Fatty liver, fibrosis, cirrhosis and liver dysfunction Flashcards
Describe MASH
Defined histologically, in presence of neglibile alcohol consumption (<20g per day) and negative viral serology - with findings of:
- Steatosis (macro and microvesicular)
- Hepatocyte balloon degenration
- Mild diffuse lobular acute and chronic inflammation
- Perivenular and perisinusoidal collagen deposition
MASH = fat + inflammation +/- fibrosis
What are alternative ways that liver fibrosis can be investigated?
- Scored based on standard laboratory blood tests e.g. FIB4
- Measurement of molecules in serum related to fibrosis e.g. ELF
- Measurement of physical properties of liver e.g. vibration controlled transient elastography = FibroScan
- Imaging - Ultrasound, CT, MRI - pick up cirrhosis well but NOT earlier stages of fibrosis
Other common methods are:
- Ultrasound guided liver biopsy
- Biopsy under microscope (comes with risk of bleeding, expensive, sampling variation) - THIS IS THE GOLD STANDARD
But these come with their own disadvantages, so hence the alternative methods above may be used.
Describe non-invasive serum tests of liver fibrosis
NAFLD fibrosis score:
- = 1.675 + 0.037 x age x 0.094 x BMI + 1.13 x IFG/diabetes + 0.99 x AST/ALT ratio - 0.013 x platelets - 0.66 x albumin
- A score of less than -1.455 excludes fibrosis (NPV 88-93%)
- A score of greater than 0.676 predicts fibrosis
FIB-4 score:
- = (Age x AST) / (Platelets x Sqrt (ALT))
- A score of less than 1.3 excludes fibrosis (NPV 95%)
- A score of greater than 3.25 predicts fibrosis (PPV - 70%)
Describe Fibroscan
- Measures liver elasticity
- Stiffness score correlates to fibrosis score
- Useful in managing NAFLD
Describe the hepatic lobule
Consists of:
- Portal triad (bile duct, portal vein, hepatic artery)
- Sinusoids
- Central vein (hepatic vein)
- Hepatocyte
- Kupffer cell
Describe the Space of Disse
- Perisinusoidal space b/w endothelial cells and hepatocytes
- Fenestrations in endothelium and microvilli on hepatocytes facilitate uptake and release of proteins and other components from/to plasma
Describe Stellate cell
- Reside in perisinusoidal space - Space of Disse
- Major cell type involved in liver fibrosis
- In normal liver are quiescent, represent 5-8% total liver cells
- Long protrusions wrap around sinusoids
- Major store vit A and retinol in intracellular lipid droplets
Describe Kupffer cells
- Line sinusoids, adhere to endothelium
- Largest population tissue-resident macrophages in body
- 1st line of defence against gut bacteria, endotoxins etc transported from GI tract in portal vein
Describe the mechanism of liver fibrosis
- Following chronic liver injury, inflammatory lymphocytes infiltrate hepatic parenchyma. Chronic hepatocyte injury causes release of damage-associated patterns (DAMPs) and apoptopic bodies that activate Hepatic stellate cells (HSCs) and recruit immune cells
- Some hepatocytes undergo apoptosis, and Kupffer cells activate, releasing fibrogenic mediators
- HSCs proliferate, undergo phenotypical activation, secrete large amounts extracellular matrix proteins
- Complex multidirectional signalling b/w activated HSCs and Kupffer cells, as well as innate immune cells exist (TGF-B, platelet derived growth factor and others) and promote trans-differentiation into myofibroblasts
- Myofibroblasts synthesise and deposit extracellular matrix products and hyaluronic acid (Hyaluronic acid can stimulate fibroblasts which secrete ECM)
- Sinusoidal endothelial cells lose their fenestrations, and tonic contraction of HSCs causes increased resistance to blood flow in hepatic sinusoid
- Imbalances in ECM synthesis and degradation result in liver fibrosis. Decreased activity of ECM-removing matrix metalloproteinases (MMPs - MMP9 breaks down type III collagen to type III pro collagen propeptide) is mainly due to overexpression of their specific inhibitors, TIMPs (released from macrophages and fibroblasts and inhibit MMPs)
In advanced stages, liver contains approx 6x normal ECM, including collagens (I, III, IV), fibronectin, undulin, elastin, laminin, hyaluronic acid, and proteoglycans
How is cirrhosis involved in the development of liver fibrosis?
- Cirrhosis produces hepatocellular dysfunction and increased intraheptic resitance to blood flow, which result in hepatic insufficiency and portal hypertension, respectively
- In a normal situation, fibrogenesis is a wound healing process, but sustained and progressive fibrosis can become pathogenic
- Most causes of chronic liver injury can result in liver fibrogenesis. This proces takes many years and is often asymptomatic
- Therefore, patients have end-stage liver disease when they develop symtpoms e.g. liver cirrhosis, decompensated liver disease, hepatocellular carcinoma
Describe the fatty liver spectrum
MASLD (metabolic dysfunction-associated steatotic liver disease)
- Steatosis (NAFL) - Fat infiltration >5% w/o ballooning, with or w/o inflammation
- Steatohepatitis - Fat infiltration ≥ 5% with necroinflammation and hepatocellular injury (ballooning, hepatocyte degeneration, lobular inflammation)
- Cirrhosis - Increasing fibrosis, leading to cirrhosis (HCC)
MASLD is a multisystem disease:
- Psoriasis
- Liver -related complications
- Malignancies
- Osteoporosis
- Sleep apnea
- Abdominal obesity
- Type 2 diabetes
- CVS disease
- Cardiac abnormalities/arrhythmias
- Chronic kidney disease
- PCOS
What is MAFL?
Fat +/- mild inflammation
What are risk factors for MASLD?
- Metabolic synrome
- Obesity (most imporotant, well-described risk factor, increased prevalence of MASLD, increased severity also in obesity, obesity leads to IR leads to MASLD)
- Type II diabetes
Describe the pathogenesis of MASLD
- Dietary and environmental factors lead to obesity, raised FFAs, apidocyte proliferation and overload leading to adipose tissue damage insulin resistance
- Resistance leads to lipolysis with increased release of FFAs and release of adipoines and proinflammatory cytokines
- Systemic inflammation leads to resistance in liver and muscles
- Diet induced alteration of gut microbiome leads to ‘leaky gut’, increased delivery of bacterial products to liver, inducing inflammation as well as increased delivery of dietary carbs to liver
- Increased FFAs from fat and gut lead to synthesis of TGs +/- ‘lipotoxicity’
- FFAs normally metabolised by B-oxidation but mitochondria are overwhelmed leading to mitochondrial dysfunction, oxidative stress, production of ROS, ER stress, leading to proinflammatory and apopotic climate in liver and NASH
- Genetic factors modify on many lvls affecting progrssion to NASH or persistance of MASLD
What genetic factors are involved in MASLD?
- Allele in PNPLA3, encoding was strongly associated with increased hepatic fat lvls and with hepatic inflammation. Allele most common in hispanics
- Transmembrane 6 superfamily member 2 associated with liver lipid accumulation but reduced VLDL and CVS risk
Describe the potential mechanisms for the gut microbiome to contribute to the pathogenesis of MASLD
- Alterations of intestine microbiome (dysbiosis) result in increased gut permeability, mediated through reduced concentrations fo SCFA and altered T-reg environment
- LPS from translocated bacterial cell walls triggers TLR-4 on Kupffer cells leading to inflammation and fibrosis
- Alcohol from microbial fermentation metabolised in liver, may contribute to liver injury
- Primary bile acids converted to secondary bile acids by gut microbiota. Bile acid receptor-mediated signalling leads to profound impacts on liver metabolism with steatosis and inflammation
- Gut microbiota converts choline into methylamines. Elevated activity of choline metabolism may lead to choline deficiency and subsequently to liver injury, inflammation, and fibrosis
What are the clinical consequences of progression of liver fibrosis to cirrhosis?
- Patients with fibrosis rarely have symptoms attibutable to their liver
- Cirrhosis development heralds onset of symptoms, reflect liver dysfunction
- Symptom onset may be insidious and gradual or sudden: decompensated liver cirrhosis and acute or chronic liver failure
- In most conditions, risk of primary liver cancer (hepatocellular carcinoma) only starts to increase with development of cirrhosis (hep-B and MAFLD being exceptions)
Describe decompensated cirrhosis
- Characterised by:
- Encephalopathy
- Variceal haemorrhage
- Coagulopathy
- Ascites
- Hyponatraemia
- Diuretic resistance
- Hepatorenal syndrome
- Spontaneous bacterial peritonitis - Fluid in abdomen becomes infected
- Hepatopulmonary syndrome
- Portopulmonary hypertension
- Malnutrition
- HCC
Describe portal hypertension in cirrhosis
Increased portal pressure = Increased Portal venous outflow resistance x Increased Portal venous flow
Increased portal flow due to splanchnic vasodilation of gut, greater flow of blood to liver via portal vein
Increased Portal venous outflow resistance:
- Structural (70%) - Fibrobis, nodules, sinusoidal capillarisation
- Vascular tone (30%) - Activation of hepatic stellate cells - Increased constrictors (endothelin, TXA2, Ang II), decreased sinusoidal vasodilators (NO)
Increased Portal venous flow:
- Splanchnic vasodilation
- Increased production of intestinal VEGF and eNOS
- Increased NO
This is due to the endothelial stretching/ distension and stress caused by the fibrosis, signals stretch receptors
Describe 5 clinical stages of cirrhosis
1 - No varices (7%)
2 - Varices (8%)
3 - Bleeding (19%)
4 - Ascites (45%)
5 - Ascites Bleeding (56%)
Percentages show 5 year mortality rate
Describe the prediction of variceal haemorrhage in cirrhosis
F1 - Small and straight, flatten on insufflation
F2 - Tortous varices, <1/3 of lumen
F3 - Large coil shaped, >1/3 of lumen
Describe the West Haven Criteria of Severity of Hepatic Encephalopathy
Minimal - Normal standard clinical exam; abnormal responses to detailed psychometric tests
1 - Euphoria or anxiety; shortened attention span; mild lack of awareness
2 - Lethargy or apathy; mild distortion of place or time; mild personality changes; impaired performance on addition/subtraction
3 - Confusion, disorientation or somnolence to semistupor but responsive to verbal stimuli
4 - Coma
Describe the pathogenesis of hepatic encephalopathy
Hepatic encephalopathy - Flapping tremor, drowsiness, confusion
- Increased NH3 delivery to brain:
- Altered gut microbiota, Porto-systemic shunt, impaired ammonia metabolism, impaired glutamine metabolism, intrahepatic shunting, muscle breakdown
- Inflammation
- Systemic cytokines, nitric oxide and oxidative stress
Ammonia and glutamate converted to glutamine by glutamine synthetase in astrocytes
Secondary swelling as glutamine is an osmolyte
Depletion of glutamate, an excitatory neurotransmitter
Grade III/IV encephalopathy associated with infection/ SIRS not ammonia
What is ascites?
Accumulation of free fluid in peritoneal cavity
