PBL2 Follow-on from PBL1: hepatorenal failure Stages of effect of alcohol on the liver and other organs Treatment

ent of hypoglycaemia Liver biopsies CP450 (inducers (PCBRAS) and inhibitors Effects of alcohol on liver

1.

Framework of paracetamol: - What is the therapeutic dose of paracetamol? o The common adult dose is 500 mg to 1000 mg. o The recommended maximum daily dose, for adults, is 4000 mg. o In recommended doses, paracetamol generally is safe for children and infants, as well as for adults, although rare cases of acute liver injury have been linked to amounts lower than 2500 mg per day - What is the lethal dose of paracetamol? o A toxic dose is >4 grams within a 24-hour period o An acute paracetamol overdose in adults is minimally defined as a cumulative dose of paracetamol >4 grams and is ingested over 8 hours or less o hepatic toxicity may occur following ingestion of >7.5 grams but is unlikely if <150 mg/kg has been ingested o The definition of hepatotoxicity after paracetamol overdose is a serum AST concentration 1000 international units/L or greater. - What if they already have liver pathology; decompensated liver. - Stages of paracetamol (Hedex) overdose o Paracetamol metabolism is age- and dose-dependent. o After ingestion of a therapeutic dose, paracetamol undergoes hepatic sulfation and glucuronidation, and the resulting non-toxic metabolites are excreted in the urine. o About 4% of a therapeutic dose is metabolised by the cytochromes P450, mainly CYP2E1, to a potentially toxic intermediate metabolite Nacetyl-p-benzoquinone imine (NAPQI). o The highest concentration of CYP2El is located in centrilobular hepatocytes around the central vein (i.e., perivenular or zone 3) and reflects the initial hepatic injury produced by paracetamol. o Under normal conditions and therapeutic doses, NAPQI combines with intracellular glutathione to become a non-toxic mercapturate derivative with urinary excretion. o However, after ingestion of an overdose, the normally minor CYP2E1 pathway becomes important.

o When the production of NAPQI exceeds the capacity to detoxify it, the excess NAPQI binds to cellular components, causing mitochondrial injury and ultimately the death of the hepatocyte. o If a sufficient dose is taken, hepatocyte death may be massive and produce acute liver failure. o The presence of CYP2E1 in the kidney may be a factor in variable degrees of renal injury occasionally seen following paracetamol overdose SEs of paracetamol: (is it the same as NSAID) o Paracetamol use for fever in the first year of life was associated with an increase in the incidence of asthmatic symptoms at 67 years, and that paracetamol use, both in the first year of life and in children aged 67 years, was associated with an increased incidence of rhinoconjunctivitis and eczema. o How does it affect the mucosa in the stomach? o Prolonged daily use increases the risk of upper gastrointestinal complications such as stomach bleeding, and may cause kidney or liver damage. o How does it affect the liver and other organs? o Paracetamol is metabolized by the liver and is hepatotoxic; side effects may be more likely in chronic alcoholics or patients with liver damage Different clinical presentations (in healthy and unhealthy liver) o Many patients who present within the first 24 hours will be asymptomatic. o The presence of signs and symptoms e.g. nausea, vomiting and abdominal pain, depends on the time of presentation relative to the time of paracetamol overdose o Nausea and vomiting may also occur when hepatotoxicity peaks, 2 to 3 days after ingestion. o Signs of hepatotoxicity typically develop 2 to 3 days after ingestion. These include RUQ pain, jaundice, encephalopathy o Rarely, massive overdose of paracetamol may initially present with coma and metabolic acidosis prior to development of hepatoxicity o Coma may also be present if a combined paracetamol and opiate preparation has been taken or there has been co-ingestion of drugs (including alcohol) that reduce the consciousness level. When does paracetamol appear in the blood? o In cases of acute overdose, serum paracetamol concentration should be checked as early as possible, but at the earliest 4 hours after ingestion o The level of serum paracetamol relative to the time of ingestion will determine need for subsequent treatment Management of over dose. o Time frame of Rx: N-acteyl cysteine (antidote) must be administered within 8-10hours. How does this affect prognosis.

o Sometimes mix paracetamol with antidote Complications: hepatorenal failure (terlipressin)

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3.

o Acute liver failure: Include hepatic encephalopathy, sepsis, and gastrointestinal bleeding. Timely referral to a liver unit and assessment of patient candidacy for orthotopic liver transplantation are needed o In survivors, hepatic regeneration is normally rapid and complete, with normalisation of liver function tests within 1 to 3 weeks o Renal injury is rare, and when it occurs serum creatinine typically begins to rise soon after serum aminotransferase activity has peaked. Occasionally, renal injury occurs without liver injury. When did the change of selling paracetamol to blister packs happen? Government strategy to reduce paracetamol overdose. o Packaging o Public health interventions, such as legislation regarding paracetamol availability and packaging, may lead to reductions in deaths from selfharm. o There is some evidence that legislation introduced in 1998 in the UK limiting the number of paracetamol tablets purchased at a single time may have had a small effect in reducing the number of suicides related to paracetamol ingestion o More recently, a combination tablet of paracetamol and dextropropoxyphene (co-proxamol) has been withdrawn in the UK owing to its implication in a large number of poisoning deaths. o This has been associated with a reduction in the number of suicides and accidental poisonings attributed to co-proxamol. o Age Time frame for portal hypertension to develop? Can you get it with acute liver failure or only chronic? a. Serum to ascitic fluid albumin gradient (SAAG) is >11 g/L (1.1 g/decilitre). b. The most common cause is portal hypertension secondary to cirrhosis. The common causes of cirrhosis in the US include alcohol consumption (80 g of ethanol daily for 10 to 20 years), hepatitis B and C, non-alcoholic steatohepatitis, and autoimmune and metabolic liver diseases. c. Non-cirrhotic liver diseases (i.e., alcoholic hepatitis, fulminant hepatic failure, or massive hepatic metastasis) may also cause ascites. d. Non-hepatic causes of portal hypertension may lead to ascites. These include CHF (most common), constrictive pericarditis, and tricuspid regurgitation Ascites: a. What is it i. Ascites is defined as a pathological collection of fluid in the peritoneal cavity. ii. The most common cause is cirrhosis, accounting for approximately 75% to 80% of cases. iii. Other causes include malignancy (10%), heart failure (3%), tuberculosis (2%), pancreatitis (1%), and other rare conditions b. Common causes, focus on liver failure

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i. In cirrhosis, ascites forms due to renal dysfunction and abnormalities in portal and splanchnic circulation. Sodium retention is a major factor in pathogenesis. ii. Splanchnic arterial vasodilatation (secondary to hepatic fibrosis) leads to increased lymph formation, activation of the renin angiotension system and sympathetic nervous system, and release of antidiuretic hormone. iii. This causes renal sodium and water retention. iv. There is increased resistance to portal flow resulting in portal hypertension, collateral vein formation and shunting of blood to the systemic circulation. v. About 50% of patients with cirrhosis develop ascites within 10 years, and 50% of patients with cirrhosis and ascites will die within 2 years. Indications/criteria/eligibility for liver transplant

3 ASSESSMENT 3.1 Assessment is carried out by the transplant multi-disciplinary team. It is usually desirable for the patient's family to be involved in the assessment process. These initial assessment procedures often follow outpatient review and consultation and are undertaken over several days; patients remaining on the waiting list will be re-assessed at intervals during their wait for a donor organ. 3.2 The decision whether or not to register a patient on the transplant waiting list will be made after discussion with the patient and other relevant healthcare professionals. The patients family and partner usually will be involved as patients find that helpful and the familys support is likely to improve the eventual outcome. Other factors which will need to be considered will include the reason which gave rise to the primary cause of liver failure (for example, alcohol-induced liver diseases); a history of illegal drug use or of selfinflicted; medical or psychiatric conditions; and the patients age. These are discussed briefly below. 3.2.1 Alcohol-induced liver disease A history of excess alcohol is relevant in regard to potential or actual significant damage to cardiovascular and neurological tissue, or to the risk that patients might revert to alcohol abuse or might not comply with medication or follow up schedules and thus damage the new liver. A multi-disciplinary approach is required to select patients who are likely to comply with follow-up and not return to a damaging pattern of alcohol consumption after transplantation and may include psychological/psychiatric assessment. Appropriate follow-up strategies may be needed. 3.2.2 Illegal drug use Is not a contraindication to transplant if the patient will comply with the required schedules. However, continued intravenous drug use is considered a contraindication owing to the possible risk of infection in an immune-suppressed patient.

3.2.3 Age In itself is not a contra-indication, although the survival rate after transplant of the over 65s is significantly worse than that of younger patients. 3.2.4 Self-inflicted conditions Such as resulting from an overdose of paracetamol would only be contra-indicated if there were good reason to believe that the patient would, despite appropriate support, return to a behavioural pattern that would lead to liver failure or result in a quality of life unacceptable to the patient. The views of the family doctor and other support agencies and the family may have to be taken into account. 3.2.5 Medical and psychiatric conditions 3.2.5.1 Concurrent extra-hepatic co-morbid medical or psychiatric conditions are relevant if they will affect the patients quality of life or prospect for survival post transplant. Where uncertainty remains,evaluation should be considered in discussion with other transplant units and, where appropriate, the Managing & Transplant Director of UK Transplant/Chairman of UK Transplant Liver Advisory Group. 3.2.5.2 Patients in whom early graft damage from recurrent disease can be anticipated should only be transplanted as part of an agreed protocol of treatment. There are welldeveloped protocols now to prevent or treat the effects of recurrent HCV and HBV infections but problems remain with hepatic malignancy. 3.2.5.3 With the advent of effective treatment, those co-infected with the HIV may be suitable candidates for transplantation. 3.2.6 Regrafts Will need special consideration dependent on the circumstances which gave rise to the need for regraft, as results after early re-graft are poor and only limited benefit may be achieved. However, the principles that apply to primary grafts should also apply to re-grafts. 3.2.7 Malignancy Where potential liver allograft recipients have suffered from previous extrahepatic malignancy, the decision to proceed for liver transplantation should depend, in part, on the probability of malignancy recurring following liver transplantation. Some immunosuppressive agents may encourage the growth of malignancy. Patients should be considered in the light of section 2.2. With patients with primary hepatic malignancy, there are agreed criteria which predict a high probability of tumour persistence after transplantation: these include number of lesions, size of lesions, portal vein involvement and spread outside the liver capsule. Most data suggest that more than 3 liver tumours with a maximum diameter of 5 cm indicates that hapatocellular cancer is likely to persist following liver transplantation and the criteria in section 2.2. will not be met. However. These criteria are under regular review and a slight expansion, using the UCSF criteria, may be appropriate. The role of interventions that shrink the tumour (such as chemoembolisation) remains uncertain and extension of the conventional indications should be done in the context of agreed studies. In general, those known to have cholangiocarcinoma are not appropriate candidates for transplantation. 3.3 It also has to be recognised that patients awaiting a liver transplant are, by definition, ill and their condition may deteriorate to the extent that the probability of a 5-year survival may fall below 50%. In these circumstances, the patient will be removed from the waiting

list but only after full discussion with them. Such patients - although in greatest need - are at greatest risk of not benefiting after transplantation. 5. 6. 10 indications for referral to coroner

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Risk factors of suicide