Liver Pharmacology: Hepatic Diseases, Hepatotoxicity, Cirrhosis, and Carcinoma

Neuroscience, Endocrine & Gastrointestinal Pharmacology +/- Therapeutics

The Liver - III

Dr. Jeremy Mills Pharmacology University of Portsmouth

Outline

• Diseases of the liver
• Biliary diseases
• Hepatotoxicity
• Cirrhosis
• Genetic diseases
• Hepatocellular Carcinoma

Liver Disease Mortality Rates

· Lancet 2014

PERCENTAGE CHANGE IN STANDARDISED UK MORTALITY RATES (AGE 0-64) NORMALISED TO 100% IN 19701

600% 300% 0% 1970 2010 1970 2010 1970 2010 1970 2010 1970 2010 1970 2010 1970 2010 1970 2010 1970 2010 BLOOD ENDOCRINE / METABOLIC DIABETES CANCER HEART DISEASE RESPIRATORY CIRCULATORY STROKE LIVER

Acute Liver Disease Causes

• Commonly caused by infectious agents or toxins (drugs, bugs or autoimmune) - eg viral hepatitis, aflatoxin, alcohol
• Self-limiting . Most cases recover completely . Minority of cases advance to chronic liver disease

Types of Hepatic Damage

• Zonal Necrosis- This is the most common type of drug induced liver cell necrosis where the injury is largely confined to a particular zone of the liver lobule.
• Hepatitis- Disease of the liver causing inflammation.
• Cholestasis- Cholestasis is a condition where bile cannot flow from the liver to the duodenum.
• Steatosis- Steatosis is a condition characterised by the build up of fat within the liver, sometimes triggering inflammation of the liver

Biliary Disease

• Cholestasis - bile not adequately excreted (interference with bile flow).
• Bilirubin accumulates in the liver cells, in canaliculi, in ductules, in ducts.
• A common accompaniment of cholestasis due to obstruction anywhere in the duct system is proliferation of ductules at the edges of the portal tracts.
• Secondary biliary cirrhosis

Bile Duct Proliferation

• The biliary constriction induces proliferation in the ducts
• Increased biliary pressure
• Pain
• Discomfort 1 0 Bile Ductular Proliferation

Cholestasis Symptoms

• In response to bile duct blockage bilirubin accumulates in the liver
• Cirrhosis
• Jaundice
• Decreased liver function
• Intense itching G Swelling e Cholestasis (bile plugs) G 0

Intrahepatic Cholestasis of Pregnancy

• Affects 1 in 150 pregnancies
• Causes :- - ABCB11/4 - efflux pump - Elevated Ivls steroid hormone metabolites
• Risk of stillbirth - - 1 - 2 in 100 bile acid >40umol/L. - 4 - 5 in 100 bile acid >80umol/L. ×

Case Study: Intrahepatic Cholestasis of Pregnancy

• A 30 year old, 35 week pregnant, nulliparous woman visits her GP because of itching but no rash.
• The GP arranges an urgent antenatal clinic review, where liver function tests (LFTs), including bile acids, are reported as normal.
• At a midwife appointment two weeks later, she still has intense itching. Repeat tests show raised total bile acids (100 umol/L; reference range 0-14) and aspartate aminotransferase (150 U/L; 5-35).
• Intrahepatic cholestasis of pregnancy is diagnosed and she is offered induction of labour that day.

Jaundice

• Accumulation of free or conjugated bilirubin in blood
• Yellow colouration of skin - jaundice
• Failure of excretory pathways
• Causes :-
• Too much bilirubin produced - high rate of RBC destruction (Haemolytic)
• Impaired uptake/transport/metabolism - Liver injury/ disease/viral/cirrhosis - (Hepatitis)
• Blockage of bile excretion - gallstones (Obstructive)

Jaundice Visual Representation

@ Original Artist Reproduction rights obtainable, from www.CartoonStock.com Hep A Patient with Jaundice Jaundice (Velowang of the byes & Skin) search ID: ndw0159, "Your Jaundice makes your teeth look whiter."

Gallstones

• Cholelithiasis (10-20% of population) - More in women than men, increases with age - Most stones are cholesterol (80%) or bile pigments and calcium
• Common bile duct - obstruction and jaundice
• Cystic duct - acute cholecystitis - Surgery (cholecystectomy) main option, but can give bile acids Operation Several largest Cholesterol Stones floating in water, inside 9 cm diameter plastic container

Toxicity vs Detoxification

Foreign compound Stable metabolite Reactive metabolite 1 Detoxication Failure/overload of detoxication Antigenic conjugate Tissue damage DNA Damage Immune response Necrosis Mutation Cancer Urine Toxicity vs Detoxification

Paracetamol Preparations

• Various preparations available
• Standard - Panadol, Calpol, Palgesic
• With codeine - Co-codamol, Solpadeine, Paracodol
• Miscellaneous - Beechams powders, Disprin extra, Day-nurse etc Panadol Extra Tablets Extra effective pain ralieser Tough on pain Easy on the stomach 32 SPALPHARMA Co-codamol Tablets 8/500mg 32 tablets 16 Tablots SUGAR FREE DISPROL SCLUBLE PARACETAMOL TABLETS Fast Fever and Poin Ral er FOR CHILDREN FROM & MONTHS

Paracetamol Metabolism

• Metabolism at therapeutic dose 4g/day
• Phase II metabolism
• Glucuronidation
• Sulphation
• Cytochrome P450 - N-acetyl-p-benzoquinoneimine (NAPQI) - Detoxified - glutathione

Paracetamol Pharmacokinetics at Toxic Doses

• Metabolism at toxic doses >10g
• Phase II - Conjugating pathways saturated
• Hepatic glutathione depleted
• P450 predominates - NAPQI accumulation - Centrilobular hepatic necrosis

Chronic Liver Disease and Cirrhosis

5 UCCK'S

• Major health problem - Cirrhosis in western countries - Viral hepatitis/Hepatocellular carcinoma in developing world
• 14th most common cause of death worldwide
• 9th most common in US
• 4th most common in EU
• Leading cause of death in UK aged 35 to 49 years accounting for more than 10% of deaths

Mortality for ALD

600 Liver Circulatory 500 Ischaemic heart Cerebrovascular 400 - Neoplasms Respiratory 300 Endocrine/metabolic Diabetes 200 100 0 1970 1980 1990 2000 2010

• For every 50 people who are admitted to ICU with ALD
• 22 die in the ICU
• 7 die after ICU but during the same hospital stay
• 5 survive to leave hospital but die within 1 year of ICU admission
• 6 survive the first year but die within 5 years of ICU admission
• 10 are still alive 5 years after ICU admission

Alcohol Pharmacokinetics and Metabolism

• Hepatic metabolism - 90% 1st pass metabolism - 5-10% unmetabolised alcohol is excreted in urine and air
• Phase 1 metabolism - primarily an oxidation reaction but only 25% from CYP (MEOS)
• Main pathways are saturable

Metabolism of Ethanol

• Major pathway is oxidation catalysed by alcohol dehydrogenase - high affinity, but low capacity NAD NAD C,H5OH "2"5 11 CH,CHO 3 CH COOH 3 Ethanol Acetaldehyde Acetic Acid 0 CH2 = CH - CH2 OH CH2 = CH-C H
• Alcohol metabolised per unit time is roughly proportional to body and liver weight. Allyl alcohol Allyl aldehyde
• The enzyme is relatively non-specific and will metabolise many substrates, (1 >>2 >>>3 alcohols), and it can use NADP instead of NAD but the reaction is slower.

Fatty Liver - Steatosis

Steatosis

• Fatty cells :- - lipid metabolism - lipoprotein synthesis - unusual quantities of adipose or dietary lipid brought to liver.
• Referred to as "steatosis Adipose tissue Adiponectin -Alcohol ADH Liver Acetaldehyde ^TNF-a Į PPAR -a activity JAMPK activity SREBP-1 IPPAR -a target enzyme expression 1 ACC activity ^ Lipogenic enzyme expression ,fat oxidation ^ Fat synthesis ĮVLDL secretion > LDs catabolism Fat accumulation & Steatosis

Fatty Liver Progression

• Progression associated with inflammation, proliferation and fibrosis
• 1. NAFLD or AFLD
• 2. Non-alcohol related steatohepatitis (NASH or ASH)
• 3. NASH/ASH with fibrosis
• 4. Cirrhosis d metabolism - lipoprotein synthesis - unusual quantities of adipose or dietary lipid brought to liver. Steatosis

Liver Regeneration

• Liver regenerates when injured or partially removed.
• Hepatic proliferation - very slow, but loss of hepatic tissue - great increase in proliferation
• Continues until the original liver mass is replaced
• The regenerated liver is similar to the original
• Repeated damage causes cirrhosis, progressive disorganisation, accumulation of connective (scar) tissue, and loss of liver function

Cirrhosis and Liver Damage Stages

• Liver disease - bouts of liver necrosis, inflammation, followed by normal regeneration Occasionally, repeated lingering bouts of necrosis Non-reversible connective tissue (fibrosis) builds up and destroys the blue-print for hepatic normal architecture. Stages of liver damage Fatty Liver Liver Fibrosis Cirrhosis Deposits of fat causes liver enlargement Scar tissue forms, Growth of connec- tive tissue destroys liver cells. Source: DER SPIEGEL 38/2000 HEN EPIENEL

Other Causes of Cirrhosis

• Inherited diseases - Haemochromatosis - too much iron absorbed by the liver, XS deposited in liver etc - toxic levels lead to damage
• Polymorphic HFE gene - regulates transferrin receptor - iron uptake

Haemochromatosis Inheritance and Treatment

• V. common inherited disease
• 1 in 200 affected
• Venesection/blood removal - 1 pint/wk for 1 year initially + diet parent without GH parent with GH children are all carriers of GH parent without GH parent carrier of GH children without GH children are carriers of GH parents both carriers of GH child without GH children carriers of GH child with GH How haemochromatosis is inherited Bupa

Organs Affected by Iron Overload

Organs that may be affected by iron overload Pituitary gland Thyroid and parfyroid glind Adrenal gland Heart and Lives Man Woman Ovary Toxic iron builds up across the body and can cause serious damage to vital organs, including the heart and liver. B c A D E

Wilson's Disease

Hepatomegaly Jaundice Acute hepatitis Fulminant hepatic failure Portal hypertension: bleeding varices Cirrhosis Proximal renal tubular dysfunction Liver Bone Renal Arthritis Rickets Wilson's Disease Haem Cardiac Hemolysis Central nervous system Eye Kayser Fleischer rings Deterioration in school performance Behavioral changes Inco-ordination (handwriting deteriorates) Resting and intention tremors Dystonia Dysarthria Excessive salivation Mask-like facies Dysphagia A B C

• 1 in 40,000
• Mutated ATP7B gene
• Inability to secrete copper into the bile for elimination
• Copper accumulates 28

Wilson's Disease Treatment

• Build-up of copper in liver and other organs - Penicillamine - Copper Chelation - Zinc Acetate - Blocks GIT copper absorption Copyright Digi Doc 1996, Medical Development, Software Copper complexed to albumin Endoplasmic reticulum Copper chaperones Nucleus Apoceruloplasmin Metallothionein (copper stored as non-toxic form) Ceruloplasmin bound to six copper atoms ATP7B 8800 Biliary copper Blood Bile canaliculus