AST & ALT < 500 U/mL AST : ALT > 2:1 Increase risk of cirrhosis and death Chronic liver failure/cirrhosis Pathogenesis of NAFLD: ○ Diabetes type II ○ Central obesity ○ Dyslipidemia (high TG & LDL, low HDL) ○ Hypertension ○ Steatosis: nonalcoholic steatohepatitis (NASH) → steatofibrosis (inflammation less prominent) ○ Insulin resistance → increased activity of lipoprotein lipase → increased release of free fatty acids ○ Decreased production of adiponectin by adipocytes Decreased oxidation of FFA by skeletal muscle Increased uptake of FFA by hepatocytes ○ Activation of inflammasome (release of IL-1) ○ Products of lipid metabolism → hepatocytes injury → stellate cell activation → fibrosis ○ Clinical features: Transaminase elevation (AST : ALT < 1) Steatosis: usually asymptomatic Steatohepatitis: asymptomatic or fatigue, malaise, discomfort in right upper quadrant Low progression to NASH / cirrhosis Lecture 16: Diabetes mellitus. Types. Complications. Diabetes Mellitus: Regulation of insulin secretion: ○ Glucose: Primary physiologic stimulant of insulin release Enters β cells via glucose transporter (GLUT 2) ○ Glucokinase: Enzyme regulated by glucose Controls first step in glucose metabolism ○ Stimulators of insulin release: Vagal stimulation β-adrenergic stimulation GLP1 Amino acids ○ Inhibitors of insulin release Catecholamines Α-adrenergic stimulation Somatostatin Heterogeneous disorder defined by the presence of hyperglycemia Criteria: ○ Twice a fasting plasma glucose >/= 126 mg/dL (7.0 mmol/L) ○ Symptoms of DM plus a random plasma glucose >/= 200 mg/dL (11.1 mmol/L) ○ Plasma glucose level >/= 200 mg/dL after OGTT (oral glucose tolerance test) Names of hyperglycemic states: ○ Normal fasting plasma glucose: 70-99 mg/dL (3.4-5.5 mmol/L) ○ Impaired fasting glucose (IFG): 100-125 mg/dL (5.6-6.9 mmol/L) ○ Impaired glucose tolerance (IGT): Plasma glucose after 2 hour OGTT: 140-199 mg/dL (7.8-11 mmol/L) ○ Prediabetes: IFG or IGT ○ Diabetes: Symptoms of hyperglycemia and casual plasma glucose >/= 200 mg/dL (11.1 mmol/L) Plasma glucose after 2 hour OGTT (WHO) >/= 200 mg/dL (11.1 mmol/L) Fasting plasma glucose >/= 126 mg/dL Functional deficiency of insulin action → hyperglycemia ○ Decrease in insulin secretion by β cell of pancreas (DM 1) ○ Decreased response to insulin by target tissues → insulin resistance (DM 2) ○ Increase in counterregulatory hormones that oppose the effects of insulin (DM in endocrinopathies, gestational DM) Over 90% of cases of DM are regarded with primary DM which is associated with genetic predisposition (DM Type I or Type II) DM Type III, other specific types: account for less than 4-5% of cases Gestational DM: 4-5% of cases Etiology: ○ Type I DM:  β cell destruction usually leading to absolute insulin deficiency Immune-mediated Idiopathic ○ Type II DM: May range from: Predominant insulin resistance with relative insulin deficiency Predominant secretory defect with insulin resistance ○ Other specific types: Genetic defects of β cell function: Chromosome 20 (MODY 1) Chromosome 7 (MODY 2) Chromosome 12 (MODY 3) Chromosome 13 (MODY 4) Mitochondrial DNA Genetic defects in insulin action: Type A insulin resistance (defect of insulin receptors) Leprechaunism (dwarfism) Rabson-Mendenhall syndrome Lipoatrophic diabetes Diseases of the exocrine pancreas: Pancreatitis Trauma, pancreatectomy Neoplasia Cystic fibrosis (mucoviscidosis) Hemochromatosis Endocrinopathies: Acromegaly: results in excess growth hormone production Cushing’s syndrome: results in excess cortisol secretion Glucagonoma: pancreatic cancer that secretes glucagon Pheochromocytoma: secretes epinephrine Hyperthyroidism: increased levels of thyroid hormones Somatostatinoma: tumor producing somatostatin Aldosteronoma: tumor producing aldosterone Drug- or chemical-induced: Pentamidine Glucocorticoids Thyroid hormone Thiazides Infections: Congenital rubella Cytomegalovirus Uncommon forms of immune-mediated diabetes Other genetic syndromes sometimes associated with diabetes: Down’s syndrome  Klinefelter’s syndrome Turner’s syndrome Porphyria ○ Gestational diabetes mellitus (GDM) Diabetes Mellitus Type I: Selective destruction of over 90% of pancreatic β cells with severe insulin deficiency ○ Immune-mediated (autoimmune DM I) → 90% With autoantibodies against β cells or insulin in patient’s blood Destruction of β cells of pancreatic islets by autoimmune process: Rapidly developing: usually in children, but maybe also in adults (usually AAI antibodies) Slowly developing: usually in adults → LADA ○ Latent Autoimmune Diabetes in Adults (usually GAD antibodies) The result of an autoimmune reaction to antigens of the islet cells of the pancreas: In 80% of cases of DM I presence of autoantibodies: ○ ICA (Islets Cell Antibodies) ○ IAA (Insulin Autoantibodies) ○ IA-2 (Insulinoma-associated antigens Antibodies → against tyrosine phosphatase) ○ GADA (Glutamic Acid Decarboxylase Antibodies) New antibodies: ZnT8 (Slc30A8): antibody against type I zinc transporter Presented in β cells of pancreas Connected with mechanisms of insulin secretion Presented in 70% of patients with DM1 and only in 1% of control group If present with additional four previous antibodies → the probability of DM I development in 98% of cases (only 2% idiopathic DM) Antibodies are present in patient’s blood for several months to years before symptoms of DM I, and the next gradual loss of β cells occurs Strong association between DM I and other endocrine autoimmunities in DM I patient and his family members Ex: Addison’s disease, Hashimoto thyroiditis, Graves disease The importance of the genetic and environment influences in pathogenesis of DM I: Genetic factors (not so strong as in DM II) ○ Genetic susceptibility is linked to presence of class II Hyman Leukocyte Antigens (HLA) Molecules that are expressed on the macrophages (especially DR3, DR4, DQ8)  In 50% of cases ○ Presence of DM I in monozygotic twins only in 30-40% of cases ○ Presence of DM I in first-degree family members of DM I patients only in 2-6% of cases Environmental factors: ○ Viral infections Congenital rubella, CMV Coxsackie, Herpes, Retro-viruses ○ Early feeding cow milk or gluten: May precipitate DM I particularly in genetically susceptible individuals Immune response to foreign antigens or viruses may initiate β cell destruction Which are homology to β cells (ex: Coxsackie virus, cow milk, gluten) ○ By unknown factor (idiopathic DM I) → 10% No autoantibodies in patient’s blood Destruction of about 90% of β cells of islets by unknown factor No antibodies against β cells or insulin plasma of DM I patients There is no option for prevention of DM I development: Factors which can potentially protect against DM I development: ○ Low “body mass / height ratio” of newborn ○ Breast feeding ○ Early Vitamin D3 administration ○ Coexistence of atopic/allergic disorders ○ Theory of the lack of hygiene (early contact with infectious factors) Autoimmune or idiopathic DM I: ○ The cause of destruction of β cells is unknown and destruction occurs gradually over several years until symptoms ○ Usually affects individuals under age 30 (juvenile-onset diabetes), but may occur at any age ○ Increased ketone bodies (because of absolute insulin deficiency) First symptom → diabetic ketoacidosis ○ Low level or lack of insulin Low or undetectable C-peptide concentration in plasma ○ Requires treatment with insulin Clinical manifestations: ○ Hyperglycemia: leads to (3 x P) Glucosuria: when elevated glucose levels exceed the renal threshold for reabsorption of glucose Polyuria nocturia: because of osmosis diuresis Polydipsia: dehydration stimulates thirst  Polyphagia: because of decreased activity of the satiety center in the hypothalamus ○ Weight loss: due to dehydration and loss of calories in the urine ○ Blurred vision: because of changes in the water content of the lens of eye in response to change in osmolarity Diabetes Mellitus Type II: 10 x more common than DM I Occurs most commonly in adults Increases in prevalence with age Occurs more commonly in Native Americans, Mexican-Americans, African-Americans Particularly in women Stronger genetic predisposition than in DM I Polygenic origin of disease Mainly genetics and environmental factors Increased resistance to the effects of insulin Defective insulin secretion and insulin resistance Insulin treatment is not required for survival Genetic factors: ○ Risk of DM II development is higher, if DM II is present in: 1 parent: 40% → DM: 5% Both parents: 50% → DM: 10% Monozygotic twins: 90% → DM: 30% ○ Different genetic variants, complex susceptibility ○ Involvement of genes encoding insulin resistance, genes contributing to B cells dysfunction ○ Genetic tests are not able to indicate who develops DM II Environmental factors: ○ Changes in lifestyle (including food availability) ○ Central obesity ○ Low/Lack of physical activity ○ Diet with high amounts of carbohydrates and fat ○ Cigarettes, alcohol abuse ○ Drugs ○ Living in different areas of the world (habits, cuisine, lifestyle) ○ Increased life longtime (aging) Etiology: ○ 80% DM II is associated with obesity: Particularly central (abdominal) obesity is associated with increased insulin resistance Increased insulin levels & down-regulation of insulin receptors relative to nonobese controls  The higher the insulin levels the lower number of receptors for insulin on particular adipocyte Relative insulin deficiency cannot compensate for the increased insulin resistance caused by obesity Hormones produced by fat → lead to insulin resistance in fat and muscle Resistin (increase in obesity) Adiponectin (decrease in obesity) Weight loss in obese type II Diabetics can prevent DM Clinical manifestations: ○ Hyperglycemia: leads to (3 x P) Glucosuria: when elevated glucose levels exceed the renal threshold for reabsorption of glucose Polyuria nocturia: because of osmosis diuresis Polydipsia: dehydration stimulates thirst Polyphagia: because of decreased activity of the satiety center in the hypothalamus ○ Weight loss: due to dehydration and loss of calories in the urine ○ Blurred vision: because of changes in the water content of the lens of eye in response to change in osmolarity Gestational Diabetes Mellitus: Any hyperglycemic state that occurs or is recognized the first time during pregnancy ○ Occurs in 4% of pregnant women ○ May recur with subsequent pregnancies (in ~30%) ○ Tends to resolve at parturition ○ In 10% is not recognized DM I before pregnancy ○ Is associated with obesity ○ Usually occurs in the second half of gestation ○ In 40% predicts the future (after 15 years) DM II Diagnosed by routine screening with OGTT during 24-28th week of pregnancy or at first prenatal visit in high-risk population: ○ Overweight or obesity (BMI > 27), hypertension ○ Many pregnancies ○ Previous gestational DM ○ Previous macrosomia (weight of newborn > 4000 g) ○ Death of newborn during pregnancy ○ Pregnancy at age 35 or more ○ Family history of DM ○ Member of ethnic group ○ Polycystic ovary syndrome  DM during pregnancy (DM before pregnancy - usually DM II or LADA) → criteria of DM like for the whole population ○ Gestational DM-Revised ADA criteria (2011): 75 g OGTT at 24-28 weeks of gestation Fasting: >92 mg/dL 1 hour: >180 mg/dL 2 hour: >153 mg/dL Any 1 abnormal value → GDM Associated with elevated levels of hormones that have anti-insulin effects: ○ Somatomammotropin ○ Estrogens ○ Progesterone ○ Cortisol ○ Prolactin ○ Consequences: Increased perinatal mortality Macrosomia Neonatal hyperbilirubinemia Hypocalcemia Hypoglycemia Obesity in children LADA: Latent Autoimmune Diabetes in Adults (slow-progressing type I diabetes) Patients with LADA possess immunological and genetic features typical of DM I ○ High rates of HLA-DR3 and DR4 ○ Positive for GAD and/or islet cell antibodies (ICA) Antibodies to GAD are detected in 75% of cases ○ Strong association between LADA and other endocrine autoimmunities (ex: Addison disease, Hashimoto thyroiditis, Graves disease) in LADA patient and members of his family ○ Low plasma level of C-peptide ○ Require treatment with insulin ○ Lean body mass index Patients with LADA possess some features typical of DM II ○ Patients of adult age (~40-50) who do not require insulin at least for some time after diagnosis Pseudo-sensitivity for oral hypoglycemic drugs which stimulate insulin release) ○ Share insulin resistance with Type II diabetic patients but display a more severe defect in maximally stimulated β cell capacity ○ Slow progression of β cell destruction with periods of its regeneration usually with residual insulin secretion DM - Complications:  Acute: ○ Diabetic ketoacidosis: in the absence of insulin, lipolysis is stimulated, providing fatty acids that are converted to ketone bodies in the liver Typical for DM I However it can also occur in DM II during: Infections Severe trauma Other stress factors In diabetic ketoacidosis coma occurs in a minority of patient (10%) Ketogenesis results in: Ketonemia Ketonuria Metabolic acidosis Metabolic acidosis stimulates respiration to compensate the disorder Deep, rapid respiration occurs (Kussmaul breathing) Symptoms: Nausea, vomiting → dehydration Abdominal pain (30%) → gastric stasis and distention Leukocytosis (not necessarily caused by infection) Symptoms of concomitant disease Hyperglycemia (~500 mg/dL) Ketoacidosis (decreased pH, ketonemia, ketonuria) Hyponatremia, hyperTG Normal or elevated serum K+ levels despite depleted total body stores ○ K+ shift out of cells due to acidosis, insulinopenia, and hyperglycemia Causes: Mistake in insulin therapy (insulin deficiency) Acute bacterial infection MI, stroke Unrecognized DM, especially DM I Pancreatitis, especially acute Alcohol abuse Pregnancy Other states with increased demands for insulin ○ Hyperosmolar coma: severe hyperosmolar states in the absence of ketosis Typical for type II DM The same mechanisms as in diabetic ketoacidosis Hyperosmolality causes coma because of cellular dehydration in the brain Coma occur when the effective plasma osmolality reaches 340 mOsm/L (normal: 280-295 mOsm/L) Ketoacidosis is absent:  Residual insulin secretion effectively inhibits lipolysis and ketogenesis Plasma hyperosmolality inhibits lipolysis Symptoms occur later with profound hyperglycemia and dehydration 10 x more mortality than in ketoacidosis Older people with many concomitant diseases Diagnostic criteria: Hyperglycemia often > 600 mg/dL (800-2400 mg/dL) Plasma osmolarity > 320 mOsm/L pH > 7.3 (sodium bicarbonate > 20 mEq/L) Absence of ketonemia ○ Hypoglycemia: Etiology: Inappropriate dosing with insulin or oral hypoglycemic drugs treatment in DM I, DM II During exercises, fasting → blood glucose levels < 70 mg/dL Symptoms: (glucagon, epinephrine, cortisol, GH) Secondary to catecholamine release (adrenergic activation): ○ Shaking ○ Palpitations ○ Weakness ○ Tremor ○ Anxiety ○ Tachycardia Secondary to cholinergic activation: ○ Sweating ○ Hunger Neuroglycopenic symptoms: ○ Confusion ○ Headaches ○ Diplopia ○ Convulsion ○ Coma Chronic: ○ Macrovascular: Atherosclerosis: Macrovascular disease increases incidence of: ○ MI ○ Stroke ○ Claudication ○ Gangrene of lower extremities Mainly associated with DM II Increased risk of atherosclerosis in DM associated with:  ○ DM is independent risk of atherosclerosis ○ Hypertension, hyperlipidemia ○ DM acts synergistically with other risk factors such as cigarettes, obesity Stroke Heart disease Hypertension: In Type I diabetes: usually occurs after the onset of nephropathy, when renal insufficiency impairs the ability to excrete water and solutes In Type II diabetes: often present at the time of diagnosis in these older, obese, insulin-resistant individuals ○ Leads to insulin resistance / hyperinsulinemia → sympathetic overactivation Peripheral vascular disease Foot problems (diabetic foot ulcers): Hypertriglyceridemia: all risk factors of atherosclerosis Increased VLDL Decreased HDL cholesterol Elevated LDL cholesterol Pathophysiology: Increased polyol pathway flux (sorbitol) Increased formation of advanced glycosylation end-products (AGEs) Activation of Protein Kinase C Increased hexosamine pathway flux Oxidative stress ○ Microvascular: Retinopathy → Diabetic eye disease (retinopathy and cataracts) Diabetes is the leading cause of new blindness among US adults Nonproliferative retinopathy: ○ In both type of DM ○ Microaneurysms of retinal capillaries ○ Hard exudates (yellow spots with distinct borders) ○ Cotton wool spots (infarcts) or soft exudates (hazy yellow areas with indistinct borders) ○ Dot blot hemorrhages ○ Macular edema Proliferative retinopathy: ○ More severe stage ○ More prevalent in type I DM ○ Major cause of blindness ○ New vessel formation (neovascularization), which are abnormal vitreous hemorrhage or retinal detachment  Nephropathy → renal disease Diabetes causes end-stage renal disease requiring kidney dialysis or transplantation End-stage renal disease is preceded by massive nephrotic-range proteinuria (> 4 g/dL) Disordered glomerular function Glomerulosclerosis: nodular component is known as Kimmelstel-Wilson nodules (due to AGE formation) Hyperfiltration Hypertension speeds that process Symptoms of nephropathy: ○ Microalbuminuria Urinary loss of albumin that cannot be detected by routine urinalysis methods (30-300 mg / 24 hours) ○ Proteinuria: Over 300-500 mg of urinary proteins detected by routine urinalysis Neuropathy: Occurs commonly in DM I and DM II Is a major case of morbidity 3 major types: ○ Symmetric distal polyneuropathy - primarily sensory (most common) Demyelination and loss of nerve fibers of peripheral nerves Effects distal nerves Clinically: a symmetric sensor loss in the distal lower extremities (stocking distribution) that is preceded by numbness, tingling and paresthesias Symptoms can also affect the hands (glove distribution) ○ Autonomic neuropathy: in individuals with distal polyneuropathy Often accompanies symmetric peripheral neuropathy Occurs more frequently in Type I diabetes Affects all of autonomic functions involving the cardiovascular, genitourinary, and GI systems Symptoms: Tachycardia at rest and orthostatic hypotension ○ Due to neurogenic and vascular factors Overflow incontinence in women  ○ Due to increased risk of UTIs ○ Loss of bladder sensation and difficulty in emptying the bladder Gastroparesis (delayed gastric emptying), constipation, diarrhea ○ Transient, asymmetric, neuropathies involving specific nerves, nerve roots, or plexuses (less common) Foot problems ○ Foot ulcers: Symmetric polyneuropathy manifested by decreased vibratory and cutaneous pressure sensation and ankle reflexes (present in 75-90% of diabetics) Often led to: Amputation (because of ischemia due to macrovascular and microvascular disease) Infections (due to alterations in neutrophil function and vascular insufficiency) Faulty wound healing (due to unknown factors) ○ Susceptibility to infections: etiology Defective neutrophil functions (phagocytosis) Abnormal cell-mediated immunity Vascular lesion More severe infections especially: Candidal infections Periodontal infections Necrotizing papillitis Malignant otitis externa Furunculus Lecture 17: Acute and chronic hepatitis. Liver cirrhosis. Pancreatitis. Gastrointestinal pain. Acute and Chronic Liver Failure: Laboratory evaluation: ○ Hepatocytes integrity: Serum aspartate aminotransferase (AST) Serum alanine aminotransferase (ALT) Serum lactate dehydrogenase (LDH) ○ Biliary excretory function: Serum bilirubin (total and direct) Urine bilirubin Serum bile acids ○ Plasma membrane proteins (damage to canaliculus): Serum alkaline phosphatase (AP)