390 bo pow can be distinguished from these disorders by an elevated serum GGT level, PFIC-3 is caused by mutations in the multidrug-resistance 3 P-glycoprotein (MDRVABAIN resulting in disruption of canalicular phospho: Tipid transport. The gene has been localized to chron 7421-26. As with the other types of PFIC, the se isa result of the severity of the mutation clinical eo and ranges from a Ix sive biliary cinrhosis and end-stage lithiasis to pro Patients with PEIC Myari Shave significant «h ability, with rom 49 20 years fof age. Symptoms include growth failure, citthosis, and pruritus, although the pruritus isfess than jaunelo that scen with PFIC=1 and -2. Clinical course és most ings that distinguish PEIC-3 from the other types of PEIC nd consistent with biliary citthosis, Laboratory include an elevated GG tcin X (LPX). Liver histolo fon and periportal fibrosis that can evolve into cirthosis. Treatment with UDCA has been suc liver transplantation is indicated for end stage n absent serum lipopro: s extensive bile duct secondary to biliary cirthosis. DRUG-INDUCED LIVER DISEASE Definitions and Epidemiology DILL in children is generally considered uncommon as compared to that reported to occur in adults. The rea~ son for this observation in children is unclear and may due to the relative infrequent use of medications and/or the lack of risk factors such as alcohol consumption, tobacco use, and obesity. Indeed, in children with cancer or neurologic disease, where multidrug use is common, drug-induced liver injury occurs more frequently. Developmental changes in hepatic drug metabolism and immune response may be sufficiently different in children than adults and confer a degree of protection from drug toxicity. Drug metabolism has been shown to vary depending on age and sex, with advanced age or female sex being independent risk factors for drug- induced hepatotoxicity. is Pathogenesis Hepatic drug metabolism, or biotransformation, can be divided into two broad phases (Figure 28-4). In phase enzymes of the cytochrome P-450 system activate thi parent compound via hydroxylation, dealkylation, and dchalogenation, usually producing a more polar inter- mediate, In phase Il, the active hydrophilic metabolite is conjugated to an endogenous substrate by glucuronsyl-, sulfo-, N-acetyl, and glutathi ransferases (GSH) FIGURE 20-4 m Crug metabolism and potential cau ary (OILY). of drug induced tives and by epoxide hydrolase. This conjugation usually completes the process of biotransformation and the compound can then be excreted in bile oF urine. Phase T reactions commonly result in a highly reactive toxic metabolite that is inactivated by phase II reactions before cell damage occurs. Hepatotoxicity results from an imbalance of these two phases. Factors that can influ- ence this balance include age, fasting or undernutrition, co-administered drugs, and enzyme polymorphisms. “These polymorphisms have been shown to exist in both phases of biotransformation and alter the balance of the reactions ‘Toxicity has been categorized as resulting from an intrinsic or idiopathic response. An intrinsic toxin results directly from the compound and causes a pre- jictable dose-dependent response in most people. Idio- pathic reactions are the most commion and include both contingent hepatotoxins and immunoallergic hepato- toxins. These reactions occur sporadically nd are not predictable or dose-dependent. Contingent hepatotox- ins cause liver injury in susceptible individuals when ‘umstances favor an imbalance between the produc tion of a toxic metabolite and its detoxification. This imbalance can result from enzyme tion/alcohol), enzyme depletion (fasting/ma or inborn genetic defects or polymorphism, Drugs that elicit an immune response are most likely a result of the individual's immunogenetic maks Hepatotoxicity is often a result of eytotosityshow- ever, the mechanism of hepatocyte death is unknown, and is probably dependent on the individual toxin. Because hepatocytes in Rappaport zone 3 (in the vici ity of central veins) have the highest concentration of cytochrome P-455, zonal necrosis is ofien seen in DILL. Cytotoxicity ean also be directed to other cells in the liver such as bile duct cells, stellate cells, and endothelial Dipindai dengan CamScannerPa | ie ——_ ag Common mi Drug-induc ledications Associated with ‘ociated with Pediatele ed Liver Disease (DIL) : Injury Type Drug Hepatocettalay ~Acetami aminophen (zonal necrosis) Halothane: Isoniazid Methyldopa Phenytoin Cyclosporine Estrogens tatic Amoxicitin Azathioprine Cholestatic Hepatocettular/chotest Chlorpromazine Exythromycin imacroides) Nitrofurantoin Steatosis Macrovesicular ‘Amiodarone Nonalcoholic metabolic syndrome) Microvesicular Tetracycline Valproic acid Vascular Peliosis Estrogens/androgens Hepatic vein thrombosis Estrogens Veno-occlusive disease Alkaloids (Senecio) Busulfon Thioguanine Adenoma/malignant tumor Anabolic steroids Estrogens a cells. Toxicity is not limited to cell death, but can be a result of interference of bile formation, accumulation of fat, fibrosis, and carcinogenesis. Toxicity can be either acute or chronic, and reversible or progressive. This sec- tion will focus on the most common causes of DILL in children (Table 28-10). Clinical Presentation “The clinical spectrum of disease is a result ofthe specitic hepatotoxin and includes clinical hepatitis, faty liver, vascular changes, and adenoma/malignant tumor for- mation (Table 28-10). Clinical hepatitis has been cate to three patterns: hepatocellular, cholestatic, cpatocellular/cholestatic), with and with- gic features. In patients with an fever, inflamma- gorized and mixed ( out immunoalle ‘ immune-allergic component, there is a tion of other organs, morbilliform rash, myocarditis, inal dysfunction, and lymphadenopathy. pancreatitis, ret “ if Laboratory findings also include eosinophilia and atyp ical lymphocytosis. CHAPTER 28 Metabolic Hepatocellular (hepatitic) pattern of injury is the its from hepatocyte apoptosis/ most common necrosis, In many eases, there is se levels; howe icute viral hepatitis. ydominal pain, Laboratory features include asymptomatic eleva- severe, symptoms are similar tients complain ol sigue, a nausea, and vomitin) ion of s mat alkaline phosphatase. Serum bi um aminotransferases, with a marked ele hormal/near rubin levels ate variable; however, an extreme elevation is a negative prognostic factor. Imaging studies show rotmal lier or, more commonly, diffe homo- teneous hepatomegaly without bile duct dilatation. In most cass, there is no specific therapy beyond identify- iid stopping the drug. Medications used in children that cause this type of injury include phenytoin, meth- ind acetaminophen. Most patients will recover once the toxin has been removed, although in rare situations an autoimmune hepatitis is triggered. This is not true for acetaminophen overdose, which isan isoniazid, haloth toxin, and specific treatiment is dis- cussed below. Cholestatic pattern of injury presents with com- plaints of jaundice and itching. Nausea, vomiting, and anorexia are prominent when symptoms are severe. Laboratory features include a marked elevation of alkaline phosphatase, GGT, and total and direct biliru- bin, with preservation of synthetic function and rela tively normal serum aminotransferase levels. Imaging studies are normal, without ductal dilation or evidence Of cholecystitis. Liver histology reveals intracellular cholestasis, bile plugs, and the absence of biliary inflammation and bile lakes. The clinical course differs from the hepatocellular pattern, as jaundice and pruri- tus can linger up to 6 months after removal of the toxin. Pediatric drugs causing cholestatic injury include estrogens and cyclosporine. In addition to removal of the toxin, patients can be treated with UDCA to enhance bile flow, Hepatocellular-cholestatie (mixed) pattern of injury involves feature of both types of injury. In gen- eral, patients present with nausea, a anorexia, vomiting, and with the more severe cases having jaundice and pruritus. Laboratory Features are variable with ele- vations of all liver tests, but usually not to the same extremes as seen in the hepatitic or cholestatic patterns, The same is true for liver histology. Drugs used in chil. slren that cause a mixed injury pattern include mac. rolide antibiotics, azathioprine, nitrofurantoin, and chlorpromazine, Treatment is similar to the other pat- terns: recognizing and removing the toxin and symp. tomatic treatment for pruritus, The typical disease course is also intermediate, being longer than that for hepatocellular injury, but shorter than the course for pure cholestatic pattern, Dipindai dengan CamScannersof the Liver 308 @ sion 4: Dison Fany liver pattern of injury (steatorie) occurs 1% esivtlan, oF small fat- droplets fat droplets, In macrove: av compo aand_macrovesicular, oF sicular steatosis there is nent as well, Macrovesiet that produce phospholipidosis, alcohol, and also liver bolic syndrome (Met; ally due to ype: micro) Ilya microvesi steatosis results from drugs alsease associated with the meta steatosis is p sling to a deficieney in mito~ oxidation of five fatty acids (FFA) and mitochondr chondrial be compromise of mitochondrial ATP production. norexia, andl vomiting, mmonia ean Patients present with nause Confusion or coma due to elevated seri be pre rude marked hyper- ammonemia, fact aminot ferases, and minimal elev ‘or GGT levels, Serum bilirubin levels reflect the severity of toxicity. Imaging studies are usually normal and histol rovesicular steatosis with min inflammatory infiltrate. Pediatric drugs associated with microvesicular steatotic injury pattern include valproic acid (VPA) and tetracycline. The usual course is rapid improvement after the toxic has been removed however, liver transplantation should be considered in patients with higher grades of encephalopathy. ent, Laboratory features acidosis elevated ser ion of alkaline phosph reveals m History Children with malignancies and seizure disorders are at increased risk of DILI and a heightened level of suspicion is warranted. In all cases, a through history of current of recent medications includes reviewing medication prep- aration, dose, and frequency of administration. The use of herbal preparations, illicit drugs, and xenobiotics needs to be ascertained. Evidence for recent infection or infectious exposures must be explored. Family history should include documentation of chronic liver disease, autoimmune conditions, early childhood/neonatal death, and stillbirths or spontaneous abortions. Differential Diagnosis ‘The differential diagnosis of suspected hepatotogicity includes acute viral hepatitis, acute ischemic liver injury, autoimmune hepatitis, congestive hepatitis, and hepatic decompensation due to Wilson's disease. Consideration of alternative causes of the cholestatic pattern includ biliary obstruction from gallstones, tumor, strictures, pancreatic disease, and autoimmune disorders such as ary sclerosing cho- iosis for the mixed condi tion includes all of the above. ‘The differential diagnosi for steatotic pattern of injury includes Reye's syndrome and inborn or acquired defects in mitochondrial fatty acid metabolism or ATP production, Glucoronidation Facune 20-5 m Actainapenmetaotin, Aebrevictin: NAPOL tyleystein ivacetyp-benzoquicaneimines NAC = acetjeystek Specific Drug Hepatotoxicities in Children Acetaminophen-induced liver disease results in a predict- able injury. Acetaminophen is a hydroxylated compound and does not require phase I activation prior to conjuga- tion (Figure 28-5). In therapeutic doses, acetaminophen is sulfated and glucuronidated by phase I! detoxification. In an overdose, phase I! pathways are saturated, and excess acetaminophen undergoes biotransformation by hepatic cytochrome P450 enzymes to produce the el trophilic intermediate, N-acetyl-p-benzoquinoneimine (NAPQI). At low rates of production, NAPQI is detoxi- fied by S-conjugation with GSH. At high rates of produc- tion, GSH is depleted, and it is assumed that NAPQIL becomes covalently bound to intracellular proteins, resulting in loss of cell function and cell death secondary to free radical-induced lipid peroxidation or an inappro- priate stimulation of an immune response. Toxicity resulting from a single large dose is distinctive, Nausea and vomiting occur immediately, followed by an asymp- tomatic interval of 12-24 hours, during which serum aminotransferase levels are increasing. Liver injury appears clinically in 2-4 days with the onset of jaundice, markedly elevated aminotransferases, and a developing coagulopathy, ultimately leading to liver failureand coma. Serum bilirubin, although elevated, is less so than in dther causes of acute liver failure and ean be a clue t0 recog nduced ALF. Treatment with, N-acetyleysteine (NAC) acts by providing a sub- strate for glutathione production. ‘Treatment must be given early as NAC will not reverse toxic effects once they have occurred. Treatment is most effective if given within 10 hours of ingestion; however, late administration of NAC has been associated with improved survival. Utiliza~ tion of NAC can be determined using a semilogarithmic acetaminophen: Dipindai dengan CamScanneragainst times NAC should be, tered for either 29 hours intraver Hai mie Although compara to aduite met arpese to be relatively resistant ee phe ene me dis they can. definitely. ir ovicit The estimated thtesholdde 1S0 mg/kg. Positive prognostic clotting factors and amr atter treatment, Liver ty Progressive liver failure toxicity should be transf Children ¢; induced liver disease Son of an inappropriate dose over several da often termed a therapeu : from shortening of the dos measuring device, or substit tion. The toxic dose is esti however, fiven anyway: The 72 hous orally Mescents children develop hepato between 120 and nelide normal ansferase levels 48 hours Ansplantation is indicated for and all patients with significant ferred to a transplant center ‘an also develop acetaminophen- 8 Fepeated administra his is misadventure, and can result ing frequency inappropriate tution of a different prepara- i imated to be about 90 mg/kj Clinicals the patent presents wit cue ty Pee for which other causes are usually suspected. Diagnosis Tequires a detailed drug history. Detecting serum act. aminophen 24 hours past the last dose, or demonstrat. ing the presence of acetaminophen protein adducts, formed by NAPQUI-glutathione, is suggestive of the diagnosis. The nomogram for treatment of acute over- dose with NAC does not apply, and these children should be treated mediately and transferred to a liver transplant center. Phenytoin-induced liver injury results from an unpredictable response to normal dosing, Although considered rare, it is second only to acetaminophen in reported incidents of pediatric drug-induced hepato- toxicity. Most patients present with hepatitis and immu- noallergic features of fever, rash, lymphadenopathy, and other organ involvement. Laboratory features include leukocytosis, atypical lymphocytosis, eosinophilia, ele- vated serum aminotransferases, and variable bilirubin levels, Severe cases can progress to liver failure. The mechanism of toxicity has not been completely defined but felt to result from abnormal metabolism of a toxic byproduct. Treatment consists of withdrawing the drug a, possi intravenous metnedilne 2 mg verse the allergic features, eae ok induced liver disease can be mild ot seve mild disease is the most common and is sminotransferases or ammonia. It is dose related an wes with dose reduction. Serious liver disease is bien ypharmacy and individual genetic probably related to polypharmacy andindvisue ene factors, A distinctive risk factor for cy js like other DILIs it is more common in chi F aoat i adults. Ldentifible risk factors include an age am ‘reatment with multiple anticonvulsants, and CHAPTER 28 Metabolic and Drug-induced Liver Disease @ 399 coexistent medical problems such as congenital abnor- malities, mental retardation, developmental delay, and n intercurrent infection, In children with these risk factors, the incidence of fatal hepatotoxicity is 1 in 600. Serum aminotransferase levels should be moni- tored for the first 6 months of treatment and with any dose escalation, A three-fold increase in serum level should prompt drug cessation. Associated symptoms of fever, nausea, vomiting, and abdominal pain are worri- some. Patients that develop progressive liver dysfunc- tion and poor seizure control will probably develop irreversible liver failure. The defective detoxification pathway is not known, but it appears that mitochondria are the target organelle. Liver histology shows microve- sicular steatosis and abnormal mitochondria. Similar to Reye's syndrome, serum carnitine is low. Prophylactic use of L-carnitine is recommended for children taking VPA and for asymptomatic hyperammonemia. NONALCOHOLIC-INDUCED LIVER DISEASE Definitions and Epidemiology NAFLD is a condition characterized by abnormal lipid dep>sition in hepatocytes in the absence of excessive alcoholic consumption. It represents a spectrum of con- ditions ranging from fatty liver without inflammation (hepatosteatosis) to fatty liver with necroinflammation (steatohepatitis). Nonalcoholic steatohepatitis (NASH) can progress to fibrosis and cirrhosis, causing portal hypertension and liver failure. NASH can coexist with other causes of fatty liver disease and, when present, can exacerbate disease activity. NAFLD is rapidly becoming the most common cause of elevated serum aminotransferase levels in chil- dren and the increase in prevalence parallels the obesity epidemic. The prevalence of pediatric NAFLD is unknown, but is estimated to be 89% of adolescents and increases to approximately 20% of obese children. The prevalence increases with age and degree of obesity, and is affected by ethnicity. Hispanic children have a higher prevalence than Caucasian or African American chil- dren, respectively. There isa significant association with type 2 diabetes mellitus (DM-2) and features of the Mets: insulin resistance, hypertrighyceridemia, hyper- tension, and visceral obesity. MetS has been reported in ‘up to 66% of children with NAFLD and is considered the hepatic manifestation of MetS."* Pathogenesis The obesity epidemic is attributed to overconsumption of dense-calorie foods containing saturated or Dipindai dengan CamScanner