Liver and biliary tract

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Chapter 34 Liver and biliary tract

Graeme Alexander

Synopsis

The liver is the most important organ for structural alteration and disposal of drugs, generating metabolites which may be biologically active or inactive (or toxic). The liver is exposed to drugs at higher concentrations than most organs because most agents are administered orally and absorbed from the gastrointestinal tract, so the whole dose passes through the liver to the systemic circulation, rendering the liver vulnerable to injury from chemicals and drugs. Conversely, disordered hepatic function is an important cause of abnormal drug handling and responses.

• Drugs and the liver.

image Pharmacodynamic and pharmacokinetic changes
image Prescribing in liver disease
image Drug-induced liver injury
image Aspects of therapy.

Effects of liver disease

Pharmacodynamic changes in liver disease

Patients with advanced liver disease have increased prothrombin time (INR) and serum bilirubin and require particular care when prescribing because they exhibit abnormal end-organ responses to drugs. Sensitivity of the central nervous system (CNS) to opioids, sedatives and antiepilepsy drugs is increased; the effect of oral anticoagulants is increased because synthesis of coagulation factors and thrombotic factors is impaired; fluid and electrolyte balance are altered; sodium retention is induced more readily by non-steroidal anti-inflammatory drugs (NSAIDs) or corticosteroids; ascites and oedema become diuretic resistant.

Pharmacokinetic changes in liver disease

The liver has large metabolic reserve and important changes in drug handling occur only with hepatic decompensation. Parenchymal liver disorders, including chronic viral hepatitis or alcohol-related liver disease, have more impact on hepatic drug-metabolising enzyme activity than cholestatic conditions, such as primary biliary cirrhosis, where elimination via biliary excretion may be impaired. Hepatocellular injury leads to decreased activity of drug-metabolising enzymes, reflected in diminished plasma clearance of drugs with hepatic metabolism. There is variation between patients and overlap with healthy subjects.

Hepatic blood flow and metabolism

Complex changes in blood flow occur with liver disease. Increased resistance to portal blood flow in cirrhosis and portosystemic/intrahepatic shunts reduce drug delivery to hepatocytes, while increasing delivery direct to the systemic circulation. The pattern of change caused by disease relates to the manner in which the healthy liver treats a drug; there are two general classes:

• Drugs metabolised rapidly with high extraction in a single pass through the liver. Clearance is limited normally by hepatic blood flow, but in severe liver disease less drug is extracted from blood passing through the liver because of poor hepatocyte function and portosystemic shunts that allow blood to bypass the liver. The predominant kinetic change for drugs given orally is increased systemic availability. The initial and maintenance doses of such drugs should be reduced. With severe liver impairment the t½ of drugs in this class may lengthen.

• Drugs metabolised slowly with poor extraction in a single pass through the liver. The rate-limiting factor for elimination of this type of drug is metabolic capacity and the major effect of liver disease is prolongation of t½. Consequently, the interval between doses may need to be lengthened and the time to reach steady-state concentration in the plasma (5 × t½) is increased.

Plasma protein binding of drug

Binding of drugs to albumin is reduced when plasma concentrations of albumin fall with defective synthesis. These changes provide scope to enhance the biological activity of drugs, but assume importance only with extensive protein binding (> 90%).

Other considerations

Patients with severe decompensated liver disease develop renal impairment, with consequences for drugs with significant renal elimination. Where possible, dosing should be guided by measuring plasma concentrations (e.g. vancomycin).

Prescribing for patients with liver disease

Prescribing of most drugs is safe in well-compensated liver disease. If in doubt, check the prothrombin time and serum bilirubin. Take particular care with:

• Impaired hepatic synthetic function (hypoalbuminaemia, increased INR).

• Current/recent hepatic encephalopathy.

• Fluid retention and renal impairment.

• Drugs with:

image high hepatic extraction
image high plasma protein binding
image low therapeutic ratio
image CNS depressant effect.

For drugs with significant hepatic metabolism, a reasonable approach is to reduce the dose to 25–50% of normal and monitor responses. Specific examples include:

CNS depressants

Sedatives, antidepressants and antiepilepsy drugs should be avoided or used with extreme caution in advanced liver disease, particularly with current/recent hepatic encephalopathy. Enhanced CNS sensitivity to such drugs is well documented. Treatment of alcohol withdrawal in patients with established liver disease is hazardous; reducing doses of chlordiazepoxide over 5–10 days is recommended (with high-dose thiamine).

Analgesics

Opiates can precipitate hepatic encephalopathy in decompensated liver disease. If required to control postoperative pain, doses should be reduced to 25–50%. Intravenous infusions risk accidental overdose. Codeine can precipitate hepatic encephalopathy through constipation alone and accumulates with renal impairment. Avoid aspirin and other NSAIDs whenever possible, as they exacerbate impaired renal function and fluid retention by inhibiting prostaglandin synthesis and precipitate gastrointestinal bleeding.

Gastrointestinal system

Antacids that contain large quantities of sodium can precipitate fluid retention and cause ascites. Aluminium- or calcium-based preparations and antimotility drugs cause constipation and may precipitate hepatic encephalopathy.

Drug-induced liver damage

The spectrum of hepatic abnormalities caused by drugs is broad (Table 34.1). Drugs tend to injure specific hepatocyte components, e.g. plasma membrane, biliary canaliculi, cytochrome P450 enzymes or mitochondria.

Table 34.1 Idiosyncratic drug reactions and the cell components that are affected

Type of reaction Effect on cells Examples of drugs
Hepatocellular Direct effect on production by enzyme–drug combination leads to cell and membrane dysfunction Isoniazid, trazodone, diclofenac, nefazodone, venlafaxine, lovastatin
Immune mediated Cytotoxic lymphocyte response directed at hepatocyte membranes altered by drug metabolite ± additional autoimmune component Nitrofurantoin, methyldopa, lovastatin, minocycline, halothane
Cholestasis Injury to canalicular membrane and transporters Chlorpromazine, oestrogen, erythromycin and its derivatives
Granulomatous Macrophages, lymphocytes infiltrate hepatic lobule Diltiazem, sulfa drugs, quinidine
Microvesicular fat Altered mitochondrial respiration, β-oxidation leads to lactic acidosis and triglyceride accumulation Didanosine, tetracyclines, acetylsalicylic acid, valproic acid
Steatohepatitis (fatty liver) Multifactorial Amiodarone, tamoxifen
Fibrosis Activation of stellate cells Methotrexate, excess vitamin A
Vascular collapse Causes ischaemic or hypoxic injury Nicotinic acid, cocaine, methylenedioxymethylamfetamine (MDMA)
Oncogenesis Encourages tumour formation Oral contraceptives, androgens
Mixed Cytoplasmic and canalicular injury, direct damage to bile ducts Amoxicillin–clavulanic acid, carbamazepine, herbs, ciclosporin, methimazole, troglitazone

Certain drugs interfere with bilirubin metabolism and excretion without causing hepatic injury. Jaundice is induced selectively with minimal or no disturbance of other liver function tests; recovery follows stopping the drug.

Examples are:

• C-17α-substituted steroids impair bilirubin excretion into hepatic canaliculi. These include synthetic anabolic steroids and oestrogens in oral contraceptives; jaundice due to the latter is rare with current formulations. Many have genetic susceptibility with mutations in ABC cassette biliary transporter proteins.

• Rifampicin impairs hepatic uptake and excretion of bilirubin; unconjugated and conjugated bilirubin levels may be raised within 3 weeks.

• Fusidic acid interferes with hepatic bilirubin excretion, causing conjugated hyperbilirubinaemia, particularly with sepsis.

Diagnosis and management of drug-induced liver injury

• Always consider the possibility. Take careful drug histories, including over-the-counter, complementary, illicit and alternative medicines.

• Consider a viral aetiology with hepatitis.

• Consider other causes of cholestatic disease.

• Underlying liver disease can cause diagnostic confusion.

• Liver biopsy is often helpful, but eosinophil infiltration, often thought to be specific for drug reaction, has many causes.

• Diagnostic challenge is dangerous, may precipitate life-threatening liver disease and is never justified.

• Monitoring liver function in the early weeks of therapy is wise in detecting early reactions to drugs with hepatotoxic potential, e.g. isoniazid. Minor abnormalities (serum transaminase levels less than twice normal) are often self-limiting and progress should be monitored. For increases exceeding three-fold, consider drug withdrawal, even in asymptomatic patients.

Aspects of therapy

Complications of cirrhosis

Variceal bleeding

Varices are dilated vessels, linking the portal and systemic venous systems, which return blood from the splanchnic circulation to the systemic circulation, bypassing the liver, decompressing the portal venous system and reducing portal pressure. Varices can be large, and haemorrhage, sometimes catastrophic, occurs from any of these vessels when intravascular pressures reach a threshold. Lower oesophageal or gastric varices, which are thin-walled and submucosal, are most prone to haemorrhage because intravascular pressures rise beyond that threshold with everyday physiological processes.

Portal pressure is a function of portal venous resistance and blood flow. In cirrhosis, both portal venous resistance and splanchnic blood flow are increased, the latter by a combination of splanchnic vasodilatation and increased cardiac output. Variceal bleeding is more likely once the pressure gradient between the portal and systemic venous systems rises above 12 mmHg (measured as the wedged hepatic venous pressure).

Fifty per cent die from hypovolaemia or associated complications after a first oesophageal or gastric variceal haemorrhage, manifest as melaena or haematemesis. Correct hypovolaemia promptly with plasma expanders and blood transfusion. The use of central venous access and monitoring is recommended; correction of coagulopathy with platelets and clotting factors appears logical. The relation between bacterial infection and haemorrhage is intriguing; bacterial infection is often found at presentation and 60% have evidence of infection within 7 days of haemorrhage. It is unclear whether infection increases the risk of haemorrhage or is a consequence. Bacterial infection should be treated, or anticipated, using broad-spectrum antibiotics with Gram-negative cover in line with local prescribing policy. Proton pump inhibitors are also recommended. Many patients cease bleeding spontaneously, but over half re-bleed within 10 days. Conservative management is rarely acceptable.

Acute variceal haemorrhage

The first step is always resuscitation. If bleeding varices are suspected, give terlipressin, as it reduces splanchnic blood flow, increases systemic blood pressure and reduces haemorrhage, which aids diagnostic endoscopy.

Oesophageal band ligation is the treatment of choice for bleeding varices identified at endoscopy. Varices are obliterated by application of small elastic bands under direct vision by an experienced operative. This has supplanted injection sclerotherapy, which involved injecting sclerosant into and around varices but which carried a higher rate of complications (oesophagitis, oesophageal stricture/perforation and distant sclerosant embolisation). Direct injection of superglue into the varix, the treatment of choice for bleeding gastric varices, requires considerable expertise. Bleeding is controlled in 90% of patients after oesophageal band ligation in conjunction with terlipressin. Obliteration of oesophageal varices requires repeated band ligation over a prolonged period.

Pharmacological reduction of portal pressure

Vasopressin, in addition to its action on renal collecting ducts (through V2 receptors), constricts smooth muscle (V1 receptors) in the cardiovascular system and particularly in splanchnic blood vessels, reducing splanchnic blood flow. Systemic, cerebral and coronary artery vasoconstriction are predictable complications necessitating treatment withdrawal in 20% of older patients. In patients with cardiovascular disease and uncontrolled haemorrhage that precludes definitive endoscopic therapy, simultaneous administration of glyceryl trinitrate (transdermally, sublingually or intravenously) allows continued use of vasopressin, reducing cardiac risk, and also reduces portal venous resistance and pressure directly.

Vasopressin is cleared rapidly from the circulation so is given by continuous intravenous infusion; with concerns about distant ischaemia, the short t½ of vasopressin is advantageous.

The synthetic analogue, terlipressin (triglycyllysine-vasopressin) has supplanted vasopressin. This prodrug is converted in vivo to vasoactive lysine vasopressin, which has biological activity for 3–4 h, and is effective as bolus injections 4-hourly for 2–5 days, reducing the risk of re-bleeding.

Somatostatin and the synthetic analogue octreotide reduce portal pressure by decreasing splanchnic blood flow. Octreotide has the advantage of a longer duration of action and is given as bolus injection. It can be used as an alternative to terlipressin, with similar efficacy and indications, but does not carry a risk of cerebral or cardiac ischaemia.

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