GASTROINTESTINAL SYSTEM
A. Acute Liver Failure 1. Definition of ALF
a. The Pediatric Acute Liver Failure (PALF) study group has refined the definition of ALF as a syndrome, not a disease, with the following criteria:
i. Hepatic-based coagulopathy defined as a PT ≥15 seconds or INR ≥1.5 not cor- rectable with vitamin K in the presence of hepatic encephalopathy
ii. PT ≥20 seconds or INR ≥2 regardless of hepatic encephalopathy
iii. Biochemical evidence of acute liver injury
iv. No known evidence of chronic liver disease (Sundaram, Alonso, Narkewicz, Zhang, & Squires, 2011)
b. Other ALF definitions (Sundaram et al., 2011):
i. Hyperacute liver failure is fulminant hepatic failure (FHF) with the time from jaundice to encephalopathy less than 7 days.
ii. ALF as FHF with the time from jaundice to encephalopathy between 7 and 28 days.
iii. Subacute liver failure as FHF from the time from jaundice to encephalopathy more than 28 days.
2. Liver disease is a significant problem, with 15,000 children hospitalized each year (American Liver Foundation, 2013), which is a statistic that has remained unchanged over the past 25 years.
3. Etiology of ALF
a. Hepatitis (inflammation of the liver) is the most frequently identified cause of hepatic fail- ure. Hepatotropic viral infectious causes include the following:
i. Hepatitis A virus (HAV)
1) On average, the incubation period is 28 days.
2) Serologic markers for HAV include hepatitis A antibodies of the immunoglob- ulin M (IgM) class (anti-HAV IgM), whose presence reflects active or recent HAV infection, and hepatitis A antibodies of the immunoglobulin G (IgG) class (anti-HAV IgG), whose presence reflects immunity.
3) The Advisory Committee on Immuni- zations Practices recommend routine vaccination for children at age 2 years living in communities with high rates of hepatitis A (Alaska, Arizona, California, Idaho, Nevada, New Mexico, Oklahoma, Oregon, South Dakota, Utah, and Washington), for those who have planned travel to endemic areas, and day-care workers.
4) Disease transmission is via the oral−
fecal route. Food, water, and shellfish contaminated by the virus are the usual sources.
ii. Hepatitis B virus (HBV)
1) The incubation period is, on average, 80 days.
2) Hepatitis B vaccine is part of the American Academy of Pediatrics recom- mended immunization schedule and has led to a decline in the incidence; need for booster unclear.
3) Serologic markers of HBV include hepatitis B surface antigen (HbsAg), whose presence reflects acute or
chronic infection; hepatitis B e antigen (HbeAg), whose presence reflects active HBV infection with active viral replica- tion and high infectivity; antibody to hepatitis B surface antigen (anti-HBs), whose presence reflects clinical recov- ery and immunity; and HBV quantifi- cation with polymerase chain reaction (PCR), which reflects a specific quantity of active HBV.
4) Disease transmission occurs through the exchange of blood or body flu- ids. Neonates can acquire the virus via maternal transmission.
5) Disease presentation varies and may consist of a prodrome, followed by insidi- ous onset, with symptoms usually resolv- ing within 1 to 3 months. Unfortunately, there is a cadre of patients that develop chronic disease. A small percentage of infected individuals develop FHF.
iii. Hepatitis C virus (HCV)
1) Incubation time is 2 to 26 weeks.
2) Serologic markers for HCV include anti-HCV antibody, indicating expo- sure to HCV and PCR, whose presence reflects HCV infection.
3) Perinatal transmission is now the most common mode of acquiring HCV in children (Lee & Jonas, 2015).
4) No vaccine available.
iv. Clinical presentation of hepatitis involves three stages:
1) Preicteric stage has a duration of approximately 1 week. Signs and symp- toms include fever, chills, anorexia, mal- aise, abdominal pain, nausea, vomiting, joint pain, hepatomegaly, and lymph- adenopathy. HAV is characterized by nonspecific features of viral illness, including fever, headache, anorexia, and nausea. HBV is characterized by arthralgia, arthritis, transient skin rash, and later malaise, nausea, vomiting, and low-grade fever. Jaundice usually occurs 10 to 12 days after the onset of symptoms.
2) Icteric stage has a duration of 2 to 6 weeks. Signs and symptoms include weakness, fatigue, pallor, jaundice, dark urine, pale-colored stool, and pruritus.
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3) During the posticteric stage, there is res- olution of the jaundice, darkening of the stools, and normalization of LFT values.
Complete recovery occurs in most cases.
v. Other viral causes include herpes simplex virus, Epstein−Barr virus (EBV), adenovirus, parvovirus, varicella, and cyto- megalovirus (which may be congenitally acquired). Infants are at risk if the mother is infected with a primary infection and active infection is present at birth.
b. Neonatal “giant cell” hepatitis is a histolog- ically descriptive term. The disease is character- ized by large cells with many nuclei. The cause is most likely related to an autoimmune process.
c. Drug-induced acute hepatic failure.
i. The liver is the most common site for drug metabolism. Children receiving drugs known to be hepatotoxic should have serial LFT monitoring while receiving therapy.
The risk of developing FHF increases with continued use of the drug in the presence of developing hepatitis.
ii. The most common toxic drugs are acetaminophen (Tylenol), ecstasy (meth- yldioxymethamphetamine), anticonvul- sants (phenytoin [Dilantin] and valproate [Depakene]), methotrexate, halothane, and isoniazid.
d. Wilson disease is an autosomal-recessive dis- order that results in excessive accumulation of copper in the organs. The biochemical disorder of copper metabolism is a defect in the copper ade- nosine triphosphatase transporter, with decreased copper excretion, defective incorporation of cop- per into ceruplasmin, and copper accumulation (Carlson, Al-Mateen, & Brewer, 2004). Liver dys- function manifestations are variable and the child may present with FHF. Medical therapy includes administration of d- penicillamine and dietary restrictions of copper. Liver transplantation is indicated in the presence of FHF or cirrhosis with decompensation.
4. Pathophysiology
a. Pathophysiology of ALF is presumed to be multifactorial. Portal-systemic shunting (caused by progressive liver destruction) allows blood flow from the intestine to be shunted around the liver, bypassing any remaining viable hepato- cytes. The liver is unable to remove toxic metab- olites normally formed by intestinal bacterial degradation of proteins, amino acids, and blood
(e.g., ammonia). Altered blood−brain permeability is hypothesized to be related to toxin(s) of intesti- nal origin bypassing the portal filtration, resulting in a disruption of the blood−brain barrier.
b. Neurologic pathophysiology i. Multiple proposed etiologies
1) Mechanism of the formation of cere- bral edema is not known.
2) High ammonia levels play a central role; although level does not correlate with exam and seems to be related to the accu- mulation of other neurotoxic substances.
c. Renal pathophysiology
i. More than one type of renal failure may be present. Careful differentiation of the type of renal failure must be made before appropriate therapy can be initiated.
ii. Prerenal azotemia occurs when prerenal blood flow and renal perfusion are compro- mised. Treatment includes addressing the cause of decreased renal perfusion (i.e., fluid resuscitation).
iii. Acute tubular necrosis is related to paren- chymal damage to the kidney associated with a chronic prerenal or postrenal condi- tion (e.g., toxic chemical exposure or glomer- ulonephritis). It may occur with concomitant sepsis, hemorrhage, and ischemia.
iv. Hepatorenal syndrome (functional renal failure of liver disease) is likely to be related to an unidentified vasoconstrictive substance causing a decrease in renal perfusion result- ing in oliguric renal failure in the presence of hepatic failure. Renal failure resolves with improvement of the hepatic dysfunction;
however, the associated mortality is high.
d. Hematologic pathophysiology
i. Coagulopathy is related to an abnormal production of prothrombin and other clot- ting factors produced by the liver, signifying impaired hepatic synthetic function, and inef- fective removal of activated clotting factors.
ii. Hypersplenism results from increased portal venous pressures delaying the blood flow through the splanchnic bed with resultant congestion and enlargement of the spleen. Splenic overactivity increases destruction of RBCs, platelets, and WBCs.
The sequelae of splenomegaly includes ane- mia, platelet dysfunction (quantitative and qualitative), leukopenia, and DIC.
5. Clinical Presentation a. History
b. Physical examination 6. Signs and Symptoms
a. Staging of hepatic encephalopathy
i. Stage I. Normal level of consciousness, periods of lethargy and euphoria
ii. Stage II. Disorientation, increased drowsiness, and agitation with mood swings
iii. Stage III. Marked confusion, sleeping most of the time
iv. Stage IV. Coma
b. Jaundice. Yellow discoloration of the skin, mucous membranes, and sclera is caused by excessive bilirubin levels.
c. Renal-failure symptoms depend on the type of renal failure the child is experiencing. Azotemia should be evaluated carefully in the presence of hepatic failure, as nitrogenous wastes cannot be metabolized appropriately. Increased serum creat- inine levels and oliguria are present.
d. Coagulopathy is recognized by an ele- vated PT. A PT that is uncorrectable despite IV vitamin K (AquaMEPHYTON) administra- tion reflects significant parenchymal disease.
In addition, there will be platelet dysfunc- tion. Other signs include bruising and bleed- ing from mucosal surfaces and the presence of petechiae.
B. Chronic Liver Failure