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