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Questions and Answers
Which enzyme is primarily increased during biliary damage?
What condition can lead to disproportionate increases in GGT compared to ALP?
What normal range is generally accepted for alkaline phosphatase (ALP) levels?
Where is gamma-glutamyl transpeptidase (GGT) primarily found?
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From which part of hemoglobin is bilirubin derived?
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What is the primary characteristic that distinguishes MAFLD from NAFLD?
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Which of the following clinical features is commonly associated with Non-Alcoholic Fatty Liver Disease (NAFLD)?
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Which diagnostic method is considered definitive for confirming the presence of fibrosis in NAFLD?
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What is a common risk associated with Non-Alcoholic Fatty Liver Disease (NAFLD)?
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Which of the following is NOT typically used in the diagnosis of NAFLD?
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What is the most significant environmental risk factor associated with insulin resistance?
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Which type of obesity is considered more critical in the context of insulin resistance?
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What phenomenon contributes to the difficulty in studying the genetic causes of body weight variance?
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Which statement is true regarding caloric intake in obese individuals?
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What is indicated as an independent risk factor for insulin resistance aside from obesity?
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What role do AGRP neurons play in the homeostatic regulation of energy intake?
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How does increased serotonin signaling affect energy intake regulation?
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What effect does the agonist Lorcaserin have in terms of energy intake?
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What is the effect of nutrient presence on POMC neurons in the arcuate nucleus?
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What is a consequence of the inhibition of AGRP neurons when nutrients are sufficient?
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What are the three major options the liver has when levels of FFAs are elevated?
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What is VLDL primarily responsible for in the body?
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Which of the following apoproteins is NOT a key apoprotein for VLDL?
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What is the consequence of hepatic steatosis in the liver?
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Which pathway do lipoproteins take after being synthesized in the liver?
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What is the primary outcome when insulin resistance develops in skeletal muscle and subcutaneous fat?
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In the context of the twin cycle hypothesis, what initiates the first cycle involving the liver?
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What factor exacerbates the transition from early insulin resistance to a loss of beta cell mass in T2DM?
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Which of the following conditions is most associated with early insulin resistance according to the twin cycle hypothesis?
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What happens to circulating glucose levels when insulin resistance develops in skeletal muscle?
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Study Notes
Non-Alcoholic Fatty Liver Disease (NAFLD)
- NAFLD comprises a spectrum of liver disease: healthy liver, simple steatosis, nonalcoholic steatohepatitis (NASH), and cirrhosis.
- NASH features ballooned hepatocytes and pericellular fibrosis near central veins.
- Cirrhosis presents with bridging fibrosis around micronodules.
- Clinical symptoms often absent until advanced liver failure; fatigue and right-sided abdominal pain are possible.
- Increased risk of hepatocellular carcinoma is associated with NAFLD.
- Diagnosis involves liver enzyme tests but relies on scores from age, BMI, fasting glucose, AST, and ALT to determine inflammation.
MAFLD vs NAFLD
- MAFLD: Metabolic dysfunction-associated fatty liver disease; requires a 5% hepatic steatosis level.
- NAFLD diagnosis excludes other liver disease causes, such as alcohol use.
- MAFLD criteria include the presence of metabolic drivers like type 2 diabetes, obesity, or a composite metabolic dysfunction score.
Liver Enzyme Tests
- ALP (Alkaline Phosphatase): Increased in biliary damage, with normal levels ranging from 35 to 100 IU.
- GGT (Gamma-Glutamyl Transpeptidase): Sensitive but not specific; elevated in alcohol-use disorder. Normal levels are 9 to 85 U/L.
- 5' Nucleotidase (5-NT): More specific for hepatobiliary disease than GGT; normal levels are 0 to 18 U/L.
Liver Function Tests - Bilirubin
- Bilirubin is a breakdown product of hemoglobin, processed by macrophages into unconjugated bilirubin, which is converted to conjugated bilirubin by hepatocytes.
- Unconjugated bilirubin indicates hemolysis or RBC damage; conjugated bilirubin indicates blockage or liver damage.
- Elevated bilirubin may reflect hepatocyte damage or impaired bile flow.
Liver Function Tests - Albumin
- Albumin is synthesized by the liver, maintaining oncotic pressure and carrying hydrophobic molecules like bilirubin.
- Decreased serum albumin indicates chronic liver disease, protein malnutrition, or fluid overload.
- Albumin has a long half-life, indicating prolonged liver dysfunction before significant drops occur.
Liver Function Tests - PT/INR
- Fibrosis can be assessed using elastography or imaging; scoring systems predict fibrosis presence based on metabolic criteria and liver enzyme elevations.
MAFLD Screening Tests
- FIB-4 score includes patient age, AST, ALT, and platelet count.
- NAFLD fibrosis score assesses age, BMI, insulin resistance, and liver enzymes.
Etiology of Eating Disorders
- Psychological Factors: Traits like OCD, emotional sensitivity, and history of trauma contribute to disorders like anorexia nervosa and bulimia.
- Biological Factors: Strong genetic components (50%), serotonin and dopamine dysregulation, hypothalamic control, and effects of malnourishment on psychiatric conditions.
- Sociocultural Factors: Societal ideals of thinness and dieting as triggers for eating disorders.
Complications of Eating Disorders
- Mortality rates are significantly higher (2-10x) compared to the general population.
- Common complications include vitamin deficiencies, stunted growth, and reduced gastric motility.
- Consequences of malnutrition include bradycardia, hypotension, and osteopenia.
- Purging leads to severe health issues like esophageal tears and cardiomyopathies.
Pathogenesis of Obesity
- Obesity is the primary environmental risk factor for insulin resistance, especially central obesity.
- Genetic and environmental factors together influence insulin resistance, with Type 2 Diabetes Mellitus (T2DM) showing a high heritability.
- Only about 5% of population variance in body weight is attributed to genetic factors, complicating studies of environment-gene interactions.
Obesity and Eating Behavior
- Obese individuals may eat more in general, but studies show variation in caloric intake reporting.
- Impaired satiety mechanisms, including leptin resistance, are common in obese populations, often leading to increased caloric intake.
Hypothalamic Control of Appetite
- The arcuate nucleus (ACN) and paraventricular nucleus (PVN) in the hypothalamus help integrate peripheral and central signals related to hunger and satiety.
- Presence of nutrients activates POMC neurons in the ACN, leading to MSH release which suppresses hunger.
- AGRP neurons inhibit MSH signaling; when nutrients are present, AGRP activity decreases promoting satiety.
Serotonin’s Role in Satiety
- Serotonergic neurons from the raphe nucleus influence MSH neurons in the ACN and hedonic pathways.
- Increased serotonin correlates with activated MSH neurons and inhibited AGRP neurons, promoting weight loss via agonists like Lorcaserin.
- Human studies indicate serotonin's critical role in appetite regulation and satiety.
Hedonic Pathway and Obesity
- Lean individuals show better reward pathway activation compared to obese individuals, suggesting "reward deprivation" in obesity.
- Striatal dopamine release is impaired in obesity, decreasing D2/D3 receptor activity.
- Visual exposure to palatable foods can heighten reward anticipation, influencing eating behaviors negatively in obese individuals.
Peripheral Factors in Energy Regulation
- Key hormones involved in energy regulation include:
- Leptin (adipocyte-derived)
- Ghrelin (orexigenic, produced in the stomach)
- Insulin (produced by pancreatic beta-cells)
- GLP-1, CCK, and peptide YY (from the GI tract, suppress appetite).
Hypothalamus and Peripheral Signals
- The hypothalamus interacts with peripheral signals, aided by a "leakier" blood-brain barrier.
- Vagal connections relay peripheral information directly to the hypothalamus, influencing hunger and energy balance.
Types of Adipose Tissue
- White adipose tissue (WAT) primarily stores triglycerides and acts as an endocrine organ, while brown adipose tissue (BAT) is involved in thermogenesis, decreasing with age.
- Brown adipose tissue employs uncoupling proteins to convert fat into heat without generating ATP, primarily activated by catecholamines.
- Exercise and cold exposure can induce “browning” of WAT, leading to the formation of beige adipose tissue.
Homeostatic Pathway Mediators
- Leptin is an anorexigenic hormone, secreted in response to insulin and suppresses appetite by acting on NPY and AGRP.
- Insulin aids in activating the hedonic pathway through receptors in the ventral striatum, enhancing satiety signaling from the hypothalamus.
Gastrointestinal Hormones in Appetite Regulation
- Ghrelin stimulates hunger and is released during fasting; it’s countered by CCK, which promotes satiety.
- Human studies with CCK agonists show limited weight loss outcomes.
- Interaction between gut microbiota and the mesolimbic system may contribute to neuroinflammation affecting appetite regulation.
Microbiota-Gut-Brain Axis and Metabolism
- GLP-1 is secreted in response to nutrients, increases insulin secretion, and delays gastric emptying.
- Transplanting healthy microbiota can enhance insulin sensitivity in metabolic syndrome patients.
- Gut dysbiosis correlates with inflammation, potentially affecting glucose metabolism through mechanisms such as increased intestinal permeability, leading to systemic inflammation.
Twin Cycle Hypothesis and T2DM
- Type 2 diabetes mellitus (T2DM) often arises from prolonged insulin resistance.
- Transition from insulin resistance to beta cell loss is related to disrupted lipid and glucose metabolism across organs including liver, muscle, pancreas, and adipose tissues.
First Cycle – The Liver
- Diabetic patients reach a "tipping point" of energy storage.
- Healthy energy storage occurs primarily in:
- Subcutaneous fat (major storage)
- Muscle (glycogen)
- Liver (glycogen)
- Visceral fat (minor storage)
- Early insulin resistance leads to longer retention of glucose in the bloodstream and reduced triglyceride storage due to impaired adipose tissue function.
- Circulating free fatty acids (FFAs) increase due to insulin resistance, leading the liver to manage excess FFAs.
Liver’s Response to Elevated FFAs
- Liver options when overwhelmed by FFAs:
- Burn energy through beta oxidation.
- Store energy, leading to hepatic steatosis (unhealthy).
- Export energy via very low-density lipoprotein (VLDL) production.
- Insulin resistance creates an imbalance between insulin and glucagon signaling, leading to fat accumulation in hepatocytes and disruption in gluconeogenesis.
Consequences of Hepatitis Steatosis
- Steatosis exacerbates insulin resistance, increasing blood glucose and pancreatic insulin secretion.
- A cycle emerges of fat accumulation in the liver and pancreas, resulting in increased VLDL output and further compromise in insulin secretion.
Second Cycle – The Pancreas
- Pancreatic changes in T2DM include lipid accumulation affecting insulin secretion.
- Positive feedback loop:
- Insulin resistance → increased liver steatosis and VLDL → triglyceride and FFA buildup in pancreas → impaired insulin secretion → hyperglycemia → more fat and elevated FFAs.
Lipoprotein Metabolism
- VLDL synthesized in the liver consists mainly of triglycerides and apoproteins (ApoC-II, ApoA-V, ApoB-100).
- VLDL transitions to intermediate density lipoprotein (IDL) and eventually low-density lipoprotein (LDL) as triglycerides are removed.
- IDL and LDL are cleared by the liver, with oxidized LDL being a major atherosclerosis risk factor.
Subcutaneous Fat Saturation
- Adipose tissue has a storage limit for fat; insulin resistance leads to a reduction in triglyceride formation and increased FFA release.
- The secretion of adiponectin from subcutaneous fat decreases relative to leptin secretion, leading to poor regulation of food intake in T2DM.
Testing the Twin Cycle Hypothesis
- Evidence for the hypothesis includes observing improvements in fatty liver, fatty pancreas, weight loss, and triglyceride levels with T2DM treatment.
- The DiRECT trial demonstrated the effectiveness of a weight-loss program in managing T2DM.
DiRECT Trial Overview
- Involved 306 recently diagnosed T2DM patients with a focus on an intense dietary intervention.
- Participants followed an 825-853 kcal/day diet for three months, with all diabetes medications halted.
- Results showed a significant weight loss of 15 kg or more in 24% of participants from the intervention group after 12 months.
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Description
This quiz covers important aspects of Non-Alcoholic Fatty Liver Disease (NAFLD) as studied in BMS 150. It includes the spectrum of liver pathology from healthy liver to cirrhosis, highlighting key features like steatosis and NASH. Test your understanding of these critical liver conditions.
