BMS200 - Week 1

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.