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Human Diseases > W5 22 hepatopancreaticobiliary pathology > Flashcards

W5 22 hepatopancreaticobiliary pathology Flashcards

1
Q

What is a cholestectomy?

A

Removal of gallbladder for gallbladder disease

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2
Q

What are the types of gallstones?

A

Cholesterol stones
Pigment stones

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3
Q

What causes cholesterol stones and what do they look like? (Pg235)

A

Due to excess cholesterol or deficiency of phospholipids and/or bile acids (substances that keep cholesterol soluble)
Usually yellow colour and can be crumbly

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4
Q

What causes pigment stones and what do they look like? (Pg235)

A

Due to the presence of unconjugated bilirubin in the gallbladder eg following haemolysis. Stones tend to be darkly pigmented and solid.

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5
Q

Describe the pathogenesis of gallstone disease

A
  1. Supersaturation - supersaturation of the liquid bile by cholesterol. In levels of high cholesterol or low phospholipids (keeps the cholesterol in liquid form), the cholesterol becomes concentrated and forms an intermediate crystal structure.
  2. Crystallisation - allows the cholesterol molecules to form a true crystal which is the nucleus (centre of the stone)
  3. Stone growth - after nucleation, stones can continue growing with deposition of more cholesterol on the outer layers
    (Similar process with unconjugated bilirubin for the formation of pigment stones)
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6
Q

What exacerbating factors are there for gallstone disease?

A

Gallbladder hypomotility
Mucus hypersecretion
Bacterial infection
Oestrogen

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7
Q

How does gallbladder hypomotility make gallstone disease worse?

A

If the gallbladder is less able to contract and expel the bile, there is increased likelihood of cholesterol saturating the bile that is there.

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8
Q

How can mucus hypersecretion make gallstone disease worse?

A

Can cause imbalances in composition of the bile and lead to concentration of the cholesterol

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9
Q

How can oestrogen make gallstone disease worse?

A

It causes increased cholesterol secretion
(thus gallstones are more commonly seen in overweight women)

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10
Q

What is cholecystitis?

A

Inflammation of the gallbladder

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11
Q

What is acute cholecystitis?

A

Caused by obstruction of gallbladder neck by stones. Accumulated bile products in the gallbladder become toxic to the gallbladder epithelium. The damaged epithelium induces acute inflammation via inflammatory mediators (especially PG’s)

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12
Q

What is chronic cholecystitis?

A

May be a consequence of previous episodes of acute cholecystitis, or from chronic mucosal irritation from a supersaturated bile (with cholesterol). Characterised by a chronic inflammatory cell infiltrate and fibrosis.

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13
Q

Differences between the cells and features of acute and chronic cholecystitis (pg236/7 histological images)

A

Acute - numerous neutrophils and extensive haemorrhage, blood vessels damaged from inflammation and blood leaks out. epithelium damaged.
Chronic - epithelium better preserved. Infiltrates of predominantly plasma cells. Fibrosis and smooth muscle proliferation.

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14
Q

What are some other complications of gallstone disease?

A

Empyema
Perforation
Fistula formation with adjacent structures
Obstructive jaundice - if stone passes from gallbladder into common bile duct
Gallstone ileus
Pancreatitis

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15
Q

What is empyema?

A

Accumulation of pus within gallbladder lumen.
Occurs in examples of severe acute cholecystitis.

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16
Q

What is gallstone ileus?

A

Erosion of gallstone into adjacent small bowel causing obstruction

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17
Q

What is pancreatitis?

A

Inflammation of the pancreas. There is acute and chronic.

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18
Q

Why does pancreatitis have significant clinical consequences?

A

The pancreas contains numerous digestive enzymes with the potential to cause catastrophic tissue destruction

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19
Q

What aetiological factors causes acute pancreatitis?

A

Gallstones
Alcohol
(Other lesson common)

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20
Q

What is acute pancreatitis?

A

Auto-digestion of the pancreas by inappropriately activated pancreatic enzymes, massively exacerbating the tissue damage.

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21
Q

Describe the pathogenesis of acute pancreatitis caused by pancreatic duct obstruction.

A

Eg a stone lodged in the ampulla of Vater obstructs the flow of pancreatic juices in the main pancreatic duct. This increases introduction pressure, leading to accumulation/leakage of enzyme rich fluids into interstitial space. Enzymes like lipase cause tissue injury and elicits acute inflammation (through release of DAMPs). This causes oedema which compromises local blood flow by compressing the structures, causing ischaemias and further injury.

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22
Q

What are the causes of acute pancreatitis? (PG238 FLOW CHART)

A

Duct obstruction
Direct acinar cell injury
Defective intracellular transport

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23
Q

What is the end result of all of the processes causing acute pancreatitis?

A

Acinar cell injury, resulting in activated pancreatic enzymes, leading to massive interstitial inflammation and oedema, proteolysis, fat necrosis and haemorrhage, due to the damaged caused to the tissues by the enzymes

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24
Q

What things can cause direct acinar damage?

A

Alcohol, drugs, trauma, ischaemia, viruses

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25
Q

What are the consequences of acute pancreatitis?

A

Induces a massive inflammatory response:
- increased micro vascular permeability leads to profound hypovolaemia, patients become very sick very quickly
- disseminated intravascular coagulation (DIC)
- acute respiratory distress syndrome (ARDS)
Endotoxaemia and infection following breakdown of barriers between gut and bloodstream
Acute renal failure

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26
Q

What healing occurs following acute pancreatitis?

A

Regeneration of damaged tissue through proliferation of stable acinar cells (normally in G0 but stimulated to proliferate)
Granulation tissue formation and remodelling of extra-cellular matrix
Pseudocyst formation

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27
Q

Describe a pseudocyst formed following healing of acute pancreatitis

A

Necrotic pancreatic tissue walled off by fibrosis
Cyst contents rich in enzymes eg amylase (released in the acute inflammatory response)
Can sometimes cause compression and become symptomatic for patients

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28
Q

What are some causes of chronic pancreatitis?

A

Long term alcohol abuse
Long-standing pancreatic duct obstruction
Autoimmune pancreatitis

29
Q

The pathogenesis of alcoholic chronic pancreatitis is not well understood, but what do the mechanisms include?

A

Duct obstruction by concretions - alcohol increases protein content of Pra created secretions which can form plugs in the ducts, predisposing to chronic pancreatic injury
Direct toxic effect of alcohol on acinar cells - free radical formation, IL8 production
TGF-b secretion, leading to fibrosis

30
Q

How can we treat autoimmune pancreatitis?

A

With steroids (since it is immune-mediated destruction of the pancreas)

31
Q

What happens in type 1 autoimmune pancreatitis?

A

Numerous IgG4+ plasma cells, phlebitis (inflammation of veins), fibrosis
Associated with systemic IgG4+ disease
Associated with TH2 activation (associated with IL4,5,13) leading to IgE production and activation of mast cells and recruitment of eosinophils

32
Q

What is IgG4 disease?

A

A multisystem disorder, typically affecting pancreas but also retroperitoneal fibrosis, thyroid disease and liver disease etc, named after IgG4+ plasma cells.

33
Q

What happens in type 2 autoimmune pancreatitis?

A

Duct centric lymphocyte inflammation
(Not associated with IgG4 disease)

34
Q

What types of reaction are type 1 and 2 autoimmune pancreatitis?

A

Hypersensitivity autoimmune reactions

35
Q

What is hepatitis?

A

Inflammation of the liver parenchyma
Acute or chronic

36
Q

What is a biochemical feature of hepatitis?

A

Raised liver transaminases (ALT, AST) as a result of hepatocyte injury

37
Q

How long does inflammation of the liver have to last to be classed as chronic hepatitis?

A

Inflammation of the liver continuing without improvement for at least 6 months

38
Q

What are some aetiological factors of acute hepatitis?

A

Viral hepatitis
Autoimmune hepatitis
Drug-induced liver injury
Often undetermined (seronegative)

39
Q

What viruses can cause acute hepatitis?

A

Hepatotropic viruses - specifically targeting the liver (HBV, HCV, HAV …)
Non-hepatotropic viruses (eg adenovirus)
Hepatitis B viral infection
Hepatitis C viral infection

40
Q

What are the aetiological causes of chronic hepatitis?

A

Viral hepatitis - hep B and C viral infections
Autoimmune hepatitis
Drugs

41
Q

Describe the pathogenesis of viral hepatitis

A

Damage mainly from host inflammatory response rather than virus
Hepatotropic viruses infect hepatocytes within the liver
Antigens produced from these viruses are presented in APCs like dendritic cells
These activate T cell responses - cytotoxic CD8+ T cell responses which can directly induce cell death, and stimulation of T helper CD4+ pathways, including activation of TH1 and TH2 subsets.
Key inflammatory cytokines including TNFa and IFNy drive hepatocyte damage

42
Q

What is the pathogenesis of autoimmune hepatitis?

A

Self-antigens are presented in APCs and these abnormally activate CD8 and CD4+ T cells
These migrate to the liver and cause injury both directly and through cytokines and antibodies to the liver parenchyma cells, resulting in their death
This cell death further elicits inflammatory responses

43
Q

What type of reaction is autoimmune hepatitis?

A

T-cell mediated (type IV) hypersensitivity reaction

44
Q

What part of the liver does acute and chronic hepatitis inflammation affect?

A

Acute hepatitis is normally associated with lobular inflammation
Chronic hepatitis is normally associated with portal inflammation

45
Q

What cells are acute and chronic hepatitis mediated by?

A

Both mediated by lymphocytes

46
Q

What is nodularity a sign of in a liver?

A

A reflection of hepatocyte necrosis that’s caused the liver to shrink down

47
Q

What is a submissive hepatic necrosis?

A

Extensive necrosis tissue leaving portal tracts but no useable liver behind (loss of parenchyma)

48
Q

What happens in hepatocyte injury?

A

Swelling, bilirubinostasis, damage can become apoptotic/necrosis - and can be massive/submissive if severe

49
Q

What happens to acute hepatitis if the cause is short lived and stimulus is removed?

A

It has healing capacity - healing by regeneration without fibrosis. The PARENCHYMA can normally fully regenerate.

50
Q

What does chronic hepatitis mainly involved?

A

Characterised by interface hepatitis, mainly involves the portal tracts

51
Q

How does chronic hepatitis heal and what does this lead to?

A

May heal by fibrosis, ultimately leading to cirrhosis

52
Q

What is cirrhosis?

A

Chronic liver disease characterised by:
- loss of normal lobular architecture
- modular regeneration of hepatocytes
- fibrosis
(Affecting the whole liver)

53
Q

Histologically, how is the liver different in cirrhosis?

A

Characterised by nodules of hepatocytes, surrounded by fibrous tissue
Normal liver should have extensive sheets of hepatocytes with a lobular arrangement of portal tracts between - completely lost in cirrhosis

54
Q

What are some aetiological causes of liver cirrhosis?

A

Any cause of chronic liver disease
Immune mediated - autoimmune hepatitis, primary biliary cholangitis, primary sclerosing cholangitis, transplant rejection
Drug induced - alcohol, therapeutic agent
Infectious - non-alcoholic fatty liver disease, inherited/acquired metabolic disease
Vascular disorders - outflow obstruction

55
Q

What is the pathogenesis of cirrhosis?

A

Cirrhosis occurs when an insult is persistent over many months or years. Changes explained by fibrosis and vascular remodelling.

56
Q

How does fibrosis occur in liver cirrhosis?

A

Damage to hepatocytes stimulates Kupffer cells (resident macrophages) to produce chemical mediators that activate perisinusoidal stellate cells
This results in perisinusoidal fibrosis with inflammation around hepatocytes and formation of portal-central, and central-central fibrous septa (on a larger scale)
Damage to portal structures activates portal fibroblasts and results in fibrous expansion of portal tracts and portal-portal bridging fibrosis

57
Q

What chemical mediators do Kupffer cells produce to activate perisinusoidal stellate cells?

A

TNF and PDGF (platelet derived GF) - leads to proliferation of stellate cells/fibroblasts
TGF-b - leads to collagen deposition and fibrogenesis

58
Q

What is the function of the sinusoids epithelium in a normal healthy liver?

A

Usually has a specialised function to allow transfer of nutrients from circulation into hepatocytes and vice versa

59
Q

What happens to the sinusoidal endothelium in vascular remodelling in cirrhosis?

A

‘Capilarisation’ of sinusoidal endothelium due to loss of fenestrations (in cytoplasm) and perisinusoidal fibrosis, preventing the transfer of nutrients and molecules across that space.

60
Q

What else happens during vascular remodelling in liver cirrhosis?

A

Increased resistance in PTs and hepatic venues due to fibrosis
Formation of septal shunts within portal-central fibrous septa
Intrahepatic portal and hepatic vein thrombi

61
Q

What does the formation of septal shunts in vascular remodelling in cirrhosis do?

A

Blood becomes shunted from portal-central regions via septa that are form, so does not perfused the liver parenchyma as well and prevents multiple functions of the liver from occurring.

62
Q

In a normal liver, blood flows through sinusoidal channels where it can easily interact with the hepatocytes which line the sinusoids. What happens to the blood in cirrhosis?

A

The portal vein mixes with arterialised blood in arterial-venous shunts, so we get a pooling of the blood. When it enters the sinusoidal channel, it is separated from the hepatocytes by the perisinusoidal fibrosis.
The endothelial cells have lost their fenestrations so also form a barrier to allow nutrients to cross the space. The result is the blood becomes shunted in the channels, leaving the liver without hepatocytes able to perform their metabolic functions.

63
Q

What can liver cirrhosis lead to?

A

Hepatocellulwr failure
Portal hypertension
Hepatocellular carcinoma

64
Q

Clinical features of hepatocellular failure

A

Jaundice
Hypoalbuminaemia (since hepatocytes are main producer of albumin)
Bleeding tendency (reduced synthesis of clotting factors)
Neurological disturbances (hepatic encephalopathy from accumulation of substances)
Impaired oestrogen metabolism
Spontaneous infection

65
Q

How does portal hypertension occur from liver cirrhosis?

A

From increased resistances to flow through the liver, resulting in back pressure and portal hypertension.

66
Q

What are th effects of portal hypertension?

A

Acites - fluid leaks out into peritoneal space
Splenomegaly - increased pressure causes pooling of blood within the spleen
Porto-systemic shunts - high pressure portal system drains into the systemic system.

67
Q

What is hepatocellular carcinoma (HCC)?

A

Malignant neoplasm with hepatocellular differentiation, usually occurring on a background of cirrhosis. Most common cause of liver cancer.

68
Q

What are the driver mutations of HCC? (should be familiar with these)

A

Telomerase reverse transcriptase (TERT) promoter mutation
TP53 mutation
CTNNB1 mutation

69
Q

What could be a pathogenesis or HCC?

A

Integration of virus into host genome causing genomic instability
Free radicals generated in fatty liver disease causing genomic damage
(complex pathogenesis depending on aetiology of liver disease)

Human Diseases (75 decks)

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