Drug-Induced Liver Disease Flashcards
Drug Induced Liver Disease
Drug-induced liver disease is generally divided into hepatocellular, cholestatic or mixed. There is however considerable overlap, with some drugs causing a range of changes to the liver
Drugs causing a Hepatocellular Picture
The following drugs tend to cause a hepatocellular picture: paracetamol sodium valproate, phenytoin MAOIs halothane anti-tuberculosis: isoniazid, rifampicin, pyrazinamide statins alcohol amiodarone methyldopa nitrofurantoin
Drugs causing a Cholestatic Picture
The following drugs tend to cause cholestasis (+/- hepatitis):
Antibiotics: flucloxacillin, co-amoxiclav, erythromycin*
COCP and testosterones
Anabolic steroids
phenothiazines: chlorpromazine, prochlorperazine
sulphonylureas
fibrates
rare reported causes: nifedipine
*risk may be reduced with erythromycin stearate
Drugs causing Liver Cirrhosis
Liver cirrhosis
methotrexate
methyldopa
amiodarone
Drug induced Abnormal LFTs - Example Question
A 55-year-old male was referred to the gastroenterology clinic after presenting with a 3-month history of yellow discolouration of his skin. He stated that his skin had become rather itchy, and in addition, his urine had become darker. After following the ‘Abnormal Liver Function Test Protocol’ the GP referred the patient to the clinic, having not been able to identify a cause of his symptoms. The gentleman was otherwise well in himself, denying the presence of abdominal pain, bloating or weight loss. He smoked 10 cigarettes per day and consumed 42 units of alcohol per week. His past medical history comprised diet controlled type 2 diabetes mellitus, hypertension, hypercholesterolaemia and asthma for which he was prescribed amlodipine 5mg OD, simvastatin 40mg ON, Seretide 125 BD and salbutamol PRN. Of note, he has hospitalised 4 months ago with pneumonia and was treated with 2 days of intravenous co-amoxiclav, before being switched over to oral co-amoxiclav for a further five days.
Examination revealed the presence of a well male, with a temperature of 37.1 C, heart rate of 72 bpm, respiratory rate of 16 and blood pressure of 152/76 mmHg. He appeared mildly jaundiced but other than this examination of his gastrointestinal system was unremarkable. Examination of his cardiovascular and respiratory systems was otherwise also unremarkable.
Initial investigations revealed:
Hb 139 g/l
Platelets 222 * 109/l
WBC 6.1 * 109/l
INR 1.0
HbA1c 52 mmol/mol Bilirubin 62 µmol/l ALP 112 u/l AST 24 u/l ALT 26 u/l γGT 64 u/l Albumin 38 g/l Protein 78 g/l Adj calcium 2.32 mmol/l
Anti nuclear antibody negative p-ANCA negative c-ANCA negative Anti-mitochondrial antibodies negative Anti smooth muscle antibodies negative Anti liver and kidney antibodies negative Serum electrophoresis normal appearance
USS liver, abdomen and pancreas: normal appearance of all intraabdominal organs including that of liver and pancreas. Normal appearance of the biliary tree.
What is the most likely diagnosis?
> Cholestasis secondary to co-amoxiclav Non alcoholic steatohepatitis (NASH) Alcoholic hepatitis Primary biliary cirrhosis Primary sclerosing cholangitis
His liver function tests here illustrate a cholestatic picture with the presence of raised ALP GGT and bilirubin but with normal ALT and AST. This in conjunction with the normal ultrasound scan makes the diagnosis of NASH very unlikely, which tends to manifest with a raised ALT and classic ultrasound appearances. It also makes the diagnosis of alcoholic hepatitis less likely. Of the remaining options, there is a history of co-amoxiclav exposure which combined with a normal autoantibody screen and a well gentleman makes answer 1 the most likely option. Other drugs causing cholestasis include flucloxacillin, sulphonamides and the oral combined contraceptive pill.
When to stop N-Acetylcysteine in Paracetamol OD? - Example Question
A 23-year-old woman is reviewed following admission for paracetamol overdose. She ingested 25 grams of paracetamol and was started on N-acetylcysteine as her paracetamol level was 812 micromol/L eight hours following ingestion. She feels well, denying any abdominal pain or other symptoms. At what point should N-acetylcysteine be stopped?
> When INR <1.3 and ALT less than 2x upper limit When abdominal pain resolved When pH is >7.35 When paracetamol levels become undetectable After 48 hours
The correct answer is when INR <1.3 and ALT less than 2x upper limit. Note that the primary measure of synthetic liver function is clotting which is why it is so closely monitored in paracetamol overdose and helps indicate when the liver is improving. pH is a useful measure for criteria for a liver transplant but is not helpful in most cases as it generally remains normal despite severe liver dysfunction. Abdominal pain is often present but not always and is therefore not a very sensitive marker. Paracetamol levels do not reflect the extent of liver damage and they can be very difficult to interpret in staggered overdoses. Depending on the extent of liver damage, treatment may need to be longer than 48hrs and in some cases shorter.
Antibiotics > Abnormal LFTs - Example Question
A 62 year old patient is referred to the acute medical service with jaundice. This has come on suddenly in the last few days. The patient denies any excessive alcohol consumption drinking only the occasional glass of wine every other week. There only previous history of note is recurrent urinary tract infections. This has been managed in the community with once daily prophylactic antibiotics.
Liver function tests reveal:
Total bilirubin 74 µmol/l Unconjugated bilirubin 35 µmol/l Conjugated bilirubin 39 µmol/l ALP 110 u/l AST 219 u/l
What is the most likely causative agent for these results?
Cephalexin Co-amoxiclav Amoxicillin Trimethoprim > Nitrofunrantoin
The results above represent a hepatocellular cause of jaundice. This is shown from the elevated unconjugated bilirubin levels and differentiates it from a post-hepatic (obstructive) jaundice. All of the agents above can cause a cholestatic (obstructive) picture but the most likely cause of a hepato-cellular janudice is nitrofurantoin. This occurs with chronic use of the medication. It is associated with hepatic necrosis and should be stopped immediately when there is any evidence of hepatic necrosis. The side effects of nitrofurantoin can be fatal and as such attention must be paid to its appearance on a drug history. Toxic effects can manifest as hepatic disease as shown here but also as both an acute and chronic respiratory condition, agranulocytosis and the acute hypersensitivity reaction of Stevens-Johnson Syndrome.
There is no clear guidance in the use of antibiotic prophylaxis in adult patients. However, recent Cochrane review questioned the use in children. The other common advice given to patients is to drink cranberry juice to prevent further infections, but this again has not been backed up by the study data. Therefore there is currently no consensus, but recurrent UTI should warrant further investigations by either a gynaecologist or urologist in adults and most certainly a paediatrician in children.
Drug- Induced Pruritis and Jaundice - Example Question
A 62 year old man presents to the medical assessment unit with intense pruritus and jaundice. He has recently been prescribed a new medication from his GP, but cannot remember the name.
His blood tests reveal the following:
Bilirubin 78 µmol/l
ALP 300 u/l
ALT 50 u/l
γGT 45 u/l
Which of the following medications would most likely be responsible?
Metformin > Flucloxacillin Ibuprofen Sodium valproate Doxycycline
These liver function tests, are example of cholestatitic jaundice. The alkaline phosphatase and the bilirubin are raised out of proportion to the liver transaminases.
Common drugs causing cholestasis: Flucloxacillin Erythromycin Chlorpromazine Oral contraceptives Anabolic steroids
Anaesthetic-related Hepatitis - Example Question
You are asked to review a 29-year-old man who is an inpatient on the orthopaedic ward having undergone emergency surgery for a fractured femur some 36hrs earlier. Surgery was uneventful, there were no significant episodes of hypotension. The staff are concerned as they have seen a marked rise in his transaminases since the surgery. He has no past medical history of note and takes no regular medication. On examination his blood pressure is 115/80 mmHg, his pulse is 80 beats per minute and regular. He is apyrexial and looks comfortable at rest. Abdomen is soft and non-tender with no masses. His leg is elevated in a cast.
Investigations reveal:
Bilirubin 22 µmol/l ALP 220 u/l ALT 1150 u/l γGT 520 u/l Albumin 32 g/l
Which of the following is the most likely diagnosis?
> Anaesthetic related hepatitis Hepatic ischaemia Staphylococcal septicaemia Transfusion reaction Viral hepatitis
Although the incidence of anaesthetic related hepatitis has decreased over recent years with the introduction of modern agents such as desflurane and sevoflurane, cases are still reported. The rapid rise in transaminases, gamma GT and alkaline phosphatase so soon after surgery fits well with the diagnosis. Supportive therapy is the only option, no therapeutic interventions, (including corticosteroids), have proved effective.
https://www.ncbi.nlm.nih.gov/pubmed/19455019
Hepatic ischaemia is unlikely given there were no episodes of hypotension during the course of surgery. Staphylococcal septicaemia would be unlikely to present only with symptoms of hepatitis, and a transfusion reaction would be seen in much closer proximity to the transfusion itself. Viral hepatitis would be subject to an interval of 2-3 weeks before symptoms occur.
Anaesthetic-related Hepatitis
Although the incidence of anaesthetic related hepatitis has decreased over recent years with the introduction of modern agents such as desflurane and sevoflurane, cases are still reported.
Presentation = rapid rise in transaminases, gamma GT and alkaline phosphatase immediately after surgery fits well with the diagnosis.
Mx: Supportive therapy is the only option, no therapeutic interventions, (including corticosteroids), have proved effective.
