1. Acute Liver Failure Dr Andrew Yeoman Consultant Hepatologist ABUHB

2. Aims This talk will: Include real life cases Hopefully provide useful pointers to identify those with a poor prognosis Highlight important considerations as to the likely cause of ALF This talk will not: Cover all aspects of the management of ALF Give you the answer to every clinical scenario!

3. Acute Liver Failure Rare clinical syndrome whereby an acute hepatitic process leads to liver and subsequent multi-organ failure Causes are multiple and treatment options are very different depending on the cause Rapid identification of the cause is essential as delays in diagnosis can lead to significant morbidity, mortality or the need for super-urgent liver transplantation

4. ALF Clinical Triad Jaundice Coagulopathy Encephalopathy Note: some patients not jaundiced (POD, AFLP) NB: Jaundice, raised INR and AST elevation represent acute, severe liver DYSFUNCTION Encephalopathy is the sine qua non of ALF

5. ALF Acute liver failure can be further subdivided on the basis of time taken to encephalopathy Hyperacute < 7 days Acute : 8-28 days Sub acute: 29-84 days Other classification: Fulminant <2 weeks Sub fulminant > 2 weeks Chronic disease is of > 6 months duration

6. Aetiology Aetiology of ALF in UK; 544 KCH admissions 1999-2005

7. Importance of Aetiology

8. Case 1 Male – 49 years of age with a history of depression Presented to A&E 31/01/2014 -Lethargy and abdo pain 3 days prior had taken mephadrone - developed abdominal pain – central and constant since Took 48 paracetamol over 2-4 hrs from 09:30 29/01/2014 Bloods at 01:07 on 31/01/2014 (40 hours post ingestion) Bili 81, ALT 6775, Alb 38 U 12.3 Cr 249 Hb 14.3, WCC 19.1 Plts 30 INR 4.3 Paracetamol 31

9. Case 1 On examination looked unwell but not confused Shivering, temp 34.5, P 115, BP 109/42 BM 6.5 Initial management – Fluid resus/Parvolex/Broad spectrum antibiotics Other investigations: ABG Lactate Ammonia Amylase

10. Other Investigations Calcium 2.34 mmol/l 2.20-2.60 PHOS Phosphate 4.24 mmol/l H 0.80-1.50 Ammonia: 98

11. Clinical progress Transferred to ITU Aggressive fluid resus and CVVHF 31/01/2012 15:30 (45 hours since ingestion)– Bilirubin 120, ALT 4567, INR 6.9, Creatinine 190 Now confused – ammonia at 15:30 on 31/01/2012 = 151 Grade III HE Intubated and ventilated and transferred to Birmingham Met listing criteria and underwent LT 3 days later Stormy post op course with sepsis and required 4 months of rehab Well now 3 years post LT

12. Prognostication in ALF Degree of HE is best prognostic indicator in ALF Ammonia predicts degree of HE INR however is the most useful dynamic marker of hepatic function Other helpful markers? Other considerations?

13. Alternative markers of poor prognosis in POD induced ALF PT in relation to hours since OD very helpful If PT > in secs than no of hours since OD then patient is headed for trouble PT peaks 72 hrs post ingestion Phosphate can be a marker of poor prognosis AFP may also be a useful marker A high amylase doesn’t necessarily mean a poor prognosis but severe pancreatitis may preclude liver transplantation

14. Super Urgent Liver Scheme: Paracetamol Category 1: Aetiology: Paracetamol poisoning: pH <7.25 more than 24 hours after overdose and after fluid resuscitation Category 2: Aetiology: Paracetamol poisoning: Co-existing prothombin time >100 seconds or INR >6.5, and serum creatinine >300 μmol/l or anuria, and grade 3-4 encephalopathy Category 3: Aetiology: Paracetamol poisoning: Serum lactate more than 24 hours after overdose >3.5 mmol/l on admission or >3.0 mmol/l after fluid resuscitation Category 4: Aetiology: Paracetamol poisoning: Two of the three criteria from category 2 with clinical evidence of deterioration

15. Learning points PT in relation to time of ingestion is useful marker of need for LT – peaks 72 hrs Degree of HE remains best prognostic marker High Phosphate also identifies those who have “run out of gas” Don’t forget about amylase in those with abdominal pain Low platelets & v high creatinine seen in <24 hrs as direct toxic effects Older age patients >40 do less well with ALF

16. Case 2 45 year old male Fit and well, no past medical history, no regular meds Attended MAU 19/04/2013 Malaise, weight loss fatigue, jaundice, Bloods: Bili 68, ALT 1609, ALP 264, Globulin 38 U 6.4 Creat 98 INR 1.0

17. What now? USS: Normal Viral screen (A, B, C neg, E pending) Autoimmune profile –ve ANA, LKM, weakly +ve SMA Immunoglobulins – IgG 15.8 (ULN 16.1) Ferritin 2500

18. Case 2: Progress 22/04/2013 – Bili 84, ALT 1750, Globulin 40, INR 1.0, Cr 100 Re-admitted 28/04/2013 under surgeons Bili 85, ALT 1540 Cr 95 MRCP normal DC 4 th May with bilirubin now >100 for urgent hepatology fu but liver biopsy arranged 14/05/2013 – pre liver biopsy bloods Bili 540, ALT 2146, PT 13.5 secs

19. Case 2: Progress Biopsy undertaken 14 th May as a day case Re-admitted late 20 th may with increasing lethargy Defined to Hepatology and seen following day Bili 560, ALT 2919, PT 18.6 Mild liver flap What did we do?

20. Case 2: Liver biopsy There is a considerable degree of hepatitis. There is a mixed inflammatory cell infiltrate comprising lymphocytes, neutrophils and some eosinophils these are seen both in the parenchyma and in portal tracts. The edges of portal tracts are considerably blurred suggesting piecemeal necrosis There is perhaps some fibrous expansion of the portal tracts of uncertain significance.

21. Progress Diagnosis: AIH induced ALF IV hydrocortisone – 200mg stat then 100mg tds IV Tazocin Discussion with Birmingham re transfer and listing By following day – flap resolved, symptomatically better

22. Clinical Progress

23. Super-Urgent Liver Scheme: Non paracetamol Category 5: Aetiology: Seronegative hepatitis, Hep A, Hep B, or an idiosyncratic drug reaction. Prothrombin time >100 seconds or INR >6.5, and any grade of encephalopathy Category 6: Aetiology: Seronegative hepatitis, Hep A/B or an idiosyncratic drug reaction. Any grade of encephalopathy, and any three from the following: unfavourable aetiology (idiosyncratic drug reaction, seronegative hepatitis), age >40 years, jaundice to encephalopathy time >7 days, serum bilirubin >300μmol/l or INR >3.5 Category 7: Aetiology: Acute presentation of Wilson’s disease, or Budd-Chiari syndrome. A combination of coagulopathy, and any grade of encephalopathy

24. Learning points Unexplained jaundice remains a medical emergency Refer patients early Biopsy as soon as possible if LFTs worsening Acute severe presentations of AIH autoantibodies & IgG may be normal Don’t regard a LT as being a success – exposed someone to a very major operation & committed them to far more intensive immunosuppression than is otherwise often needed

25. Case 3 39 year old female History of previous ETOH abuse (60u per week) Presents 29/40 in 1 st pregnancy on 11/03/2015 RUQ pain, high fever T 39, generally unwell Bloods on admission Bili 16, ALT 750, ALP 270, Albumin 28, CRP 378, Creatinine 76 Been diagnosed with ICP 5 days earlier on basis of ALT of 253 and bile acids of 33 but no itch. Commenced on Urso

26. 3 rd Case USS: enlarged bright liver, trace of ascites Repeat bloods – Bili 16, ALT 850 Other bloods: Lactate 1.8, Ammonia 33, Amylase 33 LDH 1110 Platelets 250 PT 11.4 Fib 5.6

27. 3 rd Case Hepatology consult: Likely systemic insult secondary to viral process On 13 th March becomes more unwell acutely confused drops GCS to 8 blood glucose drops to 3.3 (GCS does not respond to glucose) BP also drops and becomes more tachycardic What is the diagnosis and what would you do/advise O&G?

28. Progress Emergency CS as gynae felt this was probably AFLP & patient unstable Liver biopsy arranged at same time Patient deteriorates further with respiratory sepsis and grows candida in blood cultures

29. Diagnosis: Liver Biopsy Liver biopsy: The normal architecture of the liver is preserved. However, there are areas of hepatic necrosis with acute inflammatory response. Some of the hepatocytes show intra nuclear inclusions raising the possibility of viral infection. There is minimal fatty change. Throat swabs: HSV Serology: Confirms acute HSV with high viral load Commences acyclovir, prolonged ITU phase with readmissions due to pneumonia but eventually clears virus and leaves hospital with a healthy infant

30. Why this was NOT pregnancy related LD This was not PET or HELP as no criteria met - Was it AFLP?? Swansea Criteria for AFLP = six or more following in absence of another cause: Vomiting - no abdominal pain - yes polydipsia/polyuria - no encephalopathy – no but ? elevated bilirubin > 14 µmol/l - no hypoglycaemia < 4 mmol/l - yes elevated urea > 340 µmol/l - No leucocytosis > 11 x 10⁹ /l - Yes ascites or bright liver on ultrasound scan - yes elevated transaminases (AAT or ALT) > 42 IU/l - yes elevated ammonia > 47 µmol/l - no renal impairment: creatinine > 150 µmol/l - no coagulopathy: prothrombin time > 14 seconds or APPT > 34 seconds - no microvesicular steatosis on liver biopsy – noliver biopsy

31. Learning points Important to consider ALF mimics Remember if it doesn’t quite fit – think again consider biopsy don’t forget the “other” viruses in acute severe liver injury – throat swabs Beware heuristics!! Other rare multisystem disorders that can mimic liver failure: DRESS syndrome Adult stills HLH

32. Summary ALF remains a rare entity with a multitude of causes each with different disease trajectories Remains difficult to predict which patient will develop ALF ALF however carries a high morbidity and mortality Failure to identify early can have catastrophic consequences “Miss the boat” for LT or unnecessary LT had specific therapies been used earlier High index of suspicion and early specialty input essential to ensure optimal outcomes