day 1 - hepatitis, cirrhosis and liver failure

Question 1

liver macroanatomy

Answer 1

The liver is the largest internal organ in the body, consisting of right and left lobes, and smaller caudate and quadrate lobes. The normal adult liver weighs 1400 to 1600 g. It has a dual blood supply, consisting of the portal vein and the hepatic artery, and is drained by the hepatic vein. From a functional point of view, the liver is divided into sectors and segments, corresponding to the vascular supply and biliary drainage.

Question 2

what is the port hepatis

Answer 2

The porta hepatis is the region where the hepatic artery and portal vein enter the liver and the common bile duct exits.

Question 3

liver microanatomy

Answer 3

Hepatocytes are polygonal cells arranged in trabeculae, or liver cell plates, that are 1 – 2 cells thick. They are stable cells, and are able to replicate and regenerate in response to a stimulus, such as resection at surgery. The vascular spaces between the hepatocyte plates are called sinusoids and are lined by sinusoidal endothelial cells, which have fenestrae (windows) facilitating fluid and molecular exchange between the vascular space and the space of Disse (the space between the sinusoids and the hepatocytes, which contains extra-cellular matrix). The blood feeding into the sinusoids comes from both the hepatic artery and the portal vein branches, and the drainage is via the terminal hepatic venules, tributaries of the hepatic vein.

Question 4

bile drainage path from liver

Answer 4

Bile drainage begins with the bile canaliculi - formed by the contact surfaces of hepatocytes - which drain into thin walled canals (canals of Hering and bile ductules), and then into portal bile ducts. These drain into larger septal ducts, segmental ducts, and main right and left hepatic ducts.

Question 5

what are the ‘portal tracts’

Answer 5

Portal tracts contain branches of the hepatic artery, portal vein, and bile duct (the portal triad), set in fibro-elastic connective tissue. The meeting of the portal tract with the limiting plate of hepatocytes is called the interface, and is one of the sites of inflammatory activity in hepatitis. Nerves are also present in the portal tract, and are part of the autonomic nervous system.

Question 6

what are Kupffer cells

Answer 6

macrophages attached to the endoluminal surface of the sinusoidal endothelium, that have a main function of phagocytosis

Question 7

what do hepatic stellate cells do

Answer 7

hepatic stellate cells (also known as Ito cells, which lie in the space of Disse). In their quiescent state, Ito cells are involved with the storage of vitamin A, but when activated in response to hepatic injury they can transform into myofibroblast-like cells, and begin to lay down collagen

Question 8

what is a liver lobule (Kiernan)

Answer 8

The lobule is an hexagonal area of liver parenchyma centred on a tributary of the hepatic vein (the central vein), and is surrounded by portal tracts.

Question 9

what is the liver acinus

Answer 9

the liver acinus, proposed by Rappaport. An acinus is an area of liver parenchyma centred on two portal tracts, which extends to the terminal hepatic venule (the central vein of the hepatic lobule). It can be subdivided into zones1-3, from portal tract to hepatic venule. Zone 3, around the terminal hepatic venule, is the least perfused area and is prone to various types of damage, particularly viral, toxic and ischaemic injury.

Question 10

the most important clinical manifestations of acute liver damage

Answer 10

Probably the most important clinical manifestations of acute liver damage are tender hepatomegaly, jaundice, and coagulopathy, as well as the less specific malaise and abnormal LFTs. Severe acute liver damage may lead to coma and death.

Question 11

biliary atresia.

Answer 11

Biliary atresia is a disease of the bile ducts that affects only infants. Bile is a digestive liquid that is made in the liver. It travels through the bile ducts to the small intestine, where it helps digest fats.

In biliary atresia, the bile ducts become inflamed and blocked soon after birth. This causes bile to remain in the liver, where it starts to destroy liver cells rapidly and cause cirrhosis, or scarring of the liver.

Question 12

primary biliary cirrhosis (PSC)

Answer 12

• Presumed auto-immune aetiology.
• F:M ratio > 6:1.
• Anti-mitochondrial Ab (M2 fraction) highly specific.
• Microscopic features: destruction of intrahepatic bile ducts, lymphocytic infiltrate, granuloma formation, ductular proliferation, and cholestasis.
• Progressive fibrosis.

Question 13

primary sclerosing cholangitis (PBC).

Answer 13

• ERCP and radiological diagnosis.
• Beading on cholangiography.
• Scarring and destruction of extrahepatic +/- intrahepatic bile ducts.
• Fibrosis of bile ducts, lymphocytic infiltrate, obliteration of lumen.
• Associated with UC.
• Increased risk of cholangiocarcinoma.

Question 14

first stage of liver pathology

Answer 14

fatty liver - This is a common but non-specific reactive change with many causes (alcohol, diabetes mellitus, obesity, drugs/toxins, starvation, etc) whereby the hepatocytes accumulate lipid droplets in the cytoplasm. The severity varies with the severity of the insult, and it is usually reversible on removal of the stimulus.

Macroscopic changes
The liver is enlarged, soft, yellow and greasy.

Question 15

Reye’s syndrome

Answer 15

Reye syndrome or Reye’s syndrome is a potentially fatal syndrome that has numerous detrimental effects to many organs, especially the brain and liver, as well as causing a lower than usual level of blood sugar (hypoglycemia).[1] The classic features are a rash, vomiting, and liver damage. The exact cause is unknown and, while it has been associated with aspirin consumption by children with viral illness, it also occurs in the absence of aspirin use.

The disease causes fatty liver with minimal inflammation and cerebral edema (swelling of the brain). The liver may become slightly enlarged and firm, and there is a change in the appearance of the kidneys. Jaundice is not usually present.[3]

Reye syndrome largely affects children. Cases in adults are extremely rare and are more responsive to treatment. Early diagnosis is vital; although most children recover with supportive therapy, it may lead to severe brain injury and death.

Question 16

Steatohepatitis

Answer 16

A second form of fatty change - microvesicular steatosis - is rare but important, as it
usually indicates a severe metabolic derangement (e.g. acute fatty liver of pregnancy, Reye’s syndrome, mushroom poisoning).

Question 17

causes of acute hepatitis

Answer 17

This group of disorders is acute in onset, usually over a couple of weeks. A characteristic pattern of damage is seen pathologically. Many things have been found to be responsible for inflammation of the liver.
Aetiology

• Hepatotropic viruses - A to E, with more being described (see Robbins, 6th edition, Table 19-3, p. 856). HCV often has a subclinical or asymptomatic acute phase.
• Drugs/toxins – these can have a predictable, dose dependent toxicity (e.g. paracetamol), or an idiosyncratic, patient-related effect (e.g. antibiotics, such as flucloxacillin). Drugs and toxins can also be responsible for conditions other than acute hepatitis, e.g. cholestasis.
• Alcohol - distinctive microscopic appearances are seen (see above).
• Other infections – systemic viral infections can involve the liver, including infectious
mononucleosis (Epstein Barr virus), cytomegalovirus, rubella, adenovirus, herpes,
enterovirus in the newborn or immunosuppressed, and yellow fever.
• Autoimmune liver disease may also present acutely, although it is - strictly speaking -
considered a chronic liver disease.

Question 18

what is chronic hepatitis

Answer 18

The strict definition of chronic hepatitis is diffuse inflammation of the liver lasting longer than 6 months, although clinico-pathological evidence of disease may be present within this timeframe, allowing diagnosis. The symptoms, signs, and LFTs may vary both between patients and with time.
Diagnosis depends on a combination of clinical, chemical, pathological and immunological findings.

Question 19

aetiology of chronic hepatitis

Answer 19

• Hepatotropic viruses: HBV +/- HDV, HCV (HAV and HEV never cause chronic hepatitis). Treatment is with antiviral agents and interferon.
• Auto-immune: predominantly affects females (70%), with high auto-antibody titres (anti-smooth muscle, anti-nuclear, and/or anti-mitochondrial antibodies). Dramatic response to treatment with immunosuppressive medication.
• Rarely caused by drugs or toxins, as liver toxicity is usually identified, and medication ceased or changed.
The progression of chronic hepatitis is related to its aetiology, and some host factors, particularly the integrity of the immune system. For example, HCV infection is much more rapidly progressive post-transplant, or in the setting of HIV co-infection.

Question 20

what is cirrhosis

Answer 20

A diffuse process characterised by fibrosis and a conversion of normal architecture into structurally abnormal nodules.

Regeneration of nodules may also be present, which gives the nodules a more rounded shape, but it is not necessary to see this to make the diagnosis of cirrhosis. The best classification of cirrhosis is by aetiology, e.g. alcoholic cirrhosis. This may be reflected in the morphology or size of the nodules, which gave rise to the description of macro- and micro-nodular cirrhosis, but this is an unreliable method for determining the aetiology, particularly in the setting of more than one aetiological factor. Traditionally, liver fibrosis and cirrhosis was thought to be a progressive and irreversible, but recent papers have suggested that this may not always be the case, and improved treatment regimes are being investigated.

Question 21

common causes of liver cirrhosis

Answer 21

• Chronic viral hepatitis.
• Alcoholic liver disease.
• Auto-immune liver disease.
• Metabolic liver diseases.
• Biliary diseases.
• Vascular (rare) – e.g. chronic Budd–Chiari syndrome.
• Not strictly a cause, but those of undetermined cause may be labelled ‘cryptogenic’ – current opinion is that some of these may be due to NASH.

Question 22

complications with liver cirrhosis

Answer 22

Cirrhosis can be described clinically as being compensated or decompensated, relating to the effect on the person’s wellbeing. The main complications are related to the following:

• Hepatocellular failure is most evident in decompensated cirrhosis, with jaundice,
hypoalbuminaemia, and coagulopathy. Lesser degrees of these may be seen in compensated cirrhosis.

• Portal hypertension (which may have causes other than cirrhosis, such as
schistosomiasis) – this leads to the development of porto-systemic anastomoses. Common sites for the formation of these anastomoses are in the oesophagus, around the spleen, around the umbilicus (caput medusae), and in the perianal veins. Varices often form at these sites of anastomosis, which are at risk of rupture and life- threatening haemorrhage.

• Ascites is formed, influenced by the combination of portal hypertension and hypoalbuminaemia.
• Porto-systemic shunting of blood is possible through these anastomoses, bypassing the liver and first pass metabolism of drugs and toxins.
• Encephalopathy ensues as toxins, particularly ammonia, reach the central nervous system.
• Systemic infections with enteric organisms are more common, particularly in relation to ascites and spontaneous bacterial peritonitis.
• Hepatocellular carcinoma is increased in all causes of cirrhosis, but there are some with a higher incidence, e.g. HCV, HBV, haemochromatosis.

Question 23

what is hepatocellular carcinoma

Answer 23

Hepatocellular carcinoma (HCC) is the most common primary malignant liver neoplasm, and has aetiological associations with HBV, HCV, aflatoxins, chemicals, and metabolic liver diseases. Epidemiologically, there is worldwide geographical variation in the pattern of presentation of HCC, largely related to the endemicity of HBV infection, and other factors such as aflatoxin exposure.

Question 24

primary malignancies of the liver

Answer 24

• Hepatocellular carcinoma (HCC)
  • Cholangiocarcinoma – associated with UC, PSC, liver flukes.
  • Angiosarcoma –rare and associated with exposure to vinyl chloride or arsenic.
  • Hepatoblastoma – a rare neoplasm of young childhood.
  • Lymphoma and sarcoma can also affect the liver.

Question 25

what happens in wilson’s disease

Answer 25

Wilson’s Disease
• Failure of copper excretion, with the accumulation being hepatotoxic.
• Autosomal recessive, with many mutations characterised.
• Usually presents in children and young adults.
• Can also affect the brain, particularly the basal ganglia, and Kaiser-Fleischer rings may
be seen on the cornea.

Question 26

what happens in Alpha-1-antitrypsin Deficiency

Answer 26

Alpha-1-antitrypsin Deficiency
• Autosomal dominant.
 • Variable age of presentation.
• Abnormal enzyme produced, which is not released from the endoplasmic reticulum of hepatocytes. This shows as pink cytoplasmic globules on D-PAS stain, and can be
demonstrated using immunohistochemistry.
• May present with panacinar emphysema.

Question 27

what happens in Haemochromatosis

Answer 27

• Autosomal recessive inheritance (HFE gene on chromosome 6).
• Abnormal excessive iron absorption.
• Presents in middle age, with affected women protected by menstruation and
pregnancy.
• Other organs affected: pancreas, skin, joints, pituitary, heart, gonads.
• Sometimes known as “bronze diabetes”.

Question 28

Alcohol has distinguishable pathological features that separate it from these other causes of hepatitis. such as?

Answer 28

Repeated insults of toxic levels of alcohol lead to progressive liver damage, which has the characteristic pathological features of steatohepatitis.

Microscopic changes
The inflammatory infiltrate associated with steatohepatitis characteristically contains neutrophil polymorphs. Hepatocytes show ballooning, and intermediate cytoplasmic filaments aggregate, forming Mallory bodies. There is usually some fatty change, and a degree of fibrosis indicating chronicity, in particular pericellular fibrosis in zones 3.

Question 29

what can cause steatohepatitis other than alcohol

Answer 29

NASH (Non-Alcoholic Steato-Hepatitis) which is usually attributed to obesity or diabetes

Question 30

pathological changes in acute hepatitis

Answer 30

Macroscopic changes
Although the whole liver is not normally seen in acute hepatitis, from the few cases that have had laparoscopy we know the liver is red, swollen and oedematous. In cases of acute liver failure (ALF), which have either been fatal or have proceeded to transplantation, the liver is shrunken and soft, with a wrinkled capsule and dark red haemorrhagic areas.

Microscopic changes
There is an inflammatory cell infiltrate of portal tracts, liver parenchyma, and the interface, with the parenchymal damage being most marked. This is composed predominantly of lymphocytes, with macrophages and some plasma cells. Evidence of hepatocyte damage is seen through cellular swelling, acidophil or Councilman bodies (thought to be apoptotic hepatocytes), and areas of necrosis, particularly in zones 3. These changes can vary in pattern with the severity and nature of the insult. In more severe cases, the necrosis becomes confluent, and areas of necrosis join (so-called bridging necrosis). In fulminant hepatitis, massive hepatic necrosis is the dominant feature.

Question 31

pathological changes in chronic hepatitis

Answer 31

Microscopic changes
There is a chronic inflammatory cell infiltrate, composed mainly of lymphocytes, sometimes forming follicles (especially in HCV). Plasma cells may predominate in autoimmune chronic hepatitis. This infiltrate mainly affects the portal tracts and interface, although focal parenchymal activity is usually seen. Assessment of these areas of inflammation gives a GRADE.

There is an accompanying portal tract fibrosis and architectural disruption, progressing eventually to cirrhosis if the disease process continues, the assessment of which is referred to as the STAGE of disease.
Similar changes can be seen with A1AT deficiency, Wilson’s disease, PBC, & PSC, although each of these diseases has pathological features that may indicate the specific diagnosis.

Question 32

Budd–Chiari syndrome.

Answer 32

Budd–Chiari syndrome is a condition caused by occlusion of the hepatic veins that drain the liver. It presents with the classical triad of abdominal pain, ascites and hepatomegaly. Examples of occlusion include thrombosis of hepatic veins. It occurs in 1 out of a million individuals

The cause for the disease cannot be found in about half of the patients.

Primary Budd–Chiari syndrome (75%): thrombosis of the hepatic vein

Secondary Budd–Chiari syndrome (25%): compression of the hepatic vein by an outside structure (e.g. a tumor)

Hepatic vein thrombosis is associated with the following in decreasing order of frequency:
Polycythemia vera
Pregnancy
Post partum state
Use of oral contraceptives
Paroxysmal nocturnal hemoglobinuria
Hepatocellular carcinoma
Lupus anticoagulants
Budd–Chiari syndrome is also seen in Infection such as tuberculosis, congenital venous webs and occasionally in inferior vena caval stenosis.

Often, the patient is known to have a tendency towards thrombosis, although Budd–Chiari syndrome can also be the first symptom of such a tendency. Examples of genetic tendencies include Protein C deficiency, Protein S deficiency, the Factor V Leiden mutation, Hereditary anti-thrombin deficiency and Prothrombin Mutation G20210A.[2] An important non-genetic risk factor is the use of estrogen-containing (combined) forms of hormonal contraception. Other risk factors include the antiphospholipid syndrome, aspergillosis, Behçet’s disease, dacarbazine, pregnancy, and trauma.

Question 33

Three stages of progression of alcoholic liver disease

Answer 33

Three stages of progression

1. Alcoholic fatty liver.
2. Alcoholic hepatitis.
3. Alcoholic cirrhosis.

• Spectrum: Alcoholic Steatosis - Alcoholic steatohepatitis -
Cirrhosis
• Not all heavy drinkers develop liver disease; genetic predisposition thought likely
• Damage due to toxic metabolites of alcohol

Question 34

Autoimmune hepatitis features

Answer 34

• Usually females
• High autoantibody titres
• (anti-smooth muscle, anti-nuclear, and/or anti-liver- kidney microsomal antibodies)
• Hepatitic derangement of liver enzymes • Chronic inflammation
• Inflammatory cell = plasma cell
• Marked interface hepatitis
• +/- fibrosis

Question 35

common causes of fatty liver

Answer 35

• Toxins - Alcohol, drugs
• Obesity
• Fatty liver of pregnancy
• Metabolic stress - Diabetes mellitus/ hypoxia/kwashiorkor

Question 36

classical features of steatohepatitis

Answer 36

• Micro - Steatosis
Hepatocellular ballooning
Mallory hyaline Neutrophilic infiltrate Pericellular fibrosis
• Prior to fibrosis process REVERSIBLE

Question 37

overview of liver neoplasms

Answer 37

• Reactive – Focal nodular hyperplasia

• Benign:
– Adenoma
– Haemangioma – Hamartoma

• Malignant:
Primary – uncommon
Metastatic – common

Question 38

Cirrhosis Clinical Features