Klinische complicaties bij acute en chronische virale hepatitis. K.J. van Erpecum

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1 Klinische complicaties bij acute en chronische virale hepatitis K.J. van Erpecum

2 Complicaties acute virale hepatitis

3 Wat staat oa in de DD bij AST en/of ALT > 1000 IU/mL Alcohol hepatitis altijd relatief lage transaminasen: AST<500, ALT<250 Belangrijkste oorzaken: paracetamol, ischemische hepatitis, viraal, choledocholithiasis. Medicamenteus, homeopathie, kruiden autoimmuun hepatitis, 10% van choledocholithiasis transen > 1000IU/mL in eerste 48 uur

4 Acuut leverfalen Zeldzaam ziektebeeld Hoge mortaliteit Kenmerken: Gestoorde stolling (INR > 1.5) Hepatische encefalopathie Geen onderliggende leverziekte Duur ziekte < 24 weken Uitsluiten van acute-on-chronic liver failure Polsen J,Lee WM, Hepatology 2005; O Grady JG et al. Lancet 1993, Trey C and Davidson CS, Prog Liver Dis Worm et al. Microbes and Infection 2002

5 Klinische presentatie Acuut ziektebeeld +/- na inname van paracetamol / amanita / XTC etc. Buikpijn, malaise, ziek, verward Icterus Hoge transaminasen Gestoorde stolling Progressief beeld met oligurie, metabole acidose, hypotensie Worm et al. Microbes and Infection 2002

6 Hepatische encefalopathie: voorwaarde voor het stellen van de diagnose

7 Incidentie en oorzaak van ALF Europa en US: 1-6/miljoen/jaar Afhankelijk van werelddeel Europa & US 1.DILI 2.Viraal (A,B,E) 3.Onbekend 4.AIH 5.Ischemisch 6.Wilson 7.Budd-Chiari 8. Ontwikkelings landen 1.Viraal (E,B,A) 2.Onbekend 3.DILI 4..

8 Alkaline phosphatase/bilirubin ratio <4 very specific and sensitive for diagnosing Wilson disease in acute liver failure (bili in mg/l). Korman. Hepatology 2008;48:

9 Acuut leverfalen en kans op overlijden Afhankelijk van presentatie en oorzaak Gemiddelde kans: 30 % Belangrijkste oorzaken van overlijden: Sepsis /Infectie Multi-orgaan falen Hersenoedeem/ inklemming Bloeding Worm et al. Microbes and Infection 2002

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11 Diagnostiek bij ALF

12 Eerste opvang bij patiënt met ALF Infuus met glucose 5 % PPI Antibiotica N-acetylcysteïne (NAC) Monitoring van ademhaling, bewustzijn, circulatie, nierfunctie, leverfuncties, stolling, infectie etc.

13 Behandeling van acuut leverfalen Opname op intensive care Oorzakelijke behandeling (NAC, bevalling, lamivudine, steroïden) Intubatie bij HE graad 3 of 4 Herstel van circulatie (MAP > 65 mm Hg) Voorkomen en behandelen van complicaties

14 Behandeling van acuut leverfalen Pre-emptief starten met antibiotica en antimycotica

15 Behandeling van acuut leverfalen Geen stollingscorrectie, tenzij. Lisman T et al. J Hepatol 2010 Lisman T et al. J Thromb Haemost 2012 Ganey P et al Hepatology 2007

16 Het grote gevaar: hersenoedeem Neurologische complicaties : hersenoedeem intracraniale hypertensie Pathogenese : circulerende neurotoxinen Incidentie Hersenoedeem & ICH graad 1 & 2 : zeldzaam graad 3 : 25-35% graad 4 : 65-75% Regelmatig klinisch neurologisch onderzoek Biochemische parameter : arterieel NH 3 NH 3 < 100 µmol/l: zelden ICP NH 3 > 100 µmol/l ~ ICP Bernal W et al. Hepatology 2007

17 Bepalen van prognose KING S COLLEGE HOSPITAL CRITERIA FOR TX IN ALF (KCC) NON-PARACETAMOL INDUCED ALF PARACETAMOL INDUCED ALF Either: PT > 100s (INR > 6.5) (encephalopathy present but irrespective of grade) or Any 3 of the following (encephalopathy present but irrespective of grade) patient age < 10 or > 40 years serum bilirubin > > 300 umol/l time jaundice to HE > 7 days PT > 50s (INR > 3.5) etiology: non hepatitis A/B or druginduced Either: arterial ph < 7,3 following adequate volume resuscitation and irrespective of HE grade or all 3 of the following criteria HE grade III-IV PT > 100s (INR > 6.5) serum creatinin > 300 umol/l O Grady J et al. Gastroenterology 1989

18 Complicaties chronische virale hepatitis

19 Cumulative probability of liver-related events in patients with compensated cirrhosis due to hepatitis C Colombo et al. Hepatology 2006;43:

20 varices

21 Therapy varices: beta blockers and/or endoscopic band ligation

22 VARICES INCREASE IN DIAMETER PROGRESSIVELY Varices may Increase in Diameter Progressively No varices Small varices Large varices 7-8%/year 7-8%/year Merli et al. J Hepatol 2003;38:266

23 MANAGEMENT ALGORITHM FOR THE PROPHYLAXIS OF VARICEAL HEMORRHAGE - SUMMARY Prophylaxis of Variceal Hemorrhage Diagnosis of Cirrhosis Endoscopy No Varices Follow-up EGD in 2-3 years* Small Varices Follow-up EGD in 1-2 years* Medium/Large Varices *EGD every year in decompensated cirrhosis Beta-blocker therapy Stepwise increase until maximally tolerated dose Continue beta-blocker (life-long) No Contraindications Contraindications or Beta-blocker intolerance Endoscopic Variceal Band Ligation

24 Primary prophylaxis for variceal bleeding NSBB: Propranolol, starting dose 10 mg BID Endoscopic follow-up in patients with primary prophylaxis with NSBB is unnecessary In patients who have contraindications to NSBB EVL. de Franchis. J Hepatology 2010

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26 Wat is het streef Hb bij varix bloeding? A) 4,2 mm B) 5 mm C) 6 mm D) 7 mm

27 Restrictive (4.3 mm) vs liberal transfusion (5.6 mm) strategy for acute GI bleeding Villanueva et al. New Engl J Med January 3, 2013

28 Restrictive (4.3 mm) vs liberal transfusion (5.6 mm) strategy for acute GI bleeding Villanueva et al. New Engl J Med January 3, 2013

29 Secondary profylaxis of variceal bleeding

30 Ascites

31 Leuco dif: lymphocytosis!!

32 Therapeutic considerations ascites : sodium restriction (5 g NaCl/2 g Na + /88 mmol Na + ) aldactone 100 mg + furosemide 40 mg (cave hyperkalemia, especially in diabetics/renal insufficiency) Measure: weight loss (<0.5-1 kg/day: if significant edema faster weight loss allowed) 24 hrs urinary Na + and creatinin excretion (or Na + / K + ratio in spot urine) Alternative: large volume paracentesis, TIPS

33 An cirrhotic ascites patient is treated with dietary sodium restriction, aldactone 200 mg, furosemide 60 mg, but ascites does not decrease and weight tends to increase. Laboratory results: serum Na mm, K mm, creat 138 mm, 24 hr urinary Na + excretion 160 mmol: Your conclusion is A) diuretic resistance due to impending hepatorenal syndrome B) patient not compliant to instituted therapy, needs further counselling C) patient needs water restriction D) diuretic dosage should be increased E) large volume therapeutic paracentesis is indicated.

34 Spontaan bacteriele peritonitis

35 Diagnosis of SBP: EDTA tube: ascites granulocytes >0.25x10 9 /L, with or without positive culture Clotting disorders no contraindication to diagnostic puncture Ascites leuco dif (automatic count in edta vial) bedside inoculation aerobic/anaerobic blood culture bottles (>10 ml) In case of granulocytes >0.25x10 9 /L: consider additional blood cultures (low yield of ascites culture). Rimola. J Hepatol 2000;32:142-53

36 Additional albumin reduces mortality in spontaneous bacterial peritonitis Rodes et al. New Engl. J. Med. 1999;341: SBP pt randomized for cefotaxim + albumin albumin 1,5 g/kg on day 1: 1 g/kg on day 3

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39 Post-hoc analysis: albumin benefits subgroups of SBP patients with high bili/renal insufficiency Benefit albumin in subgroups of spontaneous bacterial peritonitis patients with: bili > 70 umol/l creatinin > 110 umol/l

40 Spontaneous bacterial peritonitis: prophylaxis After first episode of SBP secondary prophylaxis with norfloxacin 400 mg/day often emergence gram-positive quinolone resistant microorganisms. Stop if ascites disappears!

41 Hepatorenaal syndroom

42 HEPATORENAL SYNDROME CLINICAL TYPES Type 1 - Rapidly progressive renal failure: - Clinical presentation: acute renal failure - Often in setting of infection (SBP) Type 2 - Stable/gradually progressive renal failure - Clinical setting: refractory ascites International Ascites Club, Hepatology 1996

43 SURVIVAL IN THE DIFFERENT TYPES OF HEPATORENAL SYNDROME (HRS) Survival in Different Types of Hepatorenal Syndrome (HRS) Survival probability Type 2 p = Type 1 Gines et al., Lancet 2003; 362: Months

44 TREATMENT OF HEPATORENAL SYNDROME VASOCONSTRICTOR DRUGS Vasopressin analogues - Terlipressin + albumin - Ornipressin Alfa-adrenergic agonists - Norepinephrine - Midodrine Other - Octreotide

45 Response (%) HEPATORENAL SYNDROME TERLIPRESSIN. RESPONSE TO TREATMENT N:45 N:112 p=0.017 p= % 34% % TAHRS trial* 13% North American trial** Albumin Terlipressin + albumin Placebo + albumin * Martín-LLahí M et al., EASL 2007 ** Sanyal A et al., AASLD 2006

46 Contraindications to terlipressin use (15% complication rate in various studies) History of coronary artery disease Dilated and non-dilated cardiomyopathies Cardiac arrithmias Cerebrovascular disease Obliterative arterial disease of lower limbs Hypertension Asthma, chronic obstructive pulmonary disease Age > 70 years Lebrec. Hepatol 2006;43:385-94

47 Various forms of renal insufficiency: ends of a spectrum Prerenal Volume expansion (albumin) Hepatorenal syndrome Terlipressin + albumin Acute tubular necrosis Dialysis?

48 Some clues to differentiate between hepatorenal syndrome type 1 (responsive) and acute tubular necrosis (non-responsive) HRS type 1 Acute tubular necrosis Recent shock no frequent Recent nephrotoxic drugs no frequent Fractional Na + excretion * <1% >1% Fractional Ureum excretion: ATN >33% / prerenal 21-33% /HRS <21% ((HEPATOLOGY 2018;68: ) Lebrec. Hepatol 2006;43: * urine Na+ /serum Na+ urine creat /serum creat X 100

49 Hepatic encephalopathy

50 Lactulose remains first line therapy for hepatic encephalopathia

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52 Resultaten (3) 52

53 Conclusie Rifaximin verlaagt het risico op ontstaan van HE in combinatie met lactulose Rifaximin in combinatie met lactulose is effectiever dan lactulose als monotherapie Vermindert het aantal ziekenhuisopnames 53

54 Rifaximin and driving performance in minimal hepatic encephalopathia

55 Hepatocellular carcinoma

56 Surveillance for hepatocellular carcinoma Ultrasound every 6 months with or without alfa fetoprotein Population group Cirrhosis Threshold incidence for efficacy of surveillance (%/year) Incidence of HCC Hepatitis B cirrhosis %/yr Hepatitis C cirrhosis %/yr Hemochromatosis cirrhosis %/year Alcoholic cirrhosis 1.5 probably >1.5%/year Stage 4 primary biliary cirrhosis %/yr No cirrhosis Asian male hepatitis B carriers over age 40 Asian female hepatitis B carriers over age 50 Hepatitis B carrier with family history of HCC %/year %/year 0.2 Incidence higher than without family history African/North Am. Blacks>20 yrs 0.2 HCC occurs at a younger age Bruix and Sherman, revised AASLD Practice Guideline 2011

57 Surveillance benefit uncertain: insufficient evidence to recommend screening Population group Cirrhosis due to non-alcoholic steatohepatitis Threshold incidence for efficacy of surveillance (%/year) Incidence of HCC??? Cirrhosis from autoimmune hepatitis %/yr Cirrhosis from α1 antitrypsin deficiency???? Cirrhosis due to cystic fibrosis???? Bruix and Sherman, revised AASLD Practice Guideline 2011

58 Sensitivity of 6-month ultrasound to detect early HCC (within Milan criteria) Singal. APT 2009;30:37: Kim et al. Abstract aasld 2007:368

59 Algorithm for investigation of small nodules found on screening in patients at risk for HCC Suspicious Nodule < 1cm > 1cm Repeat imaging every 3 mos Dynamic imaging (4 phase CT scan, MRI) 2 yrs stable: assume benign disease Arterial enhancement and Venous washout Bruix and Sherman revised AASLD Practice Guideline 2011 Yes HCC No Second imaging or Biopsy

60 Key features of hepatocellular carcinoma