Ischemic hepatitis

Teepawit Witeerungrot, MD.

NKC Institute of Gastroenterology and Hepatology

Songklanagarind Hospital, PSU

Contents

• Pathogenesis

• Clinical causes and features

• Diagnosis

• Management and prognosis

Ischemic hepatitis

• Acute liver injury

• Mainly cause by insufficiency of oxygen uptake by

the hepatocyte.

• Massive transient rise in serum aminotransferase

activities caused by anoxic necrosis of

centrilobular liver cells.

• Common finding in critically illness patients.

• Asscociated with poor outcome.

Fuhrmann V, et al, Wien Klin Wochenschr 2010; 122: 129-39

The prevalence of ischemic hepatitis

Conditions of patients Prevalence

Admission in hospital 0.1%

Admission in ICU 1%

Cardiogenic shock 22%

Septic shock 13.8%

Henrion J. Hypoxic hepatitis. Liver international 2012; 1039-52.

Henrion J, et al. J Hepatol 1994; 21: 696–703.

Raurich JM, et al. J Anesth 2011; 25: 50–6.

Shock liver Ischemic hepatitis

Hypoxic hepatitis

Misnomer Misnomer

Pathophysiology

• Hepatic blood flow 800-1,200 ml/min (20-25% of cardiac blood flow)

• The liver is well protected against hypoxic stress. – 2 vascular

mechanisms

Laut WW. Gastroenterology 1981; 81: 159-73

The first mechanism: Macrocirculation of the Liver

Dual blood supply

•2/3 from Portal vein :

Nutrient rich

– High glucose, water soluble

vitamins, amino acid, TG

– Oxygen deficient

•1/3 from Hepatic artery :

Oxygen rich

– > 50% of oxygen delivered

to liver

– Little netritive value

Ilan S, et al, Clin Liver Dis 2011; 15: 1-20

Autoregulation of hepatic blood flow (Hepatic artery buffer system)

Portal flow Portal flow

adenosine concentration

adenosine concentration

Smooth m. of

hepatic arterioles relaxation

Smooth m. of

hepatic arterioles constriction

Arterial flow Arterial flow

+ Nitric Oxide mediated -

Ilan S, et al, Clin Liver Dis 2011; 15: 1-20

The second mechanism: Anatomic specificities of liver sinusoids

• Sinusoids are special capillaries

designed to favour exchanges between blood and liver cells. – Multiple fenestrae and free of

basal membranes.

– Favours diffusion of oxygen to liver cells.

• The ability of liver cells to

extract oxygen may exceed 90% of available oxygen

• This capacity is unique to the liver

Laut WW. Gastroenterology 1981; 81: 159-73

Pathogenesis of ischemic hepatitis : 2 conditions

Long standing

passive hepatic

congestion

Profound

hypotension

Giallourakis CC, et al, Clin Liver Dis 2002; 6: 947-67 Seeto RK, et al, Am J Med 2000; 109: 109-13

Patients with Ischemic Hepatitis vs. Shock Due to Trauma

Characteristics

Ischemic

Hepatitis

(Case Group)

(n = 31)

Shock Due to

Traumatic Injury

(Control Group)

(n = 31)

Percent or Mean ± SD

Male sex

Age (yr)

Organic heart disease

Rt side heart failure

Hypotension

Chronic renal failure

Serum ALP

Serum bilirubin

Prothrombin time(seconds)

71%

51 ± 17

100%

94%

97%

32%

154 ± 106

2.3 ± 1.7

17.0 ± 5.6

68%

41 ± 22

0

0

100%

0

50 ± 17

0.8 ± 0.6

13.9 ± 2.2

Seeto RK, et al, Am J Med 2000; 109: 109-13

Mean serum aminotransferase levels in patients with ischemic hepatitis and in patients with shock due to traumatic injury

Seeto RK, et al, Am J Med 2000; 109: 109-13

Ischemic hepatitis in patients with cardiac failure

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%High CVP

90%

38%

0

200

400

600

800

1000

1200

1400

1600

Hepatic blood flow (ml/min)

p < 0.001 p = 0.001

867

1429

Henrion J, et al. J Hepatol 1994; 21: 696–703.

Common causes of ischemic hepatitis

Systemic

hypotension

Severe hypoxemia

Increase oxygen demand

• Acute MI

• Exacerbation

of CHF

• Pulmonary embolism

• Obstructive

sleep apnea

• Respiratory

failure

• Toxic/septic

shock

Henrion J, et al, Medicine(Baltimore) 2003; 82: 392-406 Henrion J, et al, Hepatology 1999; 29: 427-33

Heart failure, respiratory failure and septic toxic shock

account for more than 90% of ischemic hepatitis cases

Clinical conditions underlying illness in ischemic hepatitis

Heart failure Respiratory failure Septic shock

Henrion J, et al. Medicine 2003; 82: 392–406.

Birrer R, et al. Intern Med 2007; 46:1063–70.

Fuhrmann V, et al. Intensive Care Med 2009; 35: 1397–405.

70%

13% 13%

62%

14% 16%

52%

20%

32%

N = 142 N = 322 N = 118

Diagnosis

1. Clinical setting of acute cardiac,

circulatory, or respiratory failure.

2. Dramatic but transient increase in serum

aminotransferase activity reaching at least

20 times the upper limit of normal.

3. Exclusion of other putative causes of liver cell necrosis.

Henrion J. Hypoxic hepatitis. Liver international 2012; 1039-52.

Exclusion

• Viral hepatitis A, B, C, E

• Drug or toxin-induced hepatitis

• Acute Budd-Chiari syndrome, veno-occlusive disease

• Biliary obstruction

• HELLP syndrome, acute fatty liver of pregnancy

• Hepatic infarction

• Acute exacerbation of autoimmune hepatitis

• Malignant infiltration

• Metabolic disease.

Clinical features

• Old aged ( > 70 years)

• ICU setting patients

• No unique physical examination finding.

– Tenderness at RUQ (painful hepatomegaly)

– Ankle edema

– Hepatojugular reflux

– Mild jaundice

– Change in mental status due to cerebral hypoperfusion

and hypoxia.

Gitlin N,et al, Am J Gastroenterol 1992;87:831-6 Cassidy WM, et al, J Clin Gastroenterol 1994: 19: 118-21

Clinical features

• Hallmark ;

– Massive increase AST/ALT, LDH levels in 1-3

days after episode of systemic hypotension and

return to normal within 7-10 days after

hemodynamic stability

– ALP level – normal or mild increase(< 2xULN)

– Increase PT INR in case severe ischemic injury

Gitlin N,et al, Am J Gastroenterol 1992;87:831-6 Cassidy WM, et al, J Clin Gastroenterol 1994: 19: 118-21

Clinical and biological data in the recent series of ischemic hepatitis

Author data Henrion

2003

Birrer

2007

Chang

2008

Fuhrmann

2009

Raurich

2010

No. of case

Age(years)

Shock (% cases)

Peak AST (x ULN)

Peak ALT (x ULN)

Peak LDH (x ULN)

Peak bili. (mg/dl)

142

68.5

55

79.6

50.6

21.9

3.1

322

70.3

51

44.2

28.6

15.2

2.2

75

65

73

147.3

70.8

-

-

118

65

-

117.2

50.4

22.2

5.7

182

59

-

67

44.5

30.9

3.8

Henrion J, et al. Medicine 2003; 82: 392–406.

Birrer R, et al. Intern Med 2007; 46:1063–70.

Chang JP, et al. Hepatology 2008; 48(Suppl): 447A.

Fuhrmann V, et al. Intensive Care Med 2009; 35: 1397–405.

Raurich JM, et al. J Anesth 2011; 25: 50–6.

Pattern of enzyme and prothrombin activities in cases of ischemic hepatitis

Henrion J. Hypoxic hepatitis. Liver international 2012; 1039-52.

Renal function in ischemic hepatitis

– Renal impairment may

be from acute tubular

necrosis

– Aid in diagnosis ischemic

hepatitis because unusual

in viral or drug-induced

hepatitis Cr > 2 mg/dl Cr > 5 mg/dl

65%

15%

Henrion J, et al. Medicine 2003; 82: 392–406.

Birrer R, et al. Intern Med 2007; 46:1063–70.

Dysglycemia in ischemic hepatitis

Hypoglycemia Hyperglycemia

Henrion J, et al. Medicine 2003; 82: 392–406.

Birrer R, et al. Intern Med 2007; 46:1063–70. Fuchs S,et al. J Clin Gastroenterol 1998; 26: 183-6

Fuhrmann V, et al. Intensive Care Med 2009; 35: 1397–405.

32.4%

14%

27.5% 31%

• No need for histological confirmation or

imaging examination in typical cases.

• Histological examination

– Widening of sinusoidal spaces

– Centrilobular liver cell necrosis(CLN)

– Long lasting centrilobular congestion, liver cells

atrophy and disappearance of liver cells around

central veins

Further investigation for ischemic hepatitis

Microcirculation of the Liver

Ilan S, et al, Clin Liver Dis 2011; 15: 1-20

Normal liver histology

1

2

3

Portal triad

Central vein

Histopathology of ischemic hepatitis

Centrolobular necrosis of Zone 3

Zone 3

Zone 2

Centrolobular necrosis of Zone 3 hepatocyte

Histopathology of ischemic hepatitis

Extensive centrolobular liver cell necrosis(CLN) of Zone 3 hepatocyte

Histopathology of ischemic hepatitis

• Little practical interest in the diagnosis

• Ultrasonography

– Easy to perform bedside of critical ill patients

– Finding: dilatation of the IVC and hepatic vein

Imaging for ischemic hepatitis

Fuhrmann V, et al. Intensive Care Med 2009; 35: 1397–405.

Raurich JM, et al. J Anesth 2011; 25: 50–6.

52.8%

45%

70.7% 72%

61.5%

Prognosis: in hospital mortality

Henrion J, et al. Medicine 2003; 82: 392–406.

Birrer R, et al. Intern Med 2007; 46:1063–70.

Chang JP, et al. Hepatology 2008; 48(Suppl): 447A.

Henrion J, et al. Medicine 2003; 82: 392–406.

Birrer R, et al. Intern Med 2007; 46:1063–70.

28.3%

23.5%

Prognosis: 1-year survival

Prognosis in ICU patients: With vs. without ischemic hepatitis

Mortality rate(%)

With IH Without IH

57%

17%

Killip T III, Payne AM. Circulation 1960; 21: 646–60.

P < 0.01

Treatment of ischemic hepatitis

• No specific therapy

– Maintain hemodynamic and hepatic blood flow

– O2 support

• Correction of the underlying circulatory or

respiratory disturbance.

• No proven clinical benefit

– Infusion of renal dose dopamine

– Adenosine infusion

– Antioxidants : N-acetylcysteine

Giallourakis CC, et al, Clin Liver Dis 2002; 6: 947-67

Anghern W, et al, J Cardiovasc Pharmacol 1980; 2: 257-65 Desai A, et al, Am J Ther 2006; 13: 80-3

In summary

• Ischemic hepatitis is not uncommon condition.

• Hepatic congestion and systemic hypotension are

major pathogenic factor.

• Diagnosis by exclusion.

• The prognosis is poor, mainly related to severity of

underlying conditions.

• No specific treatment, correct underlying diseases

Thank you