Ischemic hepatitis

INTRODUCTION

·  The liver's complex vascular supply and high metabolic activity make it particularly vulnerable to circulatory disturbances.

·  The severity and characteristics of hepatic injury depend upon the blood vessels that are involved and the degree to which injury is related to passive congestion or diminished perfusion.

·  There are several well-recognized forms of vascular injury to the liver including:

o  Budd-Chiari syndrome.

o  Hepatic veno-occlusive disease.

o  Passive congestion due to heart failure.

o  Hepatic infarction.

o  Ischemic hepatitis.

ISCHEMIC HEPATITIS (SHOCK LIVER, HYPOXIC HEPATITIS)

·  Definition: refers to diffuse hepatic injury resulting from acute hypoperfusion.

·  The syndrome is characterized by three criteria:

o  Clinical setting of circulatory failure.

o  Sharp but transient increase in either ALT or AST to levels greater than 20x upper limit of normal.

o  Exclusion of all other causes of acute hepatitis especially drug and viral induced causes.

Etiology

·  Ischaemic hepatitis is a consequence of reduced blood flow into the liver due to acute hypotension caused by low cardiac output or shock of various aetiology.

Congestive, backward heart failure
Forward heart failure (myocardial infarction, arrhythmia)
Shock of diverse etiology
Chronic respiratory insufficiency
Thromboembolism
Hematological diseases (Sickle cell syndrome)
Dissecting aortic aneurysm
Postoperative conditions in thoracic and abdominal surgery
Occlusion of hepatic artery

PATHOGENESIS:

·  Hepatic ischemia develops when there is an imbalance between hepatic oxygen supply and demand.

Regulation of blood flow

·  Hepatic oxygen delivery is related to:

o  Oxygen content of blood perfusing the liver.

o  Total hepatic blood flow.

·  Once oxygen delivery is decreasedà compensatory mechanisms à increased oxygen extraction by hepatocytes.

·  Autoregulation of blood flow

·  Blood flow is regulated primarily by the activity of smooth muscle cells that surround hepatic arterioles à constant total hepatic blood flow.

·  When portal flow declinesà smooth muscle cells around hepatic arterioles relax à increased arteriolar flow.

Blood flow under systemic stress

·  Under situations of systemic stress à redistribution of blood flow to more vital organsà compensatory decrease in peripheral and splanchnic blood flow.

·  The resulting decrease in hepatic blood flow à exceeds capacity of the liver to increase oxygen extraction à hepatocellular hypoxia.

Reperfusion injury

·  Mediated by generation of reactive oxygen species once ischemic hepatocytes are reexposed to oxygen à cell injury via lipid peroxidation.

·  Kupffer cells react to ischemia by producing cytokines, including TNF-alpha à triggers the recruitment and activation of PNLs.

Cellular mechanisms of ischemic injury

·  Disruption of mitochondrial respiration à

o  Depletion of adenosine triphosphate.

o  Rise in cytosolic calcium (and possibly sodium) levels.

o  Activation of cellular proteases.

Clinical settings that increase the risk of ischemic injury

·  Patients who have preexisting liver disease and portal hypertension

o  Total hepatic blood flow may already be reduced due to blood shunting through collateral circulation.

·  Patients who have preexisting passive congestion of the liver

o  Elevated central venous pressure à leads to atrophy of hepatocytes à fibrosisà impairs diffusion of nutrients to hepatocytes.

·  Sickle cell anemia

o  Focal interruption of the hepatic blood supply in occlusive crisis.

·  Preexisting portal vein thrombosis

Clinical manifestations:

Type of patient

·  Shocked or hemodynamically unstable admitted to the ICU with:

o  Myocardial infarction.

o  Heart failure.

o  Accident.

o  Acute respiratory failure.

o  Sepsis.

o  Severe bleeding.

o  Postoperative complication.

History

·  The patient may have history of coronary heart disease, valvular disease, sickle cell anemia, liver cirrhosis or portal hypertension, chronic obstructive pulmonary disease.

Presentation

·  The patient is shocked with hypotension, pallor, tachycardia and arrhythmia.

·  The patient may have cyanosis, tachypnea, acidosis.

·  Fever, sweating, bleeding from body orifices or wound sepsis.

·  Right upper quadrant tenderness.

·  Physical examination may provide clues toward underlying liver disease.

·  Rare patients have symptoms suggesting acute hepatitis, including nausea, vomiting, anorexia, malaise, and right upper quadrant pain.

·  Occasional patients develop changes in mental status, which generally reflect impaired cerebral perfusion rather than hepatic encephalopathy.

·  Hepatopulmonary syndrome develops in nearly one-half of patients but appears to be reversible following normalization of hepatic function.

Investigations:

·  Picture of the cause

Elevated cardiac enzymes / Leukocytosis / Disturbed blood gases
Anemia / Elevated serum urea & creatinine / DIC
Elevated ESR / Hypoglycemia / Electrolyte disturbances

·  Ischemic hepatitis is usually first detected because of elevations in liver biochemical tests following a hypotensive episode.

·  The typical pattern of liver biochemical tests consists of:

o  A rapid rise in serum aminotransferase levels.

o  Peak 25 to 250x upper limit of normal reached within 1- 3 days.

o  Decline steadily returning to normal within 7 to 10 days with stabilization.

o  Early massive rise in LDH levels.

o  Serum bilirubin level 4x upper limit of normal, usually beginning its rise after aminotransferase levels have begun to decline.

o  Serum ALP levels are rarely higher than twice the upper limit of normal.

o  Hepatic synthetic function usually remains normal or is only mildly impaired.

·  Reasonable evaluation might include:

o  Serologic testing for acute viral hepatitis.

o  Blood acetaminophen level.

o  Right upper quadrant ultrasound with Doppler studies of the portal and hepatic veins and hepatic artery.

o  Evaluation for suspected underlying causes of ischemic injury such as cardiac or respiratory failure.

Differential diagnosis

·  Ischemia should always be considered in the differential diagnosis of

Acute viral hepatitis / Spontaneous reactivation of chronic HBV. / Superimposition of HDV in a chronic carrier of HBV / Drugs & toxins (acetaminophen or herbal medications)
Acute fatty liver of pregnancy / Metabolic disorders / Hepatic veno-occlusive disease / HELLP syndrome
Acute Budd-Chiari syndrome (especially those with concomitant portal vein thrombosis). / Acute exacerbation of autoimmune hepatitis / Hepatic infarction

·  Features that suggest an ischemic rather than other causes:

o  Early rapid rise in the serum LDH level is unusual in viral hepatitis.

o  Ratio of serum ALT to LDH of less than 1.5 early in the course of acute hepatitis may be more likely to suggest ischemic hepatitis.

o  Rapid fall in serum aminotransferase levels after the initial rise is characteristic of ischemic liver injury and atypical for other causes of hepatitis.

o  End-organ hypoperfusion, especially acute tubular necrosis of the kidney.

o  Concomitant, early rise in the serum creatinine.

Pathology:

·  The histologic hallmark à necrosis of hepatocytes in zone 3 of the hepatic acinus with few inflammatory cells.

·  In patients with chronic or recurrent heart failure à sinusoidal engorgement and collagen accumulates in zone 3.

·  Hepatic architecture may return to normal after recovery from the ischemic event.

Management: (3As)

·  There is no specific therapy for ischemic hepatitis.

·  Aim: Restoring cardiac output and reversing the underlying cause of hemodynamic instability.

·  Avoid aggressive diuresis since it may worsen hepatic perfusion.

·  Augmentation of cardiac output enhances hepatic perfusion by Dopamine, at either "renal" or "cardiac" doses.

·  Supportive ventilation may be needed.

·  Correction of anemia, electrolyte and acid-base abnormalities.

·  IV broad spectrum antibiotics to correct infection.

·  Patients should be monitored closely for evidence of end-organ hypoperfusion, particularly decreased renal function and altered mental status.

Prognosis

·  The severity of the liver injury correlates with the duration and extent of the hemodynamic compromise.

·  A continually rising bilirubin and progressive prolongation of the prothrombin time are poor prognostic signs.

·  Rare patients develop fulminant hepatic failure.

·  Mortality rates may reach 60 to 100 %.

HEPATIC INFARCTION

·  Definition: focal ischemic injury of the liver.

·  It is rare because the liver has a dual blood supply.

·  Causes of hepatic infarction:

Liver transplantation / Tumor embolism / Thrombosis of the h. a. due to atherosclerosis
Hypercoagulable state / Infective endocarditis / therapeutic embolization or chemoembolization
Iatrogenic ligation of the hepatic artery after laparoscopic cholecystectomy
Toxemia of pregnancy / Sickle cell anemia / Following radiofrequency ablation of HCC
Polyarteritis nodosa / cocaine intoxication / Hepatic artery aneurysms

Clinical manifestations:

·  Precipitating cause is evident before hepatic infarction develops.

·  Asymptomatic hepatic infarction detected only on an imaging study.

·  Fever, epigastric or right upper quadrant pain, back or right shoulder pain, jaundice, nausea, and vomiting.

·  The aminotransferases rise transiently, sometimes to massive levels.

Diagnosis:

·  Suggested radiographically in patients with a compatible clinical history.

·  Abdominal CT scan with IV contrastà focal, wedge-shaped lesion of low attenuation, which may extend to the capsular surface of the liver.

o  Gas in the lesion is highly suggestive of infection.

o  Splenic and renal infarcts suggest an embolic source of the liver findings.

o  No displacement hepatic blood vessels.

·  Ultrasound or CT-guided needle aspiration establishes a definitive diagnosis.

·  Magnetic resonance angiography or celiac arteriography in HA occlusion.

·  Doppler ultrasound should be performed to assess the patency of the hepatic artery.

Pathology:

·  Complete coagulative necrosis involving all three zones of the hepatic acinus.

Management:

·  No specific therapy.

·  Identify and treat the cause (e.g. emboli, infective endocarditis).

·  In the absence of such a source, hypercoagulable states, including proteins C and S or antithrombin III deficiency, factor V Leiden mutation, lupus anticoagulant, paroxysmal nocturnal hemoglobinuria, polycythemia Vera, and possibly oral contraceptive use should be considered.

·  Serial CT scans may show resolution of the infarct over weeks, residual scarring, or atrophy of the involved lobe of liver.

·  In some patients, anticoagulation is indicated to prevent further systemic emboli or thrombosis.

·  Patients who develop hepatic infarction after liver transplantation often require urgent retransplantation.

ISCHEMIC CHOLANGIOPATHY

·  Involves principally the large intra- and extrahepatic bile ducts.

Following liver transplantation / Vascular injury during biliary tract surgery
Hypercoagulable states / Arterial infusion of the chemotherapeutic agent
Chemoembolization and radiation therapy

Clinical manifestations:

·  Biliary obstruction, such as pruritus, dark urine, clay-colored stools, and jaundice.

·  Elevations of serum bilirubin and alkaline phosphatase and variable elevations in serum aminotransferase levels.

·  Ascending cholangitis or cholangitic liver abscesses, with associated fever.

Diagnosis

·  ERCP or PTC or MRCP although it does not permit therapeutic intervention or biopsies.

·  Cholangiographic findings consist of multiple intra- and extrahepatic strictures with diffuse irregularity or beading of the ducts, (usually affecting the large perihilar bile ducts).

·  In liver transplantation à Doppler ultrasound +/- arteriography to rule out HA thrombosis

Pathology: Liver biopsy is rarely useful and misleading à biliary obstruction.

Management:

·  ERCP with dilation and stenting is effective for treatment of biliary strictures.

·  Ischemic cholangiopathy occurring within the first month after liver transplantation frequently requires urgent retransplantation.

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