NAFLD and NASH Flashcards
Explain the double blood supply of the liver
Blood is supplied through the portal vein an the hepatic artery
How is blood drained from the liver?
Venous drainage from the right and left hepatic veins
Name the major liver functions (8) - (LBM-CAP-HM)
- Lipid and lipoprotein production
- Bile formation
- Metabolism of drugs
- CHO metabolism
- AA metabolism
- Protein production and secretion
- Heme biosynthesis
- Metabolism of iron, copper, trace elements
What is the functional unit of the liver?
Acinus
What does the partial triad consist of?
Portal vein, arteriole and bile ducture
Wat lacks a basement membrane?
Sinusoids, have fenestered endothelium and kupffercells.
What joins to form bile ductules?
Bile canaliculi
What is AST?
Aspartate aminotransferase, liver test
Where is AST found?
Found throughout the body, but predominately in heart, liver
What does AST tell us?
Detect liver damage (hepatitis), drugs toxic to live, cirrhosis and alcoholism
What is ALT
Alanine aminotransferase, liver test
Where is ALT found?
Liver, kidney - if liver damaged, ALT will be released into bloodstream
What does ALT tell us?
Damage due to hepatitis or other substances toxic to liver
What liver tests are usually ordered together?
ALT and AST
If the AST/ALT ratio is increased, what does that tell us?
Indicative of alcoholic hepatitis, cirrhosis and first 1-2 days of acute hepatitis or bile duct obstruction
What is ALP?
Alkaline phosphatase
Where is ALP found?
Bone and in the cells of bile ducts
What does ALP indicate?
Blockage of one or more bile ducts, liver cancer, cirrhosis, or if hepatotoxic drugs are taken
What allows the general assessment of liver injury? How? What do elevations indicate?
- Hepatocellular enzymes
- “leak” of enzymes from hepatocytes
- parenchymal injury
What does it mean if AST/ALT >1?
Alcoholic cirrhosis
AST/ALT <1?
Not alcoholic cirrhosis, other causes
Which liver test is most specific?
ALT
What indicates disease to the biliary system?
Cholestatic enzymes
After injury, cholestatic enzymes must be ____ before they are released
synthesized
(T/F) Cholestatic enzymes allow for general assessment of liver injury
F, hepatocellular enzymes
Which cholestatic enzyme may be induced by medication, and is specific to the liver but sometimes “too sensitive” ?
GGT
Does GGT have a significant clinical indication?
No
Why is it a good thing to repeat liver tests?
Sometimes isolated elevations, “first-time” elevation, therefore repeat to confirm
What are the clinical presentations reflected in abnormal liver tests? (3C JA)
- Chronic hepatitis
- Cholestasis
- Cirrhosis
- Jaundice
- Acute hepatitis
Compare & contrasts symptoms of acute and chronic hepatitis
A: fatigue, anorexia, nausea, jaundice
C: variable
Compare & contrasts the ALT elevation of acute and chronic hepatitis
A: > 10fold
C: 1.5-10 fold
Compare & contrast the prognosis of acute and chronic hepatitis
A: Usually self-limited
C: Variable, at risk for progression
Compare & contrast the treatment of acute and chronic hepatitis
A: Supportive
C: At underlying cause
What is the most common cause of Acute hepatitis?
Viral causes (Hepatitis A,B)
Hepatitis A: Clinical cues?
History of exposure
Hep A: Diagnosis?
IgM, anti-HAV
Which medication is the # 1 drug induced cause of of liver disease?
Tylenol
What are the 3 most common causes of live diseases?
Alcohol, NAFL, viral hepatitis
Alcoholic hepatitis clinical cues?
Alcohol history, AST:ALT >2, AST<400
How can alcoholic hepatitis be improved?
Abstinence from alcohol
Clinical cues of NASH or NAFL?
Obesity, DM, hyperlipedemia
How are many liver diseases diagnosed?
Liver biopsy (Bx) or liver tests
Patient presents with following symptoms:
-Modest elevation of ALP
-No symptoms until end-stage, but some fatigue and pruritus
-PrognosisL at risk for progression
What liver disease?
Cholestasis
What is important to consider in patients with cholestasis?
Differentiate between intrahepatic and extrahepatic (usually obstructive) causes.
What is cholestasis?
Marked reduction in bile secretion and flow
What is intrahepatic cholestasis?
Disease involves liver parenchymal cells or intrahepatic bile ducts
What is extrahepatic cholestasis?
Excretory block outside of the liver, along with the extrahepatic bile ducts (typically stones)
What is a clinical presentation of cholestasis?
Jaundice due to build up of bile and bilirubin
What may be measured after ALP is elevated?
Liver fraction or GGT
What is hyperbilirubinemia ?
May be caused by hemolysis (recall that bilirubin is a breakdown product of RBCs) and characterized by elevated bilirubin within the blood –> Jaundice
Level of bilirubin in a pure obstruction?
= 15 mg/dl
Level of bilirubin in non-obstructive (mixed) case?
> 20 mg/dl
During hemolysis, bilirubin will be greater than ____ unconjugated and less than ____
80%
5 mg/dl
What are symptoms of obstruction?
Pain, fever, palpable gallbladder
Define cirrhosis
A diffuse process characterized by liver necrosis and fibrosis and conversion of normal liver architecture into structurally abnormal nodules that lack normal lobular organization
Greatest difference between normal and liver with cirrhosis?
The presence of nodules
Explain the pathology of cirrhosis
Degeneration and necrosis of hepatocyte and replacement of liver parenchyma cells by fibrotic tissues and regenerative nodules (nodularity), eventually leading to end-stage cirrhosis
There is abnormal liver architecture in cirrhosis, how are hepatocytes affected?
- Pleomorphism
- Dysplasia
- Hyperplasia
There is abnormal liver architecture in cirrhosis, discuss the gross pathology.
-Irregular surface, yellowish colour, small, firm
What leads to increased resistance in the portal vein?
Distorted sinusoidal architecture within the liver
Explain the pathophysiology of portal hypertension
The increased resistance to blood flow in the liver (cirrhosis) will cause increased pressure in the portal veins, where portal blood will become shunted into the systemic circulation (hyperdynamic circulation), leading to esophageal and anorectal varices, and caput medusea
Explain the pathophysiology of esophageal varices
The increased portal vein pressure is shunted into the distal veins in the lower esophagus, causing the bulging of veins.
Explain the danger of espohageal varices
Bulging of veins are at risk of bursting and bleeding, and possess risk of major haemorrhage and death. Patient may not notice initial bleeding (swallowed)
Explain the pathophysiology of anorectal varices
Increased portal vein pressure is shunted to systemic circulation, into the superior veins, then passing thorough middle and inferior veins (haemorrhoids)
(T/F) Esophageal varices have a higher risk of bleeding and death than anorectal
True
Explain the pathophysiology of caput medusea
Increased portal vein pressure is shunted into systemic circulation, into the umbilical artery which will cause increased pressure in subcutaneous, umbilical veins under the abdomen. Low risk of bleeding
Which consequence of portal hypertension is the most dangerous?
Esophageal varices
How can portal hypertension be treated?
Surgically, where the portal blood flow will be redirected to larger systemic veins that can handle higher pressure - such as IVC
What may cause collagen deposits, leading to cirrhosis within the liver?
Hepatic stellate cell, most important for regulating the collagen balance within the liver
What are the 5 alterations in the microvasculature in cirrhosis?
1) Activation of hepatic stellate cells
2) Collagen deposition in space of Disse
3) Construction of sinusoids
4) Defenestration of sinusoids
Discuss some key point of the impact of cirrhosis in medicine
- Most rapidly increasing disease (health & economic consequences)
- 8th leading cause of death
What are the two main consequences of cirrhosis?
- Portal HTN
- Liver insufficiency
What are the 3 main consequences of portal HTN?
- Variceal hemorrhage
- Ascites
- Encephalopathy
What are the 2 consequences of ascites?
- Spont. bacterial peritonitis
- Hepatorenal syndrome
What are the 2 consequences of liver insufficiency?
- Encephalopathy
- Jaundice
Normal portal pressure?
5-10 mmHg
Portal htn?
> 12 mmhG
Normal portal blood flow?
1-1.5 L/min
Where does the back flow occur in portal HTN? What undergoes vasodilation?
- Mesenteric veins (where portal and systemic circulation meet)
- Splanchnic vasodilation (as a consequence of increeased pressure )
What is the most common cause of PH?
Intrahepatic (80%) cirrhosis
How does cirrhosis cause PH?
Scar tissue blocks blood flow and slows liver function.
-Schistosomiasis, congentital heptaic fibrosis
What causes 20% of PH and is responsible for the extension of the umbilical vein and omphalitis (newborn?)
Prehepatic - portal vein thrombosis
What is a rare cause of PH?
Post-hepatic
What are the 4 locations that varices may form?
-Esophageal, gastric, anorectal, retroperitoneal
Besides varices, give 5 other consequences of PH
1) PH gastropathy and colopathy
2) Caput medusea
3) Ascites
4) Congestive splenomegaly
5) Hepatic encephalopathy
Explain the vicious cycle of portal HTN in the splanchnic/systemic circulation
PH leads to endothelial dysfunction, which leads to increased arterial vasodilation and collateral vessel formation, which will increased flow to portal vein and worsen PH
PH leads to ____
splenomegaly (enlargment of spleen)
Porto-systemic shunts from PH lead to ? (4)
- Lower end of esophagus by GE veins
- Anal veins
- Falciform ligament –> umbilical veins –> caput meducsa
- -Abdominal wall/retroperitoneum –> distended veins
What is the cause of ascites in cirrhosis?
PH
Explain the pathophysiology of ascites
In combination with PH, the osmotic pressure of plasma decreases due to the failure of the liver to synthesize serum proteins, such as albumin (hypoalbuminemia). Water and salt also places a role (hyperaldosteronemia)
Explain the role of water and salt in the development of ascites
Increased sodium reabsoprtion is a result on increased ADH and less ADH inactivation in liver,.
What contributes to alt retention in ascites?
Decreased renal blood flow and filtration rate
What are the MAIN 3 consequences of PH?
- Varices
- Ascites
- Encephalopathy
What is the treatment of ascites ?
- Salt restriction, diuretics
- Paracentesis
- Peritoneovenous shunting (portal vein shunt to hepatic vein)
What is encephalopathy?
Impaired mental status and abnormal neuromuscular function that results from liver failure, primary consequence of PH
`Explain the pathophysiology of encephalopathy
Likely due to the inability of the liver to detoxify products an transferred to portosystemic shunt, reaches general circulation and is toxic to the brain.
What is a dietary byproduct of metabolism that is toxic to the brain when the liver is unable to metabolize it?
Ammonia - may trigger astrocyte swelling and responsible for changes in brain function
What is ammonia a by-product of?
Proteins, amino acids and nucleic acids
Where else can ammonia be produced?
Gut flora
Where does ammonia detoxification occur in liver cirrhosis?
Mostly in muscle, but liver cirrhosis patients may experience muscle wasting which could decrease capacity to detoxify ammonia (Glutamate –> glutamine)
What is the neurotoxin hypothesis of HE?
Neurotoxins (Serotonin, GABA) produced by gut microflora will not be metabolized by liver, leading to HE
What is hyperammonemia thought to stimulate?
Glucagon, increase gluconeogenesis from from amino acids (muscle wasting, protein breakdown)
Why is lactulose (laxative) prescribed in HE?
Stimulates the passage of ammonia from body tissue into the gut lumen and inhibits intestinal ammonia production.
(T/F) As ammonia is a byproduct of protein metabolism, protein intake should be limited in HE
False, limiting protein may increase catabolism - recall that muscle plays a role in detoxifying ammonia
What should be treated aggressively with nutrition in cirrhosis?
Sarcopenia
Why treat sarcopenia?
Increases overall mortalilty
What may be suggested to increase muscle mass?
Nutritional supplementation at night
According to ESPEN guidelines, what has CHANGED in recommendations regarding fasting and surgery?
Fasting NO longer applies, as patients were seen to be more catabolic after surgery.
According to ESPEN guidelines, what are the NEW
recommendations regarding fasting and surgery?
Pre-optive fasting is unnecessary in most patients, and interruption of nutritional intake is unnecessary post-surgery.
What is the significance of pre-operative CHO loading ( glucose drink given 2hr
before surgery)
Avoids spiking glucose and insulin during surgery, as high hyperglycaemia during surgery and recovery is detrimental.
What is a consequence of using anesthesia?
- Takes time for patients to regain consciousness, longer time to resume normal feeding.
- hyperglycaemia
Nutritionally, what is a consequence of surgery under anaesthesia?
Elicits a high stress response (increased cortisol) which increases blood glucose –> hyperglycaemia
What is the two clinical tools most commonly used in prognosis of patients with cirrhosis?
Child-Turcotte-Pugh
MELD (Model for End-Stafe Liver Disease)
What criteria does the Child-Turcotte-Pugh system evaluate? (PEA-BA)
- Prothrombin time
- Ecephalopathy
- Ascites
- Bilirubin
- Albumin
Least severe liver disease according to child?
Class A (5-6 points)
Moderately severe liver disease according to child?
Class B (7-9)
Most severe liver disease according to child?
Class C (10-15)
% 1-2 year survival Class A?
100%, 85%
% 1-2 year survival Class B?
80%, 60%
% 1-2 survival Class C?
45%, 35%
What does MELD measure?
Score is based off three blood tests: (1) international normalized ratio, which tests tendency of blood, (2) bilirubin (amount of bile pigment, and (3) creatinine, which assessed kidney function
What MELD score indicates need for liver transplant?
> /= 15
Define cirrhosis
Represents the en of the pathophysiology spectrum for a wide variety of liver diseases, where healthy tissue is replaced with scar tissue.
What is NAFLD?
Non-alcoholic fatty liver disease, and refers to a wide spectrum of live disease, including NASH
What is NASH?
Non-alcoholic steatohepatitis - steatosis + necrotic –> inflammation
Who is likely to be diagnosed with NASH?
Middle-aged, overweight and obese people
What is the histology of NAFLD?
Fatty overload > 5% of liver weight
What are some risk factors of NASH?
- Established and emerging risk factors
- Absence of significant alcohol intake
- Absence of another cause of liver disease
What are the established risk factors for NASH?
- Obesity
- T2DM
- Dyslipidemia
- MetS
- HTN
What are the emerging risk factors of NASH?
- PCOS
- Hypothyroidism, hypopituitarism
- Sleep apnea
- Hypogonadism
- Pancreato-duodenal resection
What is considered significant alcohol intake?
> 21 glasses/week for men
> 14 glasses/week for women
What is the most frequent liver disease in western countries?
NAFLD
Prevalence of NASH vs NAFLD?
3-5%
25%
Presence of NAFLD in diabetics ? Obese?
70%
90%
What is the projection of NAFLD?
NAFLD –> NASH –> Cirrhosis –> hepatocellular carcinoma
Clinical sign of NAFLD
Fat accumulation in liver
Clinical sign of NASH
Fat + inflammation and scarring
Clinical sign of cirrhosis
Scar tissue replaces liver cells
Clinical sign of hepatocellular carcinoma
Presence of cancerous cells
NAFLD is a _____ based on a chronic ____
multi-system diseases
inflammatory milieu
What does NAFLD decrease?
Overall survival
What is the major
cause of death in liver disease patients?
Malignancy and CVD
What is NAFLD also a risk factor for?
T2DM (insulin resistance)
CKD
The relationship between NASH/NAFLD and diabetes is ___
bidirectional
What is the multi-factorial progression of liver disease?
Relationship between environment and genes, where poor lifestyle habits, hepatotoxic drugs and gut dysbiosis may influence progression of cirrhosis
What are the main pathogenic drivers in NASH?
Insulin resistance and obesity
How does insulin resistance and obesity impact NASH?
Drivers of MetS, and will activate cytokine, increased oxidized LDL and TLR expression, increasing inflammation in the liver
What is the multi-hit hypothesis of NASH?
That the interactions between insulin resistance, MetS and inflammation will be the drivers for accelerating the progression of liver diseases (Normal –> Steatosis –> NASH –> Fibrosis )
Is NASH hereditary? What is the important gene?
Low to moderately
Clear ethnic differences (Hispanic > Whites > Black)
PNPLA3
What does PNPLA3 encode?
Adiponutrin
