Klinische complicaties bij acute en
chronische virale hepatitis
K.J. van Erpecum
Complicaties acute virale
hepatitis
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
Acuut leverfalen
Worm et al. Microbes and Infection 2002
▪ 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. 1970
Klinische presentatie
Worm et al. Microbes and Infection 2002
▪ 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
Hepatische encefalopathie: voorwaarde voor het stellen
van de diagnose
Incidentie en oorzaak van ALF
▪ Europa en US: 1-6/miljoen/jaar
▪ Afhankelijk van werelddeel
Europa & US
1.DILI2.Viraal (A,B,E)3.Onbekend4.AIH5.Ischemisch6.Wilson7.Budd-Chiari8.…
Ontwikkelingslanden
1.Viraal (E,B,A)2.Onbekend3.DILI4.….
Korman. Hepatology 2008;48:1167-74
Alkaline phosphatase/bilirubin ratio <4 very specific and sensitive for
diagnosing Wilson disease in acute liver failure (bili in mg/L).
Acuut leverfalen en kans op overlijden
Worm et al. Microbes and Infection 2002
▪ Afhankelijk van presentatie en oorzaak
▪ Gemiddelde kans: 30 %
▪ Belangrijkste oorzaken van overlijden:
▪ Sepsis /Infectie
▪ Multi-orgaan falen
▪ Hersenoedeem/ inklemming
▪ Bloeding
Diagnostiek bij ALF
▪ Infuus met glucose 5 %
▪ PPI
▪ Antibiotica
▪ N-acetylcysteïne (NAC)
▪ Monitoring van ademhaling, bewustzijn, circulatie, nierfunctie,
leverfuncties, stolling, infectie etc.
Eerste opvang bij patiënt met ALF
▪ 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
Behandeling van acuut leverfalen
➢Pre-emptief starten met antibiotica en
antimycotica
Behandeling van acuut leverfalen
➢Geen stollingscorrectie, tenzij ….
Behandeling van acuut leverfalen
Lisman T et al. J Hepatol 2010
Lisman T et al. J Thromb Haemost 2012
Ganey P et al Hepatology 2007
Bernal W et al. Hepatology 2007
•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 NH3
NH3 < 100 µmol/L: zelden ICP
NH3 > 100 µmol/L ~ ICP
Het grote gevaar: hersenoedeem
Bepalen van prognose
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 drug-
induced
NON-PARACETAMOL
INDUCED ALF
O’Grady J et al. Gastroenterology 1989
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
PARACETAMOL
INDUCED ALF
KING’S COLLEGE HOSPITAL CRITERIA FOR TX IN ALF (KCC)
Complicaties chronische virale
hepatitis
Colombo et al. Hepatology 2006;43:1303-10
Cumulative probability of liver-related events in patients
with compensated cirrhosis due to hepatitis C
varices
Therapy varices: beta blockers and/or
endoscopic band ligation
Small varices Large varicesNo varices
7-8%/year 7-8%/year
Varices may Increase in Diameter Progressively
Merli et al. J Hepatol 2003;38:266
VARICES INCREASE IN DIAMETER PROGRESSIVELY
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
•Stepwise increase until maximally tolerated dose•Continue beta-blocker (life-long)
No Contraindications
ContraindicationsorBeta-blocker intolerance
Beta-blocker therapy
Endoscopic Variceal Band Ligation
*EGD every year in decompensated cirrhosis
MANAGEMENT ALGORITHM FOR THE PROPHYLAXIS OF VARICEAL HEMORRHAGE - SUMMARY
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
• Wat is het streef Hb bij varix bloeding?
A) 4,2 mM
B) 5 mM
C) 6 mM
D) 7 mM
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
Villanueva et al. New Engl J Med January 3, 2013
Restrictive (4.3 mM) vs liberal transfusion (5.6 mM)
strategy for acute GI bleeding
Secondary profylaxis of variceal bleeding
Ascites
Leuco dif:
lymphocytosis!!
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
• 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+ 127 mM, K+ 5.3 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.
Spontaan bacteriele peritonitis
Diagnosis of SBP:
– EDTA tube: ascites granulocytes >0.25x109/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 >0.25x109/L: consider additional blood cultures (low yield of ascites culture).
Rimola. J Hepatol 2000;32:142-53
Additional albumin reduces mortality in
spontaneous bacterial peritonitis
• Rodes et al. New Engl. J. Med. 1999;341:403-9
– 126 SBP pt randomized for cefotaxim + albumin
– albumin 1,5 g/kg on day 1: 1 g/kg on day 3
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
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!
Hepatorenaal syndroom
International Ascites Club, Hepatology 1996
HEPATORENAL SYNDROMECLINICAL 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
SURVIVAL IN THE DIFFERENT TYPES OF HEPATORENAL SYNDROME (HRS)
0 2 4 6 8 1210
Months
1
0.2
0.4
0.6
0.8
Survival
probability
0
Type 2
p = 0.001
Survival in Different Types of Hepatorenal Syndrome (HRS)
Gines et al., Lancet 2003; 362:1819
Type 1
TREATMENT OF HEPATORENAL SYNDROME
VASOCONSTRICTOR DRUGS
Vasopressin analogues
- Terlipressin + albumin
- Ornipressin
Alfa-adrenergic agonists
- Norepinephrine
- Midodrine
Other- Octreotide
HEPATORENAL SYNDROMETERLIPRESSIN. RESPONSE TO TREATMENT
Terlipressin + albumin
Albumin Placebo + albumin
0
20
40
60
80
100
Re
sp
on
se
(%
)
TAHRS trial* North American trial**
44%
9%
34%
13%
p=0.017 p=0.008
* Martín-LLahí M et al., EASL 2007
** Sanyal A et al., AASLD 2006
N:45 N:112
• 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
Contraindications to terlipressin use (15%
complication rate in various studies)
Lebrec. Hepatol 2006;43:385-94
Various forms of renal insufficiency:
ends of a spectrum
PrerenalHepatorenal
syndrome
Acute tubular
necrosis
Volume expansion
(albumin)
Terlipressin +
albumin
Dialysis?
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;68:224-233)
* urine Na+ /serum Na+
urine creat /serum creat X 100Lebrec. Hepatol 2006;43:385-94
Hepatic encephalopathy
Lactulose remains first line therapy for hepatic encephalopathia
51
Resultaten (3)
52
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
Rifaximin and driving performance in minimal hepatic
encephalopathia
Hepatocellular carcinoma
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 0.2-1.5 3-8%/yr
Hepatitis C cirrhosis 1.5 3-5%/yr
Hemochromatosis cirrhosis 1.5 3-4%/year
Alcoholic cirrhosis 1.5 probably >1.5%/year
Stage 4 primary biliary cirrhosis 1.5 3-5%/yr
No cirrhosis
Asian male hepatitis B carriers over
age 40
0.2 0.4-0.6%/year
Asian female hepatitis B carriers over
age 50
0.2 0.3-0.6%/year
Hepatitis B carrier with family history
of HCC
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
Surveillance benefit uncertain: insufficient evidence
to recommend screening
Population group Threshold incidence for
efficacy of surveillance
(%/year)
Incidence of HCC
Cirrhosis due to non-alcoholic
steatohepatitis
??? ↑
Cirrhosis from autoimmune hepatitis 1.5 1.1%/yr
Cirrhosis from α1 antitrypsin deficiency ?? ??
Cirrhosis due to cystic fibrosis ?? ??
Bruix and Sherman, revised AASLD Practice Guideline 2011
Sensitivity of 6-month ultrasound to detect early
HCC (within Milan criteria)
Singal. APT 2009;30:37: Kim et al. Abstract aasld 2007:368
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)
Arterial enhancement and
Venous washout
Yes No
HCC Second imaging
or Biopsy
Bruix and Sherman
revised AASLD Practice Guideline
2011
2 yrs stable: assume benign disease
Key features of hepatocellular carcinoma
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