Liver

What are the functions of the liver?

Metabolism (carbohydrate, protein, fat, steroid hormones, insulin, aldosterone, important for drugs). Synthesis (proteins/albumin), clotting factors, fibrinogen, cholesterol, 25-OH of vitamin D, gluconeogenesis. Immunological, storage, homeostasis, bile,

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Describe features of AST and ALT

AST (0-40 iu/L). ALT (5-30 iu/L). Enzymes found in the liver cells (hepatocytes) which leak into the bloodstream when cells are damaged. Indicate degree of inflammation in the liver. Usually higher in hepatitis (up to 20-50x ULN). Elevated in viral hepati

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Describe features of ALP and GGT

ALP (30-120 iu/L). GGT (5-55 iu/L). Enzymes found mainly in the bile ducts of the liver. Elevated ALP and GGT can indicate obstruction or cholestatic liver disease, infiltrative liver disease, and damage to the biliary tree.

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Describe features of bilirubin

Bilirubin (5-20 micromol/L). Clinical jaundice (>50 micromol/L). Breakdown product of red blood cells. Highly protein bound (transported to the liver attached to albumin). Conjugated in the liver (water-soluble) and excreted via the bile into
the intestin

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Describe features of albumin and PT

Albumin (35-50 g/dL). PT/INR (10-14s, 0.8-1.2). Protein produced by the liver, and makes up roughly 60% of total protein in the blood. Half life of albumin is 20-26 days. Levels may reduce in chronic liver disease, and oedema.

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How are LFTs interpreted?

Deranged LFTs do not always indicate hepatic dysfunction, and may not be drug-induced and therefore drug changes are not always necessary. Results considered abnormal if 2x ULN, if liver related would expect at least 2 to be deranged.

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What are the causes of liver disease?

Alcohol. Viral infections (hepatitis A, B, C, D, E, F). Inherited and metabolic disorders (Wilson disease, glycogen storage disease), immune disease of liver (autoimmune hepatitis, PBC, PSC). Vascular abnormalities (Buddi-Chiari syndrome), VOD. NAFLD, dru

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Describe the classification of liver disease

F0 (without fibrosis), F1 (initial fibrosis), F2 (intermediate fibrosis), F3 (advanced fibrosis), F4 (cirrhosis). Factors - alcohol, viral infections, NAFLD etc. Persistent, extensive hepatocyte damage - active deposition of collagen formation of scar tis

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What are the alcohol limits?

Less than 14 units per week for everyone. Considered binge drinking if >8units for men or >6units for women in a single session. No such thing as ‘safe’ alcohol limits – only ‘low-risk’. Drinking should be spread over several days in a week with ‘several’

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What are the signs and symptoms of chronic liver disease?

Abdominal pain, asterixis, jaundice, encephalopathy, spider naevi, pruritis, jaundiced, ascites, blood tests. Bilirubin (jaundice). High INR (liver is failing to synthesise all clotting factors except one). Raised GGT

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What treatments should be given to a patient for alcohol withdrawal and why?

Symptoms can range from mild to severe. Marked tremor. Fear and delusions. Restlessness and agitation. Fever. Rapid pulse. Dehydration. Seizures. Delirium tremens

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What is the treatment for alcohol withdrawal?

Combination sedatives and vitamin supplementation – Chlordiazepoxide (25-50 mg every 2 hours PRN) + Pabrinex (1-2 pairs TDS)

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Why is chlordiazepoxide used for alcohol withdrawal?

Long half-life, sedative and anti-convulsant properties. Slower onset action - low dependence forming potential

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Which other medicines can be given for alcohol withdrawal? (1)

Benzodiazepines. Front-loading- loading dose followed by repeat dosing every 90mins –light sedation. Symptom triggered dosing. Tapering dose regimen. Shorter acting: e.g oxazepam or lorazepam. More suitable in patients with hepatic impairment

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Which other medicines can be given for alcohol withdrawal? (2)

Most benzos are highly lipophilic and undergo extensive liver metabolism - cirrhosis. Most form active metabolites. Several studies – diazepam metabolism apparently
reduced in patients with hepatic impairment often
necessitating a reduction in dosage. V

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Why is Pabrinex used in the management of alcohol withdrawal?

Vitamin deficient due to poor diet (high in carbohydrate, low in protein, vitamins and minerals). Malabsorption in the intestinal mucosa. Thiamine deficiency - polyneuritis with motor and sensory defects. Wernicke's encephalopathy - reversible

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List the contents in one pair of Pabrinex

Thiamine 250 mg, ascorbic acid 500 mg, nicotinamide 160 mg, pyridoxine 50 mg, riboflavin 4 mg. Dose 1-3 pairs BD-TDS. IM preparation is available – not if coagulopathic. IV Infusion in 50-100mL NaCl 0.9% or Dex 5% over 30 minutes

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What treatment should be given for hepatitis? (1)

Corticosteroids. Likely to be most effective treatment in patients with severe disease but use subject to much debate. Usual agent – prednisolone 40mg OD for at least 5- 7 days. Aim to switch off inflammatory process.

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What treatment should be given for hepatitis? (2)

Pentoxifylline (Oxpentifylline). Non-selective phosphodiesterase inhibitor which inhibits TNFα (pro-inflammatory cytokine). RCT in 101 patients (2000) – 400mg TDS pentoxifylline for 28 days Patients had Maddrey’s discriminant function >32 (severe).

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What are the other pharmacological methods for the management of alcoholic cirrhosis? (1)

Diuretics for ascites. Propanolol for portal hypertension. Vitamin K for coagulopathy. Antibiotics for spontaneous bacterial peritonitis. Lactulose for hepatic encephalopathy (+ avoid precipitation). For some patients transplantation may be the only optio

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What are the other pharmacological methods for the management of alcoholic cirrhosis? (2)

Alcohol affects the glutamine, gamma-aminobutyric acid (GABA), dopamine, and endogenous opioid systems. Alcohol consumption is associated with a release of β-endorphins which stimulate dopamine release, thought to result in the pleasurable feelings

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What are the other pharmacological methods for the management of alcoholic cirrhosis? (3)

Alcohol inhibits excitatory glutaminergic function at lower doses, but the body compensates for higher doses by upregulating the NMDA receptors (glutamine receptors) to increase glutamate functioning. Use of abstinence aids

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How can abstinence be achieved?

Psychological treatments, pharmacological treatments, combination of both. Acamprosate, disulfiram, naltrexone

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Describe features of acamprosate

Several RCTs and meta-analysis have shown reduction in drinking days and increased abstinence rates. Stimulate GABA-ergic neurotransmission and antagonise effects of excitatory amino-acid neurotransmission. 666mg TDS with food

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Describe features of disulfiram

Irreversibly inhibits acetaldehyde dehydrogenase therefore leading to increased levels of acetylaldehyde. Initially 800mg/day then 200 mg/day then 100-200 mg/day

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Describe features of naltrexone

Like Acamprosate - RCTs and meta-analysis have shown reduction in drinking days and increased abstinence rates. Opiate antagonist. The endogenous opioid system may modulate the intake of alcohol. 50 mg OD

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What are the signs and symptoms of a variceal bleed?

Passing fresh blood, pale (low Hb), low BP, tachycardia

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What treatments should be given to a patient prior to endoscopy?

Resuscitate (fluids, blood - target Hb of 8-10 g/dL). Drugs. Correct clotting (FFP if INR >1.5, vitamin K/PPI). Correct platelets if <50 x 10^9

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Describe features of terlipressin

Synthetic analogue of vasopressin. Very potent splanchnic vasoconstriction. Administer in bolus doses 1-2mg every 4-6 hours (continue until haemostasis achieved). Blood pressure, sodium, potassium, fluid balance and side- effects including; headaches, cra

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Describe the choice of antibiotics used to manage a variceal bleed

Bacterial infections occur in 35-60% of cirrhotic patients. Administration of broad-spectrum prophylactic antibiotics decreases infection rates and improves survival. Ciprofloxacin. Piperacillin + tazobactam

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What alternative pharmacological treatments are there for acute variceal bleeding?

Somatostatin and analogues. Causes selective splanchnic vasoconstriction and reduces portal pressure and portal blood flow. Unimpressive data for octreotide vs. placebo. No significant difference as regards - mortality, failure to stop bleeding re-bleedin

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What is band ligation?

A procedure that uses elastic bands to treat enlarged veins, or varices. Meta-analysis showed band ligation superior to sclerotherapy in terms of re- bleeding and mortality. OV haemorrhage – band ligation recommended. Technical difficulties. Complications

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What other endoscopic treatments may be offered?

Banding & Sclerotherapy (Better than sclerotherapy at controlling bleeding, More complications with sclerotherapy). Balloon tamponade (Highly effective when deployed, but 50% re-bleed when deflated, high complication). TIPSS

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State features of sclerotherapy

Injection of sclerosants (“glue”) e.g. cyanoacrylate. More complications - oesphageal ulceration, sepsis. GV haemorrhage – sclerotherapy recommended

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If endoscopic therapy failed what temporary measure may be used?

Balloon Tamponade. Temporary measure (< 24 hours). Several different types e.g.
Sengstaken-Blakemore tube. Mechanical “pressure” over bleeding points. Highly effective when deployed, but high rates re-bleed when deflated. High complication rates

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What is the rationale for starting each of the following drugs: Tazocin, phytomenadione, sucralfate, omeprazole and lactulose?

Tazocin – IV broad spectrum antibiotic for 7 days, infection is common for upper GI bleed in cirrhotic patients. Phytomenadione – vitamin K, clotting, reduce bleeding risk. Sucralfate and omeprazole – GI protection for oesophageal ulceration

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What is the role of beta-blockers? When would you initiate therapy?

Propranolol/Carvedilol. Splanchnic vasoconstriction (beta2 blockade). Cardiac output results in reduced portal pressures (beta1 blockade). Beta-blockers: Prevent re-bleeding, Increase survival. Start when hemodynamically stable. Monitor BP and HR.

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What is ascites? Describe the mechanism by which it is thought to occur.

Accumulation of fluid in the peritoneal cavity leading to swollen abdomen. Cirrhosis -> portal HTN -> splanchnic arterial vasodilation -> reduction in effective blood volume -> stimulation of RAAS, argining vasopressin -> Na/H2O retention -> ascites

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What is the pharmacological management of ascites?

Diuretics - thiazide, loop, aldosterone antagonist. Or parancentesis

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What are the adverse side effects of thiazide diuretics?

Hypokalaemia, metabolic acidosis, dehydration (hypovolemia, leading to hypotension), hyponatremia, hyperglycemia in diabetes, hypercholesterolemia, hypertriglyceridemia, increased LDLs, hyperuricemia (at low doses), azotemia in renal disease patients

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What are the drug interactions for thiazide diuretics?

Hypokalaemia potentiated digitalis toxicity. NSAIDs (reduce diuretic efficacy). Beta-blockers (potentiate hyperglycemia and hyperlipidemias). Steroids (enhance hypokalemia)

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What are the adverse side effects of loop diuretics?

Hypokalemia, metabolic acidosis, hypomagnesemia, hyperuricemia, dehydration (hypovolemia - leading to hypotension), dose-related hearing loss (ototoxicity)

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What are the drug interactions for loop diuretics?

Hypokalaemia potentiated digitalis toxicity. NSAIDs (reduce diuretic efficacy). Steroids (enhance hypokalemia). Aminoglycosides enhance ototoxicity, nephrotoxicity

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What are the adverse side effects of aldosterone antagonists?

Hyperkalaemia, metabolic acidosis, gynecomastia, gastric problems (peptic ulcer)

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What are the drug interactions for aldosterone antagonists?

ACE inhibitors (potentiate hyperkalemia), NSAIDs reduce diuretic efficacy

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How is ascites managed?

Fluid/Na restriction. Diuretics (spironolactone, amiloride, furosmide). Diuretic resistant – 25-50% mortality within a year. Paracentesis for large volume. Need to maintain adequate
circulating volume – colloids, albumin, terlipressin.

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What are the monitoring requirements for ascites?

Daily U&Es – esp Na, K, Cr. Daily wt – aim for 0.5-1kg/day wt loss. Fluid chart – note fluid restriction, urine output. Avoid high Na contents preparation. Complications – dilutional hypoNa, HE, HRS, gynaecomastia, hyperK, muscle cramps, SBP.

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What is SBP and how is it diagnosed?

Spontaneous bacterial peritonitis. Infection of the ascitic fluid without intra-abdominal source of sepsis. 75% from gut, 25% from skin. Neutrophil count >250 cells per mm3. Mortality rate is 40%

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What are the drug options for SBP in terms of treatment and prophylaxis?

3rd gen cephalosporins, co-amoxiclav, Piperacillin+Tazobactam. Norfloxacin/Ciprofloxacin as prophylaxis. The long-term prognosis of cirrhotic patients following an episode of bacterial peritonitis is poor with one-year survival of around 40%.

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Liver

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