Liver Pathology Part III - MAFLD Quiz

Liver Pathology Part III - MAFLD

• MAFLD is "metabolic dysfunction associated fatty liver disease".
• NAFLD is the most common cause of liver disease in the US.
• Estimated prevalence of NAFLD is up to 40% of the population.
• NAFLD includes simple hepatic steatosis and steatosis complicated by inflammation.
• Progression to NASH (non-alcoholic steatohepatitis) is uncommon.
• NASH progresses to cirrhosis in 10-20% of cases.
• In those progressing to cirrhosis, liver cancer incidence can be as high as 1-2% per year.

NAFLD - Pathologic Findings

• Initial findings include hepatocyte ballooning, lobular inflammation, and steatosis (fat accumulation).
• Progressive disease leads to more fibrosis, eventually causing cirrhosis.
• Strongly linked to obesity and the metabolic syndrome.

NAFLD - Pathophysiology

• "Two-hit" model
• 1. Hepatic fat accumulation.
• 2. Increased oxidative stress.
• Free radicals cause lipid peroxidation of accumulated intracellular fat.
• Obesity is associated with reduced intestinal barrier function and inflammation in the liver.
• Movement of microbes from the gut to the portal circulation.

Cirrhosis Pathogenesis

• Cirrhosis is the diffuse remodeling of the liver into parenchymal nodules surrounded by fibrous bands and a variable degree of vascular shunting.
• Stellate cells become activated and differentiate into highly fibrogenic myofibroblasts.
• Activated by inflammatory cytokines (e.g., TNF-alpha), toxins, and reactive oxygen species.
• Signals implicated include PDGF, TGF-beta, and IL-17.
• ECM deposition into the space of Disse and fibrous septae formation occur in regions of hepatocyte loss.
• Hepatocytes regenerate in nodules, but the architecture of the acinus is disrupted by fibrosis.

MAFLD vs. NAFLD

• Both require a 5% level of hepatic steatosis.
• MAFLD requires the presence of metabolic drivers of hepatic steatosis and inflammation (e.g., T2DM, obesity).
• A metabolic dysfunction composite score may be considered, further details are available on subsequent slides.
• NAFLD diagnosis requires excluding other liver diseases (significant alcohol use, hemochromatosis, etc.) as possible causes.

MAFLD and NAFLD Diagnostic Criteria

• MAFLD diagnostic criteria include 2 out of 7 metabolic risk factors.
  • Elevated waist circumference
  • Blood pressure > 130/85 (or use of BP meds)
  • Elevated triglycerides (> 1.7 mmol/L)
  • Low HDL cholesterol
  • Prediabetes
  • Elevated HOMA insulin resistance score
  • Elevation in CRP
• NAFLD does not consider metabolic risk factors.

Why Diagnostic Differences Matter

• Clearer diagnoses can specify chronic viral hepatitis complicating NASH.
• Better diagnostics allow for targeted treatments.
• A MAFLD diagnosis increases the risk of diabetes, chronic kidney disease, and worsened lung function compared to NAFLD.
• MAFLD is often associated with increased "wear and tear" from metabolic dysregulation, while NAFLD may not be as strongly linked to this.
• MAFLD diagnostic criteria can mitigate issues with underreporting of alcohol consumption, a potential issue in patients with NAFLD.

MAFLD and NAFLD Pathophysiology

• Obesity and insulin resistance cluster frequently as they cause increased FFA liberation from adipocytes, converting them into triglycerides that are stored in hepatocytes.
• Elevated glucose and insulin leads to hepatic triglyceride synthesis.
• Adiponectin, an adipokine released by visceral fat, increases glucose utilization and fatty acid oxidation.
• Declines in adiponectin are associated with increased intra-abdominal fat.

MAFLD - Counteracting Pathology

• Weight loss via lifestyle modification is the best approach.
• Weight loss can reduce steatosis and improve fibrosis in patients with type 2 diabetes.
• Exercise may improve fibrosis and steatosis.

An Approach to Hepatic Investigations

• Blood tests assessing liver enzymes (ALT, AST), liver function (albumin, PT/INR), and bilirubin help diagnose liver damage severity and etiology.

Laboratory Analysis of Liver

• The different transaminases (ALT, AST), ALP, bilirubin, albumin, and PT/INR can be used for liver damage & etiology assessment
• Liver enzyme tests (ALT and AST), liver function tests (albumin and PT/INR), and bilirubin tests help determine liver pathology.

General Patterns and Concepts

• Damage to hepatocytes or biliary tree releases enzymes into the bloodstream.
• Elevated liver enzymes indicate damage.
• Hepatic function is assessed through serum albumin (maintains oncotic pressure) and bilirubin values.
• Bilirubin is a breakdown product of heme in the biliary tree, and increases signify damaged or impaired hepatic function.
• A PT/INR increase signifies time to clot increases and signifies impaired hepatic function.
• Hepatocellular pattern = increased AST and ALT, normal to mildly elevated ALP and GGT.
• Cholestatic pattern = increased ALP and GGT, normal or moderately elevated AST and ALT.

Liver Enzyme Tests

• ALT: Alanine aminotransferase, found primarily in hepatocytes, is a good indicator of hepatocyte damage.
• AST: Aspartate aminotransferase, found in hepatocytes and other cells, is less specific for hepatocyte damage than ALT.
• ALP: Alkaline phosphatase is found in hepatocytes and bone, increased levels often indicate biliary tract problems.
• GGT: Gamma-glutamyl transpeptidase is found in hepatocytes and other cells, increased levels often indicate biliary tract problem or alcohol use disorder.

Liver Function Tests

• Bilirubin: Two forms (unconjugated and conjugated) assess liver function, particularly the conjugation, transport, and excretion of bilirubin.
• Albumin: Levels help establish oncotic pressure and indicate long-term protein synthesis deficiencies.
• PT/INR: Prothrombin time (PT) or international normalized ratio (INR) evaluate the liver's ability to produce clotting factors and indicate liver dysfunction.

Liver Imaging- FYI Review

• Ultrasound is best for evaluating biliary ducts and gallbladder.
• MRI and CT provide insight into liver masses and fibrosis.
• MRCP is a specialised MRI technique to evaluate the biliary system.
• Liver biopsy is often needed as a definitive diagnosis for fibrosis or cirrhosis.

Liver Investigations in MAFLD

• Elastography is used to measure liver fibrosis.
• Elastography can have false positives.
• MRI is helpful for detailed views of the biliary system and fibrosis assessment.
• Ultrasound is a potentially cheaper and accurate way to assess steatosis.
• Liver biopsy is necessary to definitively diagnose steatosis and fibrosis.

MAFLD Screening Tests

• FIB-4 score, NAFLD fibrosis score and ELF test are some useful tests to calculate.

Etiology of Eating Disorders

• Anorexia nervosa and bulimia are complex disorders with multiple factors contributing to their etiology.
• Psychological factors include OCD traits, cognitive rigidity, heightened emotional sensitivity, impulsivity, and a history of developmental stress, trauma, and challenging interpersonal relationships.
• Body dissatisfaction and engagement in diets and strenuous athletic training are important behavioral factors.
• Biological factors include genetic effects, and dysfunction in serotonin, dopamine, norepinephrine, opioid, and cholecystokinin systems.

Complications of Eating Disorders

• All-cause mortality is 2-10 times higher than general populations of similarly aged individuals with similar demographic backgrounds.
• Independent of weight; vitamin and mineral deficiencies, stunted growth, reduced gastric motility, increased discomfort from fullness and avoidance to eat are all common.
• Consequences of malnutrition; Bradycardia, hypotension, orthostasis, hypothermia, metabolic alkalosis, hypochloremia, increased bicarbonate, osteopenia and myopathies.
• Consequences of purging; esophageal tears, intractable vomiting, hematemesis, metabolic acidosis (laxatives), hypokalemia and cardiomyopathies.