Paul Selby Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK Prescribing in patients with abnormal liver tests can be difficult, with no means to measure precisely the remaining metabolic or excretory capacity of the liver. However, patients with liver disease commonly have other comorbidities and complications that require treatment. As the principal site of metabolism and detoxification of drugs in the body, liver impairment will affect the majority of drugs used in practice, and therapy should be carefully selected. In patients with liver disease, the consideration of changes within the liver physiology adds to the complexity of prescribing decisions. The underlying physiology provides only a partial guide for prescribing adjustments, as the hepatic reserve prevents direct attribution of liver function from a specific level of liver injury. As many clinical trials exclude patients with pre‐existing liver disease, there is often a lack of clear prescribing information on dosing for these patients. Similarly, interpreting information on the safe prescribing of drugs based on abnormal liver blood tests alone is difficult. This chapter takes you through guiding principles to consider when prescribing for patients with abnormal liver tests or liver disease. An understanding of the patient’s liver health and the specifics of the liver blood tests is central to designing a management plan. Licensing information and first principles of drug handling help to identify considerations for safety. Generalists and specialists should use their existing knowledge of the therapeutic drugs they are planning to prescribe to help support prescribing in these patients. The terms “hepatic impairment” and “liver impairment” are often used in regulatory or published literature, and reflect a broad range of conditions resulting from damage to the liver. It is important to ascertain the cause and extent of liver impairment when prescribing as this will help with assessing the overall risks for an individual patient. The goal of prescribing in liver disease is to provide therapeutic benefit, while minimizing adverse effects of the drug, preserving any remaining liver function and avoiding exacerbating complications and stigmata of liver disease. In the context of prescribing, liver blood tests are useful in establishing an overall picture of the patient’s liver health. The finding of abnormal liver tests does not preclude prescribing new medicines outright; they can be used in assessing the specifics of underlying disease and therefore the risks associated with prescribing medicines. LFTs multiple times greater than the upper limit of normal should prompt further advice and guidance from specialist services. Dividing LFTs into those that show acute or continuing damage and those that represent functional impairment is helpful to understand the overall presentation. In particular, interpretation of blood tests that suggest functional impairment influences prescribing advice in liver impairment. Serum bilirubin is an important marker when prescribing in liver disease; very high levels represent a significant disease burden. It is also an indicator for cholestasis, alongside elevations in alkaline phosphatase (ALP) and gamma‐glutamyl transferase (GGT). This reflects a reduction in biliary excretion and requires consideration when prescribing medicines excreted via the biliary tract. Table 18.1 presents some information on liver blood tests and their use in identifying types of liver disease. Looking at trends in liver blood tests can also be helpful in identifying progression or resolution of liver disease. Caution is warranted in patients whose disease is progressing to avoid exacerbating or potentiating further liver damage. Repeated monitoring should be continued in patients with abnormal liver tests when starting or increasing doses of medication, including those that are perceived to be relatively safe in liver disease. In certain circumstances, bilirubin levels alone are used to guide recommendations on dose reductions for extensively biliary‐excreted medicines. This is often an approach taken in the dosing for cytotoxic chemotherapy where local protocols should be followed. In the presence of significantly raised transaminases, prescribing should be avoided where the need is not immediately required. To maintain existing function and support recovery of the liver, the cause of the dysfunction should be investigated, and, ideally, evidence of resolution of transaminases resolved before new medicines are initiated. When assessing liver impairment, some liver blood tests will suggest severe impairment. Investigation for causes should be undertaken and careful consideration should be made for prescribing, with dose reductions considered in patients with: Table 18.1 Simple interpretations and considerations for prescribing from abnormal liver function tests. ALP, alkaline phosphatase; ALT, alanine amino transaminase; AST, Aspartate amino transaminase; DILI, drug‐induced liver injury; GGT, gamma‐glutamyl transferase. Liver blood tests are important in monitoring adverse reactions in response to prescribed medicines. The monitoring of liver blood tests is often recommended in prescription medicines to detect any liver insult at an early stage. Many drugs known to cause idiosyncratic drug‐induced liver injury (DILI) require monitoring with specific guidance on dosing adjustments should liver blood tests become abnormal. Liver blood tests for monitoring continuing drug therapy should include those discussed above. Prescribing in line with licensed information is the simplest and most convenient way to prescribe specific drugs in liver disease. Where this information exists, it will be present in the manufacturer’s licensing submission, such as the summary of product characteristics or prescribing information associated with the drug. National formularies will also contain similar advice, where they exist. The term or section on “hepatic impairment” is most commonly used in licensing information when giving advice. Caution and contraindication in licensing may be listed because there is a lack of evidence to support a recommendation, or based on theoretical concerns. This merits further consideration, as the cause of a warning can help to guide the risk of prescribing the drug. Where evidence or advice is reported in manufacturers’ literature for patients with liver disease it is common to divide patients in to mild, moderate, and severe liver disease categories. Often, no indication is provided as to what these categories represent. Some studies or product information consider Child–Pugh scoring (Table 18.2) as a surrogate marker for such categories, and will direct prescribing advice for patients with either Child–Pugh class A, B, or C cirrhosis. Using these surrogate markers for the terms mild, moderate, and severe impairment, respectively, can be helpful, and is a reasonable strategy if used cautiously in conjunction with signs and symptoms present in the patient. Liver disease staging is important in establishing the presence of cirrhosis, as patients without cirrhosis generally require no dose adjustments as they are unlikely to have functional impairment. However, the involvement of the biliary system should be considered for drugs that are known to have significant biliary excretion. Although rarely discussed directly in the licensing, information on the clinical pharmacology and pharmacological properties is usually presented. Caution should be used when prescribing drugs reported to have significant hepatic excretion due to a risk of accumulation. Where prescribing information is unavailable, assessing “first principles” of how the drug is handled by the body can be used to assess the likelihood of a specific drug to be affected by liver disease. Pharmacological parameters are commonly included in prescribing information and available through medicines information departments based in primary or secondary care institutions, and pharmaceutical companies. Table 18.2 Child–Pugh score. There are situations when medicines known to cause DILI are required to be prescribed in patients with liver impairment or abnormal liver blood tests. Although DILI is an uncommon complication of drug therapy, it is a common cause of liver dysfunction and any changes to liver blood tests or liver function should arouse suspicions of a DILI. Idiosyncratic DILI can occur from hours to weeks after initiation of medicines and requires careful observation. As the number of medications prescribed increases so does the risk of DILI. Reducing and preventing polypharmacy is an important consideration when prescribing for patients with liver injury. When prescribing a drug that causes idiosyncratic liver injury in patients with pre‐existing liver test abnormalities, careful consideration should be given to whether treatment can be delayed until the cause is investigated and liver blood tests have resolved. When prescribing a drug that causes idiosyncratic liver injury in patients with existing cirrhosis and functional impairment, consideration should be given to the risks and benefits of individual drugs, and investigation of alternative options. For drugs which cause idiosyncratic DILI, existing liver disease is not related to an increased risk of liver injury, but should liver injury develop, the clinical consequences are likely to be more severe. When prescribing drugs that cause a dose‐dependent liver injury, the benefit and risks must be carefully considered and, as a general rule, such drugs should be avoided. However, understanding the mechanism of action will help to support the decision‐making process and the prescriber should use their knowledge of the drugs they are prescribing to identify risk and benefit. Dose‐dependent liver injury can be caused by cumulative use (such as steatosis caused by methotrexate) or by an individual event of high dosing (such as the hepatic insult seen in acute paracetamol overdose). In the case of paracetamol, toxicity is known to be associated with high doses and a reduction in the dose or frequency it is given to patients may be sufficient to prevent DILI occurring. Induction of cytochrome P450 (CYP) enzymes can increase toxicity in paracetamol overdose, and therefore cautions in the prescribing of paracetamol with CYP inducers such as rifampicin, carbamazepine, or phenytoin exist. Having considered the risks of DILI, it is sensible to make a management plan, which may include monitoring of liver blood tests and explanation of complications that may arise so that patients can monitor for adverse events. Interpreting the principles of pharmacokinetics and pharmacodynamics, combined with an understanding of the extent of liver dysfunction allows assessment of safety when prescribing. These principles are covered in greater detail elsewhere, but an understanding of the underlying principles can enable a safety profile and assessment to be made to make prescribing decisions. Pharmacokinetics govern the relationship between drug dosing and drug concentration in the body; all the associated pharmacokinetic processes can be affected by liver impairment. Absorption of drugs from the gastrointestinal tract is affected by a number of patient and drug‐specific factors. Following passive or active uptake in the gut, the flow of blood through the liver allows first‐pass metabolism and clearance to occur before the drug has a systemic therapeutic effect. Clearance of a drug by the liver is assessed using the hepatic extraction ratio, which is dependent on the intrinsic ability of the liver to metabolize the drug (intrinsic clearance) and the unbound fraction of the drug. Drugs with a high hepatic extraction ratio are more dependent on the rate of blood flow to the liver to increase clearance. Drugs which undergo extensive first‐pass metabolism will have low bioavailability due to the metabolism of the drug before reaching systemic circulation. A reduction of blood flow to the liver (as seen in portal hypertension or portosystemic shunts) can decrease the extent of first‐pass metabolism, resulting in an increase in bioavailability. Some drugs are administered as pro‐drugs, which require modification into active metabolites, and this is also often completed during first‐pass metabolism. Where first‐pass metabolism is impaired, the expected concentrations of the active drug will be reduced, and therapy is less likely to be successful. Complications from liver disease can affect the extent to which absorption takes place through changes to the gut. Fat‐soluble (lipophilic) drugs require bile salts to aid their absorption, and in the setting of cholestasis, a lack of bile flow into the gut may cause reduced absorption. The presence of ascites can decrease absorption of drugs. Drugs which undergo enterohepatic recycling may have reduced reabsorption with respective lower systemic levels. Distribution reflects the extent to which a drug distributes into tissues and is dependent on lipid solubility, plasma protein binding, and tissue binding of a drug. Albumin performs a significant role in binding drugs in plasma rather than as a free (active) fraction. In liver disease, a reduction in albumin can result in an increased free fraction of highly protein‐bound drugs (such as sodium valproate or phenytoin). This results in a higher concentration of the drug in the serum. Drugs that are highly protein‐bound should therefore be used cautiously. Bilirubin may displace other drugs from albumin, further causing increased levels of the drug where bilirubin is raised. Elevation of plasma volume and ascites can increase the volume of distribution (Vd; the proportion of the drug in the body compared to the measurable concentration in the blood) with complications for drugs with a high Vd. The increase in Vd results in slower elimination and a longer half‐life. The liver plays an important role in the elimination of drugs, particularly those reliant on significant metabolism in their elimination pathway, or drugs eliminated through secretion into bile. Drugs eliminated by conjugation to glucuronides, glutathione, or sulfates are also largely eliminated from excretion into bile. Elimination of these compounds will be decreased in the presence of cholestasis. It is also important to consider the presence of active metabolites in the elimination pathway, as this may also affect the safety profile of a medicine. An active metabolite excreted in bile may be increased when the parent drug is not. Metabolism can affect the bioavailability and elimination of a drug, and as the liver is the predominant site of drug metabolism, this is significantly affected in liver disease. Metabolism is usually considered to occur in two phases. Phase I typically results in a metabolite that is more reactive, allowing phase II metabolism to occur successfully. The process is usually completed enzymatically. Phase II typically results in conjugation of the metabolite, with conjugates being more water soluble that are easily excreted. In patients with liver impairment, phase I metabolism is significantly more impaired than phase II, with impairment of CYP expression and activity correlating to the severity of the liver disease [1]. The etiology may also play a part in overall effects on enzyme expression. Pharmacodynamics govern the effect of the drug on receptors and the physiological effect of a drug. In liver impairment, altered receptor sensitivity is unclear, but should be considered for individual drugs. Drugs with a narrow therapeutic index (that is where there is a small difference between therapeutic dose and toxic dose) may have altered pharmacokinetics, with increased adverse effects and should be used with caution. Drugs with cumulative pharmacological effects either from direct or indirect drug–drug interactions should also be used cautiously. A number of pharmacodynamic changes have been noted in liver impairment and should be considered when prescribing drugs affecting these sites of action. Increased effects from drugs acting on the central nervous system should be expected, including when prescribing opiates, anxiolytics, and sedatives. The blood–brain barrier is more permeable, with its association with encephalopathy and patients have increased risk from adverse effects. Opiates are associated with increased respiratory depression in liver disease. Other reported complications include reduced betablocker effect, reduced diuresis and increased risk of infections from proton‐pump inhibitor or histamine type 2 receptor antagonist use [1]. Transjugular intrahepatic portosystemic shunt is reported to increase baseline QT interval prolongation, increasing risks for drugs known to prolong the QT interval. The factors above highlight the complexity of assessing the “safe” use of drugs when prescribing in liver disease. Drugs with minimal metabolism, good oral bioavailability, renal elimination, and few pharmacodynamic and pharmacokinetic interactions are likely to represent favorable characteristics. To prescribe safely in patients with liver disease, it is important to establish the stage of liver disease, underlying pathology, and complications resulting from the patients’ liver disease. Understanding the stage of liver disease will help to suggest changes to the patient’s metabolic or excretory capacity, and therefore how the drug will be handled by the patient. Understanding the pathology can guide specific recommendations relating to how individual drugs are excreted or metabolized. Understanding the complications will guide the safety of drugs which may worsen or exacerbate symptoms already existing from the liver disease. Figure 18.1 presents a flowchart of how to approach the prescribing decision. As described above, optimizing dosing to avoid accumulation of drugs in liver disease can be achieved through assessing the pharmacokinetic and pharmacodynamic particulars of a drug. Drugs with large therapeutic indices are best suited, as dose reductions are unlikely to prevent the drug from being sub‐therapeutic, while ensuring toxicity does not become a problem. Establishing the extent of the patient’s liver impairment and the pharmacokinetic and pharmacodynamic actions of the drug to be prescribed are the backbone to making safe prescribing decisions. This is helpful in identifying drugs which are likely to be problematic, and those which might require dose adjustment or monitoring. Patients with mild fibrosis can be treated in the same way as the general population; where risk factors exist for the development of continuing fibrosis is present, regular blood tests should be completed. In patients with moderate fibrosis without cirrhosis the choice of drug and decision to prescribe needs to consider potential hepatotoxicity, particularly long‐term damage, as prevention of further liver damage, and preservation of the existing liver is important in improving prognosis for the patient. Adjustments to dosing is unlikely to be required, but the prescriber should consider any licensing requirements. When prescribing for patients with cholestatic liver disease, the prescriber should ensure that the elimination profile of the drug is considered to prevent accumulation of biliary‐excreted drugs. Figure 18.1 Prescribing flowchart. For patients with cirrhosis, the clinical condition of the patient should guide prescribing decisions, including both symptoms and staging of liver disease, particularly in those with decompensated cirrhosis. Regular monitoring of liver function should be completed prior to and on starting prescribed medication. This is particularly important for chronically prescribed treatments as liver disease can fluctuate over time. Child–Pugh and MELD (Model for End‐stage Liver Disease) scores can be useful in establishing a prognosis and therefore the likely severity of disease. However, when prescribing drugs without specific recommendations, patients with cirrhosis should be considered to have a degree of liver impairment. In patients with decompensated cirrhosis, the need for a drug should be established as being essential to control the disease. An assessment should be made to establish that the overall goals of the patient’s care is met with relation to overall prognosis. An overarching assessment of all prescribed medicines should be completed, to avoid any pharmacodynamic or pharmacokinetic interactions. It may that be an alternative drug with a safer profile in liver disease should be selected in preference to those more commonly used. The symptoms and complications of liver disease present should be taken into account for the individual patient and the individual drug prescribed. In particular, consideration should be made of: These may affect the decision to start treatment where complications could be worsened by drug treatment. Where a drug is identified as essential and there is no licensing or prescribing advice to support its use, the drug should be started cautiously, with a dose reduction considered. Dose reductions should be made for drugs with: Generally, the oral route of administration is preferred, and intramuscular injections are best avoided, particularly in patients with impaired clotting. With a reduction in function of CYP enzymes expected in decompensated cirrhosis, consideration of drugs that undergo extensive metabolism via these routes should be made in this population (Table 18.3). This is particularly important in patients co‐prescribed drugs that cause CYP inhibition or induction. The effect of CYP inhibition in addition to existing reduced function could cause a significant increase in the levels of the substrate. Specific examples of complications requiring caution when prescribing are shown in Box 18.1. Table 18.3 Cytochrome P450 (CYP) isoforms involved in phase I metabolism and the effect of liver disease on activity. Source: Pirmohamed [1] /with permission of Elsevier.
18
Prescribing in Patients with Abnormal Liver Tests or Liver Disease: A Pragmatic Approach
Introduction
Abnormal Liver Tests
Liver blood test
Simple interpretation
Notes for prescribing
ALT
Continuing hepatocyte inflammation/injury
Increased levels may suggest a DILI after newly started medication
Acute rises often seen in acute liver injury
More specific of hepatic injury
ALP
Continuing hepatocyte inflammation/injury
Consider alongside bilirubin if obstructed bile ducts suspected
Elevated in cholestasis
AST
Continuing hepatocyte inflammation/injury
GGT
Continuing hepatocyte inflammation/injury
Interpret alongside ALP for hepatic origin of elevated ALP
Elevated in cholestasis
Bilirubin (total bilirubin)
Marker of hepatocellular function
Elevated levels may indicate impairment in biliary excretion with implications for drugs excreted in bile
Elevated in chronic and acute liver disease
Albumin
Reduced levels indicate impairment of synthetic function over a long period of time
If abnormal consider chronic cirrhosis
Poor prognostic value in acute liver failure
Sarcopenia may indicate further dose reductions for low body weight
Prothrombin time/international normalized ratio
Raised levels indicate impairment of synthetic function and may reflect an acute derangement in liver function
If abnormal consider chronic cirrhosis
Platelet count
Thrombocytopenia suggests pancreatic involvement in disease and functional impairment of portal flow
If abnormal consider chronic cirrhosis; consider long‐term trend
Drug Licensing for Patients with Liver Disease and Prescribing Guidance
Clinical and biochemical measurements
Points scored for increasing abnormality
1
2
3
Bilirubin (μmol/l)
< 35
35–50
> 50
Albumin (g/dl)
> 35
28–35
< 28
Ascites
Absent
Slight
Moderate or severe
Encephalopathy (grade)
None
1–2
3–4
International normalized ratio
< 1.7
1.7–2.2
> 2.2
Total points: 5–6 = class A; 7–9 = class B 10–15 = class C
Prescribing Hepatotoxic Medication and Drug‐Induced Liver Injury
Idiosyncratic Drug‐Induced Liver Injury
Dose‐Dependent Drug‐Induced Liver Injury
“First Principles” to Consider in Prescribing for Patients with Liver Disease
Absorption
Distribution
Elimination
Metabolism
Prescribing in the Context of Liver Disease
Liver Fibrosis
Cholestatic Liver Disease
Compensated Cirrhosis
Decompensated Cirrhosis
Cytochrome P450 Enzyme System
P450 isoform
Substrates
Effect of liver disease on P450 activity
CYP1A2
Clozapine, theophylline
↓↓↓
CYP2A6
Halothane, methoxyflurane
↓↓
CYP2C9
Diclofenac, losartan, warfarin
↓
CYP2C19
Citalopram, diazepam, omeprazole
↓↓↓
CYP2D6
Codeine, haloperidol, metoprolol, nortriptyline
↔
CYP2E1
Enflurane, halothane, paracetamol
↓
CYP3A4
Amiodarone, carbamazepine, ciclosporin, tacrolimus, diltiazem
↓↓
Related posts:
Stay updated, free articles. Join our Telegram channel
Full access? Get Clinical Tree
