2 liver system and diseases

What is the first phosphorylation step in the activation of antiviral nucleosides?

• Catalyzed by nucleoside kinase

• This is the rate-limiting step

What enzyme performs the second phosphorylation of antiviral nucleosides?

• Nucleoside monophosphate kinase

• Converts nucleoside monophosphate to diphosphate

What enzyme is responsible for the third phosphorylation step of antiviral nucleosides?

• Nucleoside diphosphate kinase

• Converts diphosphate to triphosphate

What do nucleoside triphosphates compete with in viral replication?

• Compete with deoxynucleotide triphosphates

• Compete for binding to viral reverse transcriptase

How do nucleoside analogues cause viral DNA chain termination?

• They are incorporated into viral DNA

• Lack proper 3’-OH group for elongation

• Result in premature chain termination

How do antiviral nucleosides affect RNA and protein synthesis?

• Reduce synthesis of viral RNA

• Decrease viral protein production

Which interferon is used for the initial treatment of chronic hepatitis in adults?

• Interferon alpha-2a

• Used in chronic hepatitis cases

How does interferon alpha-2a mimic natural immune responses?

• Mimics glycoprotein cytokines produced by virus-infected cells

• Binds to cell surface receptors

• Inhibits viral replication

• Promotes viral clearance from hepatocytes

What is the typical administration schedule for interferon alpha-2a?

• Subcutaneous (s.c.) injection

• 3 times per week

• Treatment duration: 4–6 months

How is interferon alpha-2a metabolized, and what is its half-life?

• Metabolised in the kidneys

• Short half-life: 3–4 hours

What is PEG-interferon and why is it used?

• PEG = pegylated interferon

• Has an extended half-life

• Allows for less frequent dosing

What are the common side effects of interferon therapy?

• Headache

• Myalgia (muscle pain)

• Tremors

• Fever (typically 4–6 hours post-administration)

What delayed adverse effect is associated with interferon treatment?

• Bone marrow suppression

• Occurs after prolonged treatment

What is the underlying cause of autoimmune hepatitis?

• Autoantibodies target hepatocytes

Who is most commonly affected by autoimmune hepatitis?

• Young to middle-aged individuals

• Predominantly affects women

What are the common clinical features of autoimmune hepatitis?

• Jaundice

• Right upper quadrant (RUQ) abdominal pain

• May be associated with other autoimmune diseases

What autoantibodies are associated with Type 1 autoimmune hepatitis?

• Anti-smooth muscle antibodies (≈80%)

• Anti-nuclear antibodies (≈10%)

What autoantibodies are associated with Type 2 autoimmune hepatitis?

• Anti-liver/kidney microsomal type 1 antibodies

• More common in children

What investigation confirms the diagnosis of autoimmune hepatitis?

Liver biopsy

What are the treatment options for autoimmune hepatitis, including first-line and corticosteroid-resistant cases?

First-line treatment:

• Immunosuppressants:

  • Corticosteroids (e.g. prednisolone)

  • Azathioprine

Corticosteroid-resistant treatment:

• Cyclosporin

• Tacrolimus

• Mycophenolate mofetil

What is the definitive treatment for end-stage autoimmune hepatitis?

Liver transplant

What is the main cause of liver-related death in the UK?

• Alcoholic Liver Disease (ALD)

• Due to excessive alcohol intake leading to progressive liver damage

What are the three stages of alcoholic liver disease?

1. Fatty liver (steatosis)

2. Alcoholic hepatitis

3. Cirrhosis

What happens in the fatty liver stage of ALD?

• Alcohol metabolism → ↑ hepatic fatty acid synthesis

• Fat accumulation in hepatocytes → steatosis

• Reversible with abstinence

What characterizes alcoholic hepatitis?

• Excess fat → hepatocyte necrosis → inflammation

• Presence of Mallory bodies (damaged keratin)

• Giant mitochondria in liver cells

• Can be life-threatening

What is the final stage of alcoholic liver disease?

• Cirrhosis

• Irreversible scarring of liver tissue

• Leads to liver failure and portal hypertension

What are the clinical features of hepatic steatosis in alcoholic liver disease?

• Often asymptomatic

• Mild increase in serum bilirubin

• Mild increase in alkaline phosphatase (ALP)

What are the key pathological changes in alcoholic hepatitis?

• Hepatocyte swelling (fat and water accumulation)

• Cellular necrosis

• Neutrophilic inflammatory reaction

• Fibrosis begins to develop

What are the clinical manifestations of alcoholic hepatitis?

• Range from minimal to severe

• Nonspecific symptoms (e.g. malaise, fever, abdominal pain)

• Increased serum bilirubin

• Increased alkaline phosphatase (ALP)

What causes hepatocellular steatosis in alcoholic liver disease?

• Alcohol metabolism produces excess NADH via:

  • Alcohol dehydrogenase

  • Acetaldehyde dehydrogenase

• Excess NADH leads to:

  • ↑ Lipid biosynthesis

  • ↓ Lipoprotein assembly/secretion

  • ↑ Peripheral fat catabolism

What is the result of alcohol-induced changes in lipid metabolism in the liver?

• Lipid droplet accumulation in hepatocytes

• Leads to hepatic steatosis (fatty liver)

What are the two histological types of hepatic steatosis?

• Microvesicular steatosis

• Macrovesicular steatosis

What is the typical histological progression of hepatic steatosis?

• Starts centrilobular (around central veins)

• Progresses to panlobular (involving entire lobule)

What is the gross appearance of a liver with steatosis?

• Large, soft, yellow, and greasy liver

Is hepatic steatosis reversible?

Yes, completely reversible with alcohol abstention

What happens to liver tissue in cirrhosis?

• Functional hepatocytes are replaced by non-functional connective tissue

• Leads to impaired liver function

How does cirrhosis affect drug elimination?

• Reduced drug elimination in liver dysfunction

• Higher systemic drug levels for longer durations

• May increase drug efficacy or toxicity

how are low clearance drugs affected in cirrhosis?

• Little effect until end-stage cirrhosis or liver failure

• Clearance remains fairly stable in early disease

What is the impact of portal hypertension in cirrhosis on drug metabolism?

• Causes shunting of blood around the liver

• Leads to greater oral drug delivery to systemic circulation

• Increases systemic levels of high clearance drugs

Does cirrhosis increase susceptibility to idiosyncratic or autoimmune drug reactions?

No,

• Increased likelihood of Autoimmune-mediated drug reactions

What are the common liver-related and external causes of cirrhosis?

• Alcohol (most common cause)

• Drugs and xenobiotics

• Chronic viral hepatitis (e.g. Hep B, Hep C)

• Autoimmune hepatitis (chronic self-directed inflammation)

What biliary disorders can lead to cirrhosis?

• Chronic bile duct blockage

• Biliary atresia (congenital)

• Primary biliary cirrhosis (cause largely unknown)

• Primary sclerosing cholangitis (bile duct narrowing/blockage)

What inherited metabolic diseases can cause cirrhosis?

• Wilson’s disease ( abnormal copper accumulation)

• Haemochromatosis (abnormal2iron overload)

What are the early liver changes in alcohol-mediated hepatic cirrhosis?

Liver is yellow-tan, fatty, and enlarged

How does the liver appear in advanced alcohol-mediated cirrhosis?

Liver becomes brown, shrunken, and non-fatty

What histological changes occur in alcohol-mediated hepatic cirrhosis?

• Fibrous septa thicken and extend through sinusoids

• Formation of regenerative nodules trapping hepatocytes

How long does it usually take for cirrhosis symptoms to develop, and what is the early clinical presentation?

• Develops over many years

• Often largely asymptomatic until advanced stages ……

Is there a specific drug therapy for cirrhosis?

• No specific drug therapy for cirrhosis itself

• Treatment focuses on managing symptoms and complications

What is the most important lifestyle intervention in cirrhosis treatment?

Cessation of alcohol consumption

How is oedema managed in cirrhosis?

• Salt restriction

• Use of diuretics

How is chronic hepatic encephalopathy treated pharmacologically?

• Laxatives (e.g. lactulose) to reduce colonic neurotoxin (ammonia) production

• Oral antibacterials (e.g. metronidazole) to reduce bacterial ammonia production

What treatments are used for variceal haemorrhage in cirrhosis?

• Correct coagulation defects with platelet transfusion and plasma

• Endoscopic variceal injection with sclerosant (induces inflammation)

• Endoscopic tissue glue (cyanoacrylate adhesive) to block bleeding vessels

• Vasopressin analogues (e.g. terlipressin) cause splanchnic vasoconstriction to reduce portal pressure

What is the leading cause of acute liver failure?

Drug-Induced Liver Injury (DILI)

Does drug-induced liver injury occur in all patients taking the drug?

• No, only a small fraction of individuals are affected

How quickly can drug-induced liver injury develop?

Can be gradual, occurring weeks, months, or years after starting therapy

Why is drug-induced liver injury a major clinical concern?

• Often life-threatening

• Main reason for drugs being removed from clinical development or use

What mechanisms contribute to drug-induced liver injury?

• Direct hepatocyte damage

• Mitochondrial toxicity

• Toxic metabolite activity

• Cholestasis

• Drug-drug interactions (some predictable)

• Idiosyncratic, metabolic, or genetic factors (rare and unpredictable)

What are the three main hepatocyte zones in the liver lobule?

• Periportal region (Zone 1)

• Mid-zone (Zone 2)

• Centrilobular region (Zone 3)

What are the characteristics of the periportal region (Zone 1)?

• Highest oxygenation (mainly from hepatic artery)

• Least sensitive to ischemic injury

• Hepatocytes specialized in oxidative functions:

  • Gluconeogenesis

  • Cholesterol synthesis

  • β-oxidation of fatty acids

• Most susceptible to viral hepatitis

What are the characteristics of the centrilobular region (Zone 3)?

• Lowest oxygenation (most vulnerable to ischemia)

• Hepatocytes specialize in:

  • Glycolysis

  • Lipogenesis

  • P450 drug detoxification

• Most affected during ischemic injury