Name : Muhammad Hisyam Bin Kamarulzaman

Title : Fulminant Hepatitis

DEFINITION

Fulminant Hepatitis is a clinical syndrome where there will be a rapidly progressive loss

of hepatic function due to viral infection or other cause of inflammatory destruction of liver

tissues. It may be characterized by the rapid development of triggered apoptosis or by massive

necrosis of the liver cell resulting in severe hepatocellular dysfunction, specifically coagulopathy

and mental status changes known as encephalopathy. It may occurs suddenly in a patient without

any history of liver disease or previously stable liver disease. The onset of Fulminant Hepatitis

occurs within 8 weeks after the onset of first hepatic symptoms.

PATHOGENESIS

Aetiologically, 40% of Fulminant Hepatitis is caused by acute viral hepatitis such as

HAV, HBV, HCV, HDV and HEV. Other viruses that can cause are less common, such as

Epstein - Barr virus, HSV, cytomegalovirus, varicella and many other more. For all aetiologies,

the incidence are higher in females simply because females are generally responded more to

immunological challenge compared to that in males.

HAV is a RNA virus that causes the liver damage by both direct killing of the

hepatocytes and by the host immune response to infected hepatocytes. It is infected via fecal-oral

route. Meanwhile, HBV is a DNA virus that is transmitted sexually or via infected blood or other

bodily fluids. HBV does not kill the cell but rather causing the immune system to attack the

infected hepatocytes after recognizing the viral antigens on the surface of the cell. Excessive

immune response thus causes the fulminant hepatic failure. HCV on the other hands, is a RNA

virus generally transmitted by blood or bodily fluids, causes hepatic infection similar to HBV but

with greater progression to become chronic. HDV is a RNA virus that requires helper function of

HBV, it infected either as co-infection which occurs simultaneously with HBV or superinfection

in the chronic HBV. HEV has a common characteristic as HAV but can cause fulminant hepatic

failure in pregnant women.

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During the incubation period (HAV 15-50 day; average 28 days/ HBV 45-160 days;

average 120 days/ HCV 14-180 days; average 45 days), intense viral replication leads to the

appearance of viral component (first antigens, later antibodies) in the urine, stool and bodily

fluids. Liver cell death and an associated inflammatory response occur afterward, following by

the changes in liver function test and clinical features in liver disease. Hepatocellular necrosis

starts in the centrizonal distribution and progressing towards portal tracts.

CLINICAL FEATURES

The clinical features of Fulminant Hepatitis includes encephalopathy, the condition in

which when the liver fails, nitrogenous waste such as ammonia builds up in the blood stream and

are circulated until it reaches the brain. To clear up the waste, astrocytes in the brain will convert

glutamate into glutamine, excessive glutamine will cause the osmotic imbalance and a shift of

fluid into these cells, hence causing cerebral oedema. There are 4 grades in hepatic

encephalopathy:-

Grades Explanation

I Altered mood or sleep disturbance (e.g. reversed sleep pattern)

II Increasing drowsiness, confusion, slurred speech

III Stupor, incoherence, restlessness, significant confusion

IV Coma

Table 1. Grading in hepatic encephalopathy

Note that too much of ammonia in blood can also be detected in breath, a condition

known as Foetor Hepaticus (breath of the death/smells like pear drops).

Another significant clinical feature in Fulminant Hepatitis is the impaired synthesis of

many coagulation factors and inhibitors, known as coagulopathy. Due to the massive necrosis of

hepatocelluler, the liver can no longer produces almost all coagulation factors and some

inhibitors of coagulation and fibrinolysis. As the result, there will be a prolongation in

prothrombine time and bleeding time, making it easier for the patient to bleed and bruising.

Hence, both tests can be used to monitor the severity of hepatic failure.

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As the function of the liver fails to work, unconjugated bilirubin in the blood serum (also

known as indirect bilirubin) which are not water-soluble are unable to be conjugated with

glucoronic acid to form a water-soluble bilirubin (also known as direct bilirubin). The increase of

indirect bilirubin in the blood serum (>41.75 µmol/L/>2.5 mg/dL) will be manifested as

jaundice, a condition of yellow pigmentation of the skin, sclera and mucosa.

Sometimes, Fulminant Hepatitis can be presented in a patient as constructional apraxia. It

is a neurological disorder where the patient has inability to perform tasks or movements,

eventhough they understand and willing to do the order. As an example, the patient is unable to

draw a 5-pointed star. Asterixis can also be detected, the condition in which the patient has a

flapping tremor when the wrists are dorso-flextioned with finger spreading.

DIAGNOSIS

To diagnose Fulminant Hepatitis, patient’s history taking must be done completely,

which includes the complaints of sign and symptoms in the prodromal phase, presented as flu-

like fever, 1-2 weeks before jaundice occur. Symptoms of severe liver failure include confusion,

extreme irritability, altered consciousness (usually leading to unconsciousness or coma), blood-

clotting defects, and build up of fluid in the abdominal cavity, arms, and legs. Fever can be mild

in Fulminant Hepatitis from HAV and HEV, but can be very high from HBV. Patient may also

complaint of dark urine colour and clay-colour stool due to indirect hyperbilirubinemia.

Testing for Prothrombine Time (PT) is important to evaluate the severity of the liver

damage, prolonged PT signify intensive hepatocellulat necrosis. Based on the evidence from the

laboratorial test, serum AST and ALT (formerly known as SGOT and SGPT) will be increased,

followed by the increase in bilirubin level. When jaundice appears, it shows that serum bilirubin

may have been exceeded >41.75 µmol/L or >2.5 mg/dL, typically ranging 83-340 mmol/L or 5-

20 mg/dL. In Fulminanat Hepatits, there will be mild increased in the level of serum bilirubin,

AST and ALT with prolonged PT. Neutropenia and lymphopenia occurs in a short period, then

followed by lymphocytosis.

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MANAGEMENT

No medication can reverse Fulminant Hepatitis. People who have the disease need to be

hospitalized in an intensive care unit (ICU) so they can be cared for until their condition becomes

more stable. For some people, a liver transplant is the only lifesaving option. People younger

than age 40 who have Fulminanat Hepatitis are more likely to recover than older adults or people

who have chronic liver disease. Below are the criteria for Liver Transplantation based on King’s

College Hospital.

Paracetamol Liver Failure Non-Paracetamol Liver Failure

Arterial pH <7.3, 24 H after ingestion PT > 100 s

Or all of the following Or 3 out of 5 of the following

1) PT > 100 s

2) Creatinine > 300 µmol/L

3) Grade III or IV encephalopathy

1) Drug-induced liver failure

2) Age <10 or >40 years old

3)1 week from first jaundice of encephalopathy

4) PT > 50 s

5) Bilurubin >300 µmol/L

Table 2. King’s College Hospital Criteria for Liver Transplantation

Usually, patient with Fulminant Hepatitis will be admitted in the ICU. Endotracheal

intubation is always recommended to protect the airways. Nasogastric tube is often inserted to

avoid aspiration and to remove blood from stomach due to coagulopathy. Catheter is inserted to

monitor fluid status and to assess urine output hourly. Vital signs and pupils must also be

monitored hourly, while body weight must be checked daily.

For laboratorium investigation, Full Blood Count (FBC), ureum and creatinine, liver

function test and prothrombine test are also important to see the progression of liver damage. To

avoid hypoglycaemia, infuse 10% Dextrose IV, 1L/ 12 hours and monitor the blood level every

1-4 hours. Some patient comes with malnutrition, diet rich in carbohydrates and protein

delivered calories are preferably given oral as good nutrition lower the risk of mortality.

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If bleeding occurs, gives vitamin K IV (10 mg/ day) for 3 days together with platelets.

Fresh frozen plasma (FFP) is required under certain condition. To treat infection, give

Ceftriaxone 1-2 g/ day IV unless the sensitivities are known. Avoid Gentamicin as it could

increase the risk of renal failure. If blood sugar fall below 2mmol/L or 36 mg/dL, or

symptomatically presented as hypoglycaemia, give 50 mL of 50% glucose IV. To treat

encephalopathy, avoid sedatives but only use lorazepam if seizure occurs. Give lactulose 30-50

mL/ 8 hours PO to lower down the number of nitrogen-forming bowel organism while cerebral

oedema is treated with 20% mannitol IV and hyperventilation.

REFERENCES

1. Longmore M, Wilkinson I.B, Davidson E.H, Foulkes A, Mafi A.R. Liver failure. Oxford

handbook of clinical medicine. 8th ed. Oxford university press. China.2012. Page 258 – 9.

2. McPhee S.J, Hammer G.D. Liver disease. Pathophysiology of disease. An introduction of

medicine. Chapter 14. 6th ed. McGraw-Hill companies. China. 2010. Page 391 – 8.

3. Dienstag J.L. Acute Viral Hepatitis. Harrison principle of internal medicine. Chapter 304

(14); vol 2. 18th ed. McGraw-Hill companies. USA. 2012. Page 2537 – 56

4. Daniel C. Fulminant Hepatitis. Updated June 24, 2008 from http://hepatitis.about.com on

April 23, 2013.

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