Endgames Case Report

Jaundiced after a party

BMJ 2011; 342 doi: https://doi.org/10.1136/bmj.d3441 (Published 29 June 2011) Cite this as: BMJ 2011;342:d3441
  1. Luke A E Pratsides, final year medical student1,
  2. Jean Nehme, core surgical trainee2,
  3. Mark R Thursz, professor of hepatology3,
  4. Robert D Goldin, reader in liver and gastrointestinal pathology3
  1. 1Imperial College School of Medicine, London, UK
  2. 2Imperial College Healthcare NHS Trust, London, UK
  3. 3Department of Hepatology and Gastroenterology, St Mary’s Hospital Campus, Imperial College London, London, UK
  1. Correspondence to: L Pratsides luke.pratsides05{at}imperial.ac.uk

A 24 year old male student from Poland attended the emergency department with a one week history of jaundice. He also had orange urine and non-specific abdominal pain, which he attempted to relieve by drinking alcohol. He had experienced no vomiting or change in bowel habit or stool consistency.

There was no history of jaundice, illness, surgery, or blood transfusion. He was not taking any regular drugs and gave no history of drug allergies. He denied intravenous drug abuse but admitted taking ecstasy at a party a fortnight ago. He had recently spent two weeks in Poland over Christmas. During the previous week he had drunk about 21 units of alcohol. He was homosexual but had not been sexually active for two weeks before presentation.

On examination he was afebrile and overtly jaundiced. His abdomen was soft, non-tender, he had no palpable masses, and bowel sounds were present. It was noticed that he had an abdominal piercing. There were no signs of hepatic encephalopathy.

On admission his liver function tests were deranged: alanine aminotransferase (ALT) was 2891 IU/L (reference value <40), alkaline phosphatase (ALP) was 246 IU/L (30-130), bilirubin was 285 μmol/L (<17), albumin was 40 g/L (35-51), and international normalised ratio was 1.2 (0.9-1.2).


  • 1 What is the differential diagnosis?

  • 2 How would you confirm the diagnosis?

  • 3 How can the condition be classified?

  • 4 How would you manage this patient?


1 What is the differential diagnosis?

Short answer

The diagnosis is most likely to be drug induced liver injury associated with MDMA consumption. However, a diagnosis of acute viral hepatitis should be excluded. Alcoholic hepatitis is unlikely with an ALT greater than 300 IU/L (table 1).1

Table 1

 Differential diagnoses in this patient

View this table:

Long answer

Drug induced liver injury is an important cause of liver disease. It ranges from subclinical disease with derangement of liver function tests to acute liver failure. Variability in the presentation means that the diagnosis is often missed and it is therefore difficult to establish the true incidence. A recent review estimated an incidence at 14 cases per 100 000 people a year.2 A study from the United States stated that drug induced liver injury accounts for 12% of all cases of acute liver failure if paracetamol (acetaminophen) is excluded. Acetaminophen itself is responsible for half of all acute liver failure cases in the US.3 Consequently, drug induced liver injury has become the leading cause of fulminant liver failure in people requiring transplantation.

Various drugs and compounds have been implicated in drug induced liver injury. To date, more than 1100 medicinal compounds are known to have caused an episode of drug induced liver injury (table 2).4 These include prescription drugs, over the counter drugs, illicit drugs, and drugs used in complementary or alternative medicine, such as Chinese herbal medicines. A recent review found that analgesics, anticonvulsants, antibiotics, antiretrovirals, and anticancer drugs were the most common types of drugs to cause serious drug induced liver injury.5

Table 2

 Most common types of liver injury caused by drugs5

View this table:

However, cases of MDMA induced liver injury have rarely been reported despite the drug’s long history of use. MDMA was first produced in 1914, by Merck, who patented it as an appetite suppressant. It was used as a mood modifier in the 1970s,6 but during the past 20 years it has been mostly used as a recreational drug under its street name “ecstasy.” It is popular among dance club revellers because it increases energy levels and produces an intense euphoria. The use of MDMA is increasing in the United Kingdom because it is easy to manufacture and the price of tablets has fallen significantly. It is therefore essential that clinicians are aware of its hepatotoxic effects.7

2 How would you confirm the diagnosis?

Short answer

Drug induced liver injury is essentially a diagnosis of exclusion. Exclude other causes of acute liver dysfunction with tests for liver autoantibodies, copper, caeruloplasmin, ferritin, and viral immunology, which are normal in this condition. Hepatobiliary ultrasonography is often normal. A biopsy will show characteristic features of drug induced inflammation.8

Long answer

Drug induced liver injury may be an incidental finding in an asymptomatic patient with deranged liver function tests. The clinical presentation ranges from a non-specific rash, arthralgia, fatigue, and low grade fever with jaundice to fulminant liver failure. A low index of suspicion is needed and the drug history should be thorough—non-prescription and recreational drug use needs to be explored (in particular drugs started in the past three months). However, it may be difficult to identify a single causative agent because patients are often taking multiple drugs.8

The only test that can support the diagnosis is a drug rechallenge, but this is rarely justified because of the possibility of a severe reaction after sensitisation. Drug induced liver injury is therefore a diagnosis of exclusion. A full set of blood tests including liver function tests and coagulation profile allow the severity of the insult to be assessed. The bilirubin concentration can often be used as a marker of severity, whereas albumin determines chronicity. Viral and autoimmune serology are important. The screen should also exclude metabolic diseases such as haemochromatosis or Wilson’s disease. The results of a hepatobiliary ultrasound scan are often normal.8

A liver biopsy is not routinely recommended but may be useful in patients with unexplained acute hepatitis after exclusion of other causes. Many of these patients have deranged coagulation profiles, so the international normalised ratio may need to be corrected with fresh frozen plasma or a transjugular approach to liver biopsy used.

Several pathological features are seen in liver histology of drug induced hepatitis, including an abundance of neutrophils and eosinophils; epithelioid cell granulomas; a poorly developed portal inflammatory reaction; demarcated perivenular (acinar zone 3) necrosis; and minimal hepatitis with canalicular cholestasis. Although centrilobular necrosis with minimal portal inflammation is relatively characteristic of this condition, similar histological features can be seen in acute onset autoimmune hepatitis. Plasma cell infiltration in portal tracts, which is often prominent in autoimmune hepatitis, may be helpful for differential diagnosis in such cases. In most cases changes are non-specific for drug induced liver injury. The main role of histological examination is therefore to exclude other causes of liver injury rather than to make a final diagnosis of drug induced liver injury.8 9

Causality assessment scoring systems are available to assess the likelihood that liver injury is caused by a drug. The most widely used example is the Roussel Uclaf causality assessment method. It consists of seven criteria: time to onset, clinical course, risk factors, concomitant drugs, non-drug causes, previously published information on hepatotoxicity, and response to rechallenge. However, despite its popularity this method is widely open to reviewer variability because of the lack of specific guidelines on how to interpret and score the criteria.10

3 How can the condition be classified?

Short answer

Drug induced liver injury is classified into three types—hepatocellular, cholestatic, and mixed—on the basis of biochemical features. Hepatocellular disease is often more severe, whereas patients with the cholestatic and mixed types are more likely to develop chronic disease.

Long answer

The Councils for International Organisations of Medical Sciences’ classification of drug induced liver injury recognises three types: hepatocellular, cholestatic, and mixed. Hepatocellular injury is defined as ALT more than twice the upper limit of normal or a ratio of serum ALT to serum ALP of 5 or more. Cholestatic injury is defined as ALP more than twice the upper limit of normal or a ratio of serum ALT to serum ALP of 2 or less. Mixed injury is defined as ALT more than twice the upper limit of normal and a ratio of serum ALT to serum ALP of more than 2 but less than 5.10

4 How would you manage this patient?

Short answer

Remove the precipitating agent and then provide supportive care with fluids. If liver failure develops, give prophylactic antibiotics and lactulose to prevent hepatic encephalopathy. This should allow the liver time to recover and liver function to normalise. Assess patients who continue to deteriorate for liver transplantation.

Long answer

The first step is to remove the precipitating agent. The management of established liver failure depends on the severity of the injury. Because of the limitations of liver function tests, both clinical and biochemical findings are used to assess severity. It is therefore essential to assess patients’ neurological status and haemodynamic status daily.

After removing the underlying insult, most patients will improve with supportive treatment such as accurate fluid balance and appropriate nutrition.

Monitor the patient for renal impairment, encephalopathy, and coagulopathy because the risk of acute liver failure is high. Transfer patients with acute liver failure to a liver unit with transplantation facilities.

In the minority of patients who continue to deteriorate despite supportive treatment a liver transplant is necessary. The King’s College Hospital criteria (box) can be used to assess adverse prognostic factors and help clinicians ascertain the need for liver transplantation.11

King’s College Hospital criteria for liver transplantation11

Acetaminophen induced disease
  • Arterial pH <7.3 (irrespective of the grade of encephalopathy)

  • Or all three of the following:

    • Grade III or IV encephalopathy

    • Prothrombin time >100 sec

    • Serum creatinine >301 μmol/L

All other causes of fulminant hepatic failure
  • Prothrombin time >100 sec (irrespective of the grade of encephalopathy)

  • Or any three of the following variables (irrespective of the grade of encephalopathy):

    • Age <10 years or >40 years

    • Cause: seronegative for hepatitis A and B virus, halothane hepatitis, idiosyncratic drug reactions

    • Duration of jaundice before onset of encephalopathy >7 days

    • Prothrombin time >50 sec

    • Serum bilirubin 308 μmol/L

These criteria were modified after a study suggested that patients should be considered for liver transplantation if arterial pH is less than 7.3 after adequate fluid resuscitation.12 The study also indicated that patients with an arterial lactate concentration greater than 3 mmol/L should be considered,12 and a modified version that includes arterial lactate has been adopted by Transplant UK as part of their guidelines for adult liver transplantation.13

Patients can be discharged from hospital once liver function is steadily returning to normal and they are clinically well. Outpatient follow-up is necessary until liver function tests completely normalise. Make patients aware that they must avoid the suspected drug and educate them to spot signs of recurrence of liver failure, such as jaundice, so that any future episodes can be dealt with as early as possible.

Patient outcome

During the first two days of his admission the patient’s liver function deteriorated greatly. He was diagnosed with early fulminant hepatic failure and was managed conservatively with nutritional support, fluid support, and strict biochemical surveillance. The possibility of a liver transplant was discussed.

However, after day seven of his admission, with continued supportive management, his liver function steadily improved. He was discharged after 16 days and was followed up in the outpatients’ clinic. Twenty eight days after discharge from hospital his liver function normalised.


Cite this as: BMJ 2011;342:d3441


  • Competing interests: All authors have completed the ICMJE uniform disclosure form at www.icmje.org/coi_disclosure.pdf (available on request from the corresponding author) and declare: no support from any organisation for the submitted work; no financial relationships with any organisations that might have an interest in the submitted work in the previous three years; no other relationships or activities that could appear to have influenced the submitted work.

  • Provenance and peer review: Not commissioned; externally peer reviewed.

  • Patient consent obtained.


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