CHAPTER I INTRODUCTION

Drug-induced allergic hepatitis is a liver-specific inflammatory reaction caused by hypersensitivity to a particular drug. Although less common than other forms of drug-induced hepatotoxicity, it has more serious clinical implications, the outcome can sometimes be fatal, and it appears to increase in proportion to the number of prescribed drugs.1 The serious drug-related hepatotoxicity that is disabling or life-threatening or that requires hospitalization. Although drug-related hepatotoxicity is uncommon for many drugs, the reported incidence is between 1 in 10,000 and 1 in 100,000 patients, its true incidence is difficult to determine. The numbers may be much higher, because of under reporting, difficulties in detection or diagnosis, and incomplete observation of persons exposed. In most cases, there is no effective treatment other than stopping the drug and providing general supportive care. In the United States, drug-related hepatotoxicity is now the leading cause of acute liver failure among patients referred for liver transplantation, most of whom have had no prior liver disease, because of an intentional or unintentional overdose of acetaminophen, the drug most often implicated in such cases.2 In contrast, hepatotoxicity associated with most other drugs is idiosyncratic, which implies by definition that DILI develops in only a small proportion of subjects exposed to a drug in therapeutic doses, and the risk of acute liver failure associated with idiosyncratic hepatotoxins is usually less than 1 per 10,000 exposed patients. However, more than 1,000 drugs and herbal products have been associated with idiosyncratic hepatotoxicity, and taken together idiosyncratic hepatotoxicity is responsible for more than 10% of all cases of acute liver failure.3, 4 DILI accounts for 7% of reported drug adverse effects, 2% of jaundice in hospitals, and approximately 30% of fulminant liver failure. DILI has replaced viral hepatitis as the most apparent cause of acute liver failure. A brief search of commercial pharmacopoeia databases suggests there are more than 700 drugs with reported hepatotoxicity and approved for use in the United States. With an estimated background rate of idiopathic liver failure of 1 in 1,000,000, the U.S. Food and Drug Administration (FDA) has withdrawn drugs or mandated relabeling for severe or fatal liver injury exceeding 1 in 50,000 individuals.5 Antituberculosis drug-induced liver injury (TB DILI) is a leading cause of DILI and drug-induced acute liver failure (DIALF) in many of the developing world. Single center registries of DILI continue to highlight the high incidence of DILI and DIALF, much of it 1

due to diagnostic errors and inappropriate prescriptions. The clinical spectrum includes asymptomatic elevation in liver tests to acute hepatitis and acute liver failure. TB DILI can occur across all age groups including children with significant morbidity and mortality. Although TB DILI develops more commonly in males, ALF is noted to be commoner in females with a worse prognosis. Contrasting reports on the role of genetic and environmental factors continue to be published. The presence of jaundice, hypoalbuminemia, ascites, encephalopathy and high prothrombin time are poor prognostic markers. 6, 7 The incidence has been reported to be higher in developing countries and factors such as acute or chronic liver disease, indiscriminate use of drugs, malnutrition and more advanced TB have been implicated. A high incidence of viral hepatitis has been reported to coexist in patients with TB in developing countries, resulting in misdiagnosis of tuberculosis drugs induced hepatotoxicity, especially if serological tests are not performed. A study from Nepal reported the incidence of hepatotoxicity as 8%.7 These include isoniazid (INH), rifampicin (RIF), pyrazinamide (PZA) and ethambutol (EMB). Although a vast majority of patients tolerate the drugs, some develop adverse effects of which hepatotoxicity is the most significant. Twenty percent of patients develop asymptomatic elevation of liver enzymes which is self limiting (as a result of adaptation or discontinuance) in a majority of patients but the outlook may be less favorable in those with develop jaundice, ascites, encephalopathy or acute liver failure.5, 8 Furthermore, the ripple effects of hepatotoxicity include disruption of treatment with potential for prolongation of treatment, genesis of drug resistance and suboptimal cure. Hepatotoxicity or DILI due to antituberculosis drug-induced liver injury (DILI) encompasses a wide spectrum of liver injury ranging from asymptomatic minimal elevation of liver enzymes to acute liver failure, often leading to death or liver transplantation. Indeed, it is a leading cause of drug-induced liver injury in India and of drug-induced acute liver failure leading to death (DIALF).5, 9, 10 In this case we described a case of a boy 12 years old with drug induced hepatities due to anti tuberculosis drugs. With suportive therapy has good result.

CHAPTER 2 CASE RESUME

An 13 years old boy (MRM, medical record C183381, from Kota Waringin, Pangkalan Bun), body weight 31,5 kg, height 145 cm was referred to Kariadi Hospital at October 16th 2009 with chief complain jaundice, three and a half month before admited to the dr Kariadi hospital, the patient complained cough for 1 week, fever subfebrile, no sputum, no cold, no petechie, no nausea, no vomite, no diarrhea. The parents took him to Pangkalan Bun Hospital, and from laboratory and rontgen investigation result the child was diagnosed with pulmonary tuberculosis by a Pediatrician, and got anti tuberculosis therapy (ATT). Two and a half month before admited to the dr Kariadi hospital, after consumtion of ATT for one month, the patient complained sudden high fever for 5 days, continuously, icteric, headache, myalgia, no gastrocnemius pain, heartburn, nausea, vomite 4-5 times / day, no diarrhea, no cough, no cold. The child looked weak, loss of appetite, tawny-colored urine with normal volume, urinary frequency, no dysuria, no urgency, and normal defecation. The parents took him to the Pangkalan Bun hospital and administered for 9 days, the laboratory examination revealed anaemia (Hb 6.1 g /dl), leukocytosis (21.000/mm3), AST 199 U/l, ALT 272 U/l, total bilirubin 24.2 mg/dl, direct bilirubin 15.6 mg/dl, widal O titers of 1/320 and positive plasmodium vivax. Anti tuberculosis drugs was stop due to the increasing of the liver enzymes. The parent discharged the child from hospital due to negative improvement and want to refer to Kariadi hospital. The child was never hepatities, severe illness, alergy history, and no often taken drugs or herbal medicine, similar like his family. Total scoring TB of this case was 1, from chest x ray. There was not other family or neighboard with chronic or bleeding cough. He has already full basic imunization. The child was administered to emergency room of Kariadi hospital, he was composmentis, weak, pale, icteric, adequate spontaneous breathing, and sub febrile fever. He had epigastrial pain, nausea, vomite more than 5 times/days, loss of appetite, tawny-colored urine and normal defecation. Physical examination found pulse, HR 84 x/minute, RR 24 x/minute, 37.5 C, normal BP 100/60 mmgHg. On Inspection, his conjunctiva was anemic, icteric sclera. In auscultation, lungs and the heart sounds were normal. Abdominal palpation was flat, flexible, epigastrial pain, hypocondriaca dextra pain, involving intestine sound normal, his liver was palpated 1/3-1/3 BH with a sharp border, elastic and flat. There were no costovertebral tenderness, suprapubic pain and no gastrocnemius pain. The D5 NS infusion was administered, laboratory tests, and chest x rays, was conduct before the patient admited to C1L1. Laboratory examination revealed Hb 6.4 g/dl with normally RDW and erythrocytes index, Ht 18.2%, WBC 9.800/mm3, platelet count 522.000/mm3, Ureum 16 mg/dl, creatinine 0,57 mg/dl,

calcium 2.29 mmol/L, sodium 138 mmol/L, potassium 3,5 mmol/L, chloride 108 mmol/L, blood glucose 90 mg/dl, serum cholesterol 456 mg/dl, serum HDL 32 mg/dl, serum LDL 378 mg/dl, serum trigliserid 229 mg/dl, total protein serum 5,6 g/dl, serum albumin 4,3 g/dl, total protein 6,1 gr/dl, AST 199 U/l, ALT 272 U/l, total bilirubine 22,92 mg/dl, direct bilirubine 16,9 mg/dl. Routine urine examination showed negative proteinuria, urobilinogen 8, bilirubinurine 6, negative lekosit esterase, sediment leucocyte 0-2, sediment erythrocyte 37,4/ Ul. The chest x rays impresion no cardiomegaly, bronchitis acute and thickening of the hilar glands. Assesment was: observation of icteric, with differential diagnosis were acute hepatities, drug induced hepatities, malaria and leptospirosis. And normocitic normochromic anaemia. Patient were treated in C1L1 with intravenous fluid D 10% 960/40/10 gtt/ minute, methicol 3x 1 tablet, urdafalk 2 x 250 mg, vitamin K 1 x 10 mg, vitamin A 1 x 6.000 iu. Program: transfusion PRC 300 cc. Diet: diet hepatities, 3 x 200 cc hepatosol.

History of Illness The boy was stayed in C1L1 of Kariadi Hospital. During hospitalization, his progress of illness was as follow: Day two: Body weight 31,5 kg, height 145 cm, HAZ -1,59 SD, BMI -1,94 SD, complain icteric, fever especially at night until 39 oC, epigastrial pain, abdominal discomfort, vomite and no gastrocnemius pain. General condition: ill appearance, conscious, adequat spontaneus breathing, and icteric. Physical examination showed t: 37.5 C, RR 24/min, HR: 92/min. Other physical examinations same with the previous day. Assesment was: observation of icteric, with differential diagnosis were acute hepatities, drug induced hepatities, malaria and leptospirosis. And normocitic normochromic anaemia and well nourised. Programs: haematology analyser tubex TF, blood smear, blood smear malaria, urinalisis, faeces routine, blood culture, urine culture. Counsultation to Gastroentero-Hepatology, Haemotology and Nutrition. Therapy: intravenous fluid dextrose 10% with maintenance sodium and potasium, amoxicillin injection, per oral medication and diet similar with the previous day. Day three-eight: complains: icteric, fever especially at night, epigastrial pain, abdominal discomfort. General condition: ill appearance, conscious. Physical examination showed: t: 37C, RR 24/min, HR:92 /min, other physical examinations equal with the previous day. Result counsultation from Gastroentero-Hepatologi: suspect hepatities, sugesstion for hepatities screening,

antituberculosis therapy stop, add urdafalk. From Nutrition: porridge low fiber three times, 200 cc hepatosol 3 times/ day, extra fruit sirup. Program: haematology analyser, blood smear, SGOT, SGPT, total bilirubin, direct bilirubin, ICT malaria, hepatities screenings, and abdominal USG. Laboratory result of IgM leptospirosis was positif but hepatities and malaria were negatif. From abdominal ultrasonografi impresion hepatomegali, rough liver parenchime was posiblility of drug induced hepatities with differential diagnose viral hepatities, suspect contracted gall bladder, there were no

fattering liver or enlargement gall bladder. Assesment was: observation of icteric, with differential diagnosis were drug induced hepatities and leptospirosis. Additional therapy with amoxicillin 500 mg 4 times/ day and others therapy unchanged. Diet: hepatities diet (porridge low fiber three times, 200 cc hepatosol 3 times/ day, extra fruit sirup. Day nine-seventeen: complains: abdominal discomfort, no vomite, sometimes still febris. General condition: conscious, adequately spontaneous breathing, icteric. Physical examination showed: t: 37 C, RR:20 x/min, HR: 88x /min. Abdominal palpation was flat, flexible, no epigastrial pain involving intestine sound normal, his liver was palpated - with a sharp border, elastic and flat. Others physical examinations equal with the previous day. Programs: haematology analyser, blood smear, SGOT, SGPT, total bilirubin, direct bilirubin, coagulation study, IgM, IgG CMV and toxoplasmosis. Counsultation to Haematology impresion chronical inflamation. Result of screenig of CMV and toxoplasmosis were negative. From urine culture revealed urinary tract infection with E. Coli, abnormal coagulation. Assesment was: observation of icteric, with differential diagnosis was drug induced hepatities and leptospirosis, urinary tract infection. Therapy: additional therapy with amicacyn injection 2 x 150 mg, others therapy unchanged. Transfution of FFP 250 cc. Day eighteen- tweenty eight: no abdominal discomfort, no febris. General condition: well, conscious, icteric. Physical examination showed t: 37C, RR 20/min, HR: 92/min, conjunctiva was not anemic, other physical examinations same with the previous day. Program: fine needle biopsi, haematology analyser, blood smear, SGOT, SGPT, total bilirubin, direct bilirubin, alkalifosfatase, gamma GT, total protein, albumin, coagulation study, cholesterol, trigliserid, urinalysis, liver biopsy. Result of liver biopsy revealed hepatic injury due to drug induced hepatotoxic. Assesment was: observation drug induced hepatities, leptospirosis, urinary tract infection. Therapy: intravenous fluid medication stop, change with cefixime 2 x 150 mg, others therapy peroral similar. Day tweenty nine-thirty one: Body weight 29 kg, still icteric. General condition: well appearance, conscious, icteric. Physical examination showed a t 36,8C, RR 20/min, HR 92/min, other physical examinations same with the previous day. Assesment was: observation drug induced hepatities due to OAT, leptospirosis, and urinary tract infection. Program: abdominal USG evaluation. Result of abdominal USG were impresion hepatomegali, structure of liver parenchime looked normally, no intra and extra hepatic duct enlargement, and the gall bladder shape looked normally. Therapy: cefixim stopped, others same with the previous day. Day thirty two: Body weight 29 kg, still icteric, no abdominal discomfort, no fever. General condition: well appearance, conscious, icteric. Physical examination showed a t 36,8C, RR 20/min, HR 92/min, other physical examinations same with the previous day. Therapy: methicol 3 x 1 tablet, urdafalk 2 x 250 mg, vitamin K 1 x 10 mg, vitamin A 1 x 6.000 iu. The patient discharge from Kariadi hospital referred back to Pangkalan Bun Hospital with drug induced hepatities, leptospirosis and post urinary tract infection.

The icteric released after 8 months since went out from Kariadi Hospital, with haemoglobin 10,7 gr/dl, SGOT 29 U/l, SGPT 52 U/l, total bilirubin 3, the boy was counsulted to pediatrician in Pangkalan Bun. Table 1. Laboratory examination result in Kariadi Hospital
Date Normal limit >11,5 4,2-5,2 juta 37-44 4.500-13.000 150-400rb 77-101 23-31 29-36 11,6-14,8 10-15 23,4-36,8 10,7-13,7 180-350 74-106 136-145 3,5-5,1 98-107 2,12-2,52 15-37 30-65 15-39 0,6-1,3 0-0,3 0-1 3,4-5,0 6,4-8,2 50-136 5-85 16-10-09 6,4 18,2 9.800 522.000 78,0 27,3 35,0 21,7 17-10-09 10,5 3,82 29,3 6.860 397.000 76,8 27,4 35,6 21,0 21-10-09 9,4 3,97 28,1 13.500 366.000 77,7 28,7 37,0 20,8 16,6/10,9 (1,5) 43,3/31,7 (1,4) 20,5/20 534 26-10-09 8,2 2,85 22,2 9.320 460.000 2-11-09 9,2 3,98 28,6 9.310 510.000 75,5 28,3 37,3 19,7 13,7/9,8 42,9/29,2 16,5/16 619,3

Hb (g/dl) Eritrosit (jt/mm3) Ht (%) LED Leukosit/mm3 Trombosit/mm3 MCV (fL) MCH (pg) MCHC (g/dl) RDW % PT PTT TT Fibrinogen mg/dl GDS (mg/dl) Na (mmol/l) K (mmjol/l) Cl (mmol/l) Ca (mmol/l) SGOT (U/l) SGPT (U/l) Ureum (mg/dl) Creatinin (mg/dl) Bil direk (U/l) Bil. Total (U/l) Albumin g/dl Prot g/dl Alk fosfat U/I Gama GT U/I Cholesterol mg/dl Trigliserid mg/dl HDL mg/dl LDL mg/dl ICT malaria Smear blood malaria IgM Leptospirosis HbsAg Anti HBs Anti HCV Anti HAV IgG Toxo IgM Toxo IgG CMV IgM CMV ANA

90 138 3,5 108 2,29 199 (5,38x) 272 (4,19x) 16 0,57 16,9 22,92 4,3 5,6 1.575 456

73 131 20 0,58 26,43 33,72

16,7 19,13 3,1 6,4 876 364 402 210

200 >55 150

229 32 378 neg neg Pos Neg Neg Neg neg Neg Neg Neg Neg 22,4

20-60 U

Urin

Faeces Kultur darah Kultur urin

Coklat keruh BJ 1,02, pH 6,5,prot 25, urobilin 8, bilirubin 6, leuko 0-2, eri 37,4, bakteri 19,4 Brown, karbohidrat +, bakteri +, yeast + Steril E. Coli > 100.000 Sensitif: cefotaxim, amikacyn, gentamicin Resisten: ampicilin, ceftazidim, ciprofloxacincotrimo xazol

Tabel 2. Blood smear result

17-10-09 Diff count Eritrosit E3/B0/St3/Sg74/L14/M5 Slightly anisocytosis (microsit), slightly poikilositisis (ovalosit) Quantity , big shape The quantity looks normal 21-10-09 E4/B0/St0/Sg76/L14/M6 Slightly anisocytosis (microsit, macrosit), moderate poikilocytosis (ovalosit, elipsoit, tear drop, pear shape, target cell, fragmentosit) Quantity , big shape The quantity looks normal

Trombosit Lekosit

Tabel 3. Supporting examination result

20/10/2009 USG abdomen Rough liver parenchime there is a posibility for drug induced, differential diagnosis: hepatitis Contracted gallblader suspect There is no liver fattening or bile duct enlargement There is no anomaly on the other intraabdominal organs sonography 31/10/2009 Hepatosplenomegali Liver parenchime structure still looks normal There is no intra and extra hepatal duct enlargement The gallblader shape looks normal, gallblader lumen was not filled with liquid/ no distension No ascites Biopsi tissue representative enough Shows liver tissue pieces with 4 portal tract and 4 central vein. Liver cells architecture is still in good condition, lobulus structure still can be interpreted. There were necrotic liver cells foccuses (degeneration of hepatocytes) and bile 8/11/2009

Fine needle Biopsy Liver

pigment on several liver cell citoplasm (hepatocellular cholestasis). Several double nucleus liver cell (regenerative) Kupfer cells is not proliferated No specific sign found No mallignant cells found

Conclussion: Liver, biopsi: hepatic injury due to drugs induced ( OAT)

Fig.1. Result of liver biopsy

Hepatoceluler colestasis

Perivenulae necrosis

CHAPTER III DISCUSSION Drug-induced allergic hepatitis is a liver-specific inflammatory reaction caused by hypersensitivity to a particular drug. Although less common than other forms of drug-induced hepatotoxicity, it has more serious clinical implications, the outcome can sometimes be fatal, and it appears to increase in proportion to the number of prescribed drugs. There is convincing experimental evidence to implicate the immune system in the pathogenesis of many drug hypersensitivity reactions. The onset of a hypersensitivity reaction frequently involves covalent binding of the drug to proteins (or more often as a result of its metabolism and bioactivation) to form immunogenic conjugates, followed by antigen uptake, processing, presentation and T-cell proliferation.1, 11 Hepatocytes, because of their capability to metabolize drugs, usually form drug protein adducts, for which the immune system normally shows tolerance. Hypersensitivity reactions occur when this tolerance is impaired. Additional signals, likely a concomitant inflammatory reaction, may eventually be needed to break this tolerance. The allergic hepatitis induced by drugs is generally a type IV hypersensitivity reaction involving CD4, CD8 cytotoxic lymphocytes as well natural killer cells. Antibodies directed to the drug are much less common. Antibodies against cellular components may also occur when the sensitization process evolves towards an autoimmune reaction.1, 12 Allergic hepatitis is frequently associated with fever, rash and liver cell infiltration (drug rash with eosinophilia and systemic symptoms (DRESS) syndrome). Clinically, both hepatocellular injury and cholestasis can occur, and most episodes have good clinical prognoses upon drug discontinuation. In few cases the damage to liver cells may continue, even upon drug withdrawal, in the form of an autoimmune hepatitis. The available diagnostic tools to confirm the involvement of a given drug in an immunomediated hepatic injury are rather limited, and this is largely due to a still incomplete understanding of the pathogenesis of drug allergy in the liver. Better understanding the molecular and cellular events will definitively help to identify risk factors, and facilitate the prediction and prevention strategies.1, 11 Most cases of DILI resolve on discontinuation of the drug, but recovery can take months or rarely the disease can progress despite drug withdrawal. Drugs such as methotrexate may lead to chronic hepatitis and cirrhosis, while others such as minocycline, nitrofurantoin and methyldopa are implicated in autoimune hepatitis.3, 4

Table 4. Drugs that have caused acute fulminant hepatic failure (Medical Economics, 2000
Anesthetic Enflurane Halothane Isoflurane Antimicrobials Dapsone Isoniazid Ketoconazole Pyrazinamide Rifampisine Sulfonamides Trovafloxacin Anticonvulsants Carbamazepine Felbamate Phenytoin Valproic acid Halothane Isoflurane NSAIDs and analgesics Acetaminophen Bromfenac Diclofenac Etodolac Indomethacin Oxaprozin Piroxicam Sulindac Miscellaneous agents Disulfiram Flutamide Labetolol Nefazodone Nicotinic acid Pemoline Propythiouracil Tolcapone Troglitazone

Source: Ansari JA.3 Earlier definitions were plagued by inconsistencies in elevation of numerical levels of transaminases needed for a diagnosis of DILI. Presently, there is a fair amount of consistency in the criteria used for diagnosing DILI including TB DILI. In the absence of symptoms, elevation of transaminases up to 5 times the upper limit of normal (ULN) and in the presence of symptoms up to three times the ULN or twice the ULN of bilirubin constitutes DILI.7 Drug-induced liver injury (DILI) is common and nearly all classes of medications can cause liver disease. Most cases of DILI are benign, and improve after drug withdrawal. It is important to recognize and remove the offending agent as quickly as possible to prevent the progression to chronic liver disease and/or acute liver failure. There are no definite risk factors for DILI, but pre-existing liver disease and genetic susceptibility may predispose certain individuals. Although most patients have clinical symptoms that are identical to other liver diseases, some patients may present with symptoms of systemic hypersensitivity. Adverse drug reactions is an important cause of liver injury that may require discontinuation of the offending agent, hospitalization, or even liver transplantation.6 Drug-induced liver injury (DILI) is ultimately a clinical diagnosis of exclusion. Histologic specimens of the liver are often not obtained. Other causes of liver injury, such as acute viral hepatitis, should be methodically sought, and their absence makes the diagnosis plausible. Usually, the time of onset to acute injury is within months of initiating a drug. Rechallenge with the suspected offending agent with more than twofold serum alanine aminotransferase (ALT) elevation, and discontinuation leading to a fall in ALT, is the 10

strongest confirmation of the diagnosis.5 Increases in the levels of the liver enzymes alanine aminotransferase (ALT) and aspartate aminotransferase (AST) in serum, in combination with increased bilirubin levels, are actually considered to be the most relevant indication of liver toxicity.8 Because the liver is responsible for concentrating and metabolizing a majority of medications, it is a prime target for medication-induced damage. However, a broad range of different pharmacological agents can induce liver damage, including anesthetics, anticancer drugs, antibiotics, antituberculosis agents, antiretrovirals, and cardiac medications. Depending on the duration of injury and the histological location of damage, drug-induced liver injury (DILI) is categorized as acute or chronic, and either as hepatitis, cholestatic, or a mixed pattern of injury.8 Tuberculosis is a major health burden worldwide. Although better drugs are available for managing tuberculosis, treatment failure is one of the common problems encountered. Among the various causes which can cause treatment interuption, drug induced hepatotoxicity is a common cause. Isoniazid and pyrazinamide are the common drugs causing hepatotoxicity. Upon occurrence of hepatotoxicity, the hepatotoxic drugs should be stopped and reintroduced as per the available guidelines. The healthcare professional should also counsel the patients for recognizing the early symptoms due to hepatotoxicity which could prevent morbidity.13 The clinical presentation of tuberculosis drugs associated hepatitis is similar to that of acute viral hepatitis. Tuberculosis drugs can cause varied degree of hepatotoxicity from a transitory asymptomatic rise in transaminases to acute liver failure and the frequency of hepatotoxicity in different countries varies widely from 2-39%.6 The occurrence of drug induced hepatotoxicity is unpredictable but it is observed that certain patients are at a relatively higher risk than other populations.13 Fatality due to tuberculosis drugs induced hepatotoxicity was more likely when jaundice occurred over 6 weeks after the start of therapy, serum bilirubin levels were higher or where treatment was continued despite jaundice. It has been observed in several studies that patients with pre-existing hepatic diseases due to chronic viral infection with Hepatitis B, Hepatitis C, HIV, alcoholics, the elderly, and the malnourished are at a higher risk of developing drug induced hepatitis compared to the general population. In some studies highest incidence of hepatotoxicity was observed in those who were given empirical anti tuberculosis therapy (ATT) without a definitive diagnosis of TB.13, 14

11

In this case, from anamnesis and physical examination lead to icteric observation with differential diagnosis hepatities viral infections, leptospirosis, malaria, drug induced hepatities. We suspected drug induced hepatities based on data from anamnesis with history of taken anti tuberculosis therapy for 1 month, then the patient complained joundice, fever, nausea, vomitte, but there was not rash. From the laboratory result, we found increased of liver function tests more than 5 times from ULN for AST and 4 times for ALT, increased of total bilirubin and direct bilirubin, then negative result of hepatities and malaria screening. Serological result of IgM leptospirosis was positif. Ultrasound impreased rough liver

parenchime was posibility for drugs induced hepatities. From liver showed liver cells architecture still good condition, there were necrotic liver cells foccuses (degeneration of hepatocytes) and bile pigment on several lever citoplasma cells (hepatocelluler cholestasis) with conclusion hepatic injury due to drugs induced hepatities, but limitation of this case we didnot stain with immunohistochemical staining, so we couldnt find immuno complex, and we didnt investigation of content of drugs in the blood too. We still differential diagnosis of jaundice was drugs-induced hepatitis and leptospirosis. It was posible drugs-induced hepatities combination with leptospirosis and urinary tract infections, made clinical manifestation worse.

General Mechanisms of Hepatotoxicity DILI is commonly classified into intrinsic vs. Idiosyncratic hepatotoxicity, and the latter further into allergic vs. non-allergic. Intrinsic hepatotoxicity is regarded as dose dependent and predictable above an approximate threshold dose, whereas idiosyncratic hepatotoxicity occurs without obvious dose-dependency and in an unpredictable fashion. Allergic idiosyncratic hepatotoxicity is characterized by the presence of typical symptoms and signs of adaptive immune reactions, including fever, skin reactions, eosinophilia, formation of autoantibodies, and a short latency time particularly after re-exposure. Other clinical classifications differentiate e.g. between hepatocellular, cholestatic or mixed liver enzyme patterns, histological criteria, acute vs. chronic onset, or severity. These classifications are useful in clinical practice because they describe typical clinical signatures of DILI for specific drugs, and they can also give useful hints regarding the involved mechanisms. Nevertheless, one must realize that these classifications are descriptive and based on clinical or histopathological criteria. They can therefore be misleading if mixed with mechanistic concepts and may indeed be the foundation of some classic paradigms that are now challenged by recent advances in mechanistic hepatotoxicity. For example, common 12

misconceptions are that specific substances can be clearly classified as either intrinsic or idiosyncratic hepatotoxins, and that dose or direct cell injury play no role in idiosyncratic hepatotoxicity. However, unpredictable rare severe DILI often develops on a background of frequent and dose-dependent mild increases in transaminases. 8

A general 3-step model for drug induced liver injury Such a general mechanistic model is presented in Fig. (2). According to this model DILI involves three subsequent main steps. It also includes details on the intrinsic and extrinsic pathways emphasizing the central role of mitochondria for the mechanisms leading to apoptosis vs. necrosis. Fig. (3) additionally demonstrates the important role of risk factors in DILI.8

1. Initial Mechanisms of Toxicity: Direct Cell Stress, Direct Mitochondrial Impairment, and Specific Immune Reactions First, drug metabolites or less frequently also parent drugs cause direct cell stress, target mitochondrial function, or trigger specific immune reactions. The most important drug metabolizing enzyme system for the creation of hepatotoxic reactive metabolites is the polymorphic cytochrome P450 (CYP450) family that mediates oxidative phase-I drug metabolism. However, conjugative phase-II metabolism may also result in hepatotoxic metabolites, e.g. acyl glucuronides are well known to cause DILI. Reactive metabolites can exert initial cell stress through a wide range of mechanisms including depletion of glutathione (GSH), or binding to enzymes, lipids, nucleic acids and other cell structures. Furthermore reactive metabolites or parent drugs may specifically inhibit other hepatocellular functions such as the apical (canalicular) bile salt efflux pump (BSEP, ABCB11 gene), in which case the subsequent intracellular accumulation of its substrates may cause secondary toxic hepatocyte damage. In case of initial targeting of mitochondria, reactive metabolites or parent drugs uncouple or inhibit the mitochondrial respiratory chain causing ATP depletion and increased concentrations of reactive oxygen species (ROS), inhibit - oxidation leading to steatosis (e.g. after intramitochondrial accumulation of amiodarone), damage mitochondrial DNA or interfere with its replication, or directly cause mitochondrial permeability transition (MPT), i.e. opening of the MPT pore located in their inner membrane. There is probably an injury threshold that involves inhibition of mitochondrial electron transport below a critical threshold and an increase in cytosolic ROS and JNK activation above a critical threshold for

13

liver injury to take place. The inhibition of mitochondrial electron transport in the early stages will not be reflected by elevated ALT values, indicating the requirement for earlier markers of impending mitochondrial damage. Functional tests such as the 13C-methionine breath test or the use of NMR spectra for metabonomics may prove to be useful here.8 Specific immune responses involving cytotoxic T-cells with concomitant release of inflammatory cytokines can be evoked by reactive metabolites that covalently bind to proteins and are subsequently recognized as neo-antigens (hapten formation). Their subsequent major histocompatibility complex (MHC)-dependent presentation on antigen presenting cells may then activate formation of antibodies against haptens or autoantibodies against cell structures such as CYP450 enzymes.8 In some instances initial injury also targets nonparenchymal liver cells. Examples include toxicity against biliary epithelial cells by reactive flucloxacillin metabolites, direct activation of stellate cells by methotrexate leading to fibrosis, or sinusoidal toxicity by herbal pyrrolizidine alkaloids or chemotherapy used for hematopoietic stem cell transplantation causing sinusoidal obstruction syndrome (venoocclusive disease). Further discussion of such nonparenchymal hepatotoxicity is beyond the scope of this review, but if the resulting damage is sufficiently severe it may eventually also extend to hepatocytes and lead to acute or chronic liver failure. Different hepatotoxins are typically associated with specific patterns regarding their initial mechanism of injury. However, one should be aware of the fact that a single drug may concomitantly act through several of these initial mechanisms, and that for many drugs at least some of the involved mechanisms currently remain unknown. These initial specific injurious mechanisms can also be referred to as upstream events. In the next step they lead to subsequent rather unspecific downstream events that involve the innate immune system, which balances pro- and anti-inflammatory responses and therefore determines the further progress to severe injury or recovery.8

2. Direct and Death Receptor-Mediated Pathways Leading to Mitochondrial Permeability Transition Second, initial cell stress and/or initial specific immune reactions lead to MPT. If the initial mechanism does not directly target and impair mitochondrial function, this occurs in two principle ways, i.e. either via a direct pathway initiated by severe cell stress (intrinsic pathway), or via an indirect death receptor-amplified pathway that is triggered by mild cell stress and/or specific immune reactions (extrinsic pathway).8

14

In the intrinsic pathway severe intracellular stress activates the endoplasmic reticulum pathway, lysosomal permeabilization, or c-jun N-terminal kinase (JNK). Subsequent activation of pro-apoptotic (e.g. Bax, Bak, Bad) and inhibition of anti-apoptotic (e.g. Bcl-2, Bcl-xL) proteins of the Bcl-2 family then activates MPT. 8 In the extrinsic pathway an initial mild injury may be amplified if inflammatory responses due to mild stress and/or additional factors have modulated the innate immune system, where signaling cytokines that promote (e.g. IL-12) or prevent (e.g. IL-4, IL-10, IL13, MCP-1) injury are usually well balanced. As a consequence, sensitized liver cells become more susceptible to lethal effects of tumor necrosis factor alpha (TNF), Fas ligand (FasL) and interferon gamma (IF). This is particularly important if one considers that the liver as the central organ of detoxification is constantly exposed to cell stress that can activate TNF and FasL. If the initial event is a specific immune reaction, MHC-dependent antigen presentation will activate the release of TNF and FasL from Kupffer cells (hepatic macrophages) and cytotoxic T-cells. According to the danger hypothesis for autoimmune diseases, haptenization alone may be insufficient to trigger the development of frank allergic hepatotoxicity, which requires an additional stimulation, a so-called danger-signal. If reactive metabolites cause concomitant mild direct cell stress or if other concomitant inflammatory diseases are present, the accompanying release of injurious cytokines may constitute such a danger signal that promotes MHCII-dependent antigen presentation, renders hepatocytes more susceptible to injury, and therefore promotes autoimmune hepatotoxicity. Regardless of how the extrinsic pathway is initiated, eventually TNF and FasL bind to intracellular death receptors, and TNF and Fas receptor- associated death domain proteins (TRADD/FADD) will subsequently activate initiator caspase 8. The activating death-receptor complex is also called the death-inducing signaling complex (DISC). Although initiator caspase 8 can start apoptosis through a direct activation of effector caspases 3, 6 and 7, this direct path appears to be too weak in hepatocytes to mediate apoptosis . Therefore an amplification mechanism is required: caspase 8 can activate proapoptotic Bcl-2 proteins (e.g. Bid), as well as signaling ceramides. Like in the intrinsic pathway this leads to MPT, which therefore plays a key role and is a common step that mediates further cell death in both, intrinsic as well as extrinsic pathways.8 3. Apoptosis and Necrosis Third, impaired mitochondrial function and energy production leads to apoptotic or necrotic cell death. MPT allows massive influx of protons through the inner mitochondrial 15

membrane, which stops mitochondrial ATP synthesis. Mitochondrial ATP depletion resulting from MPT (or other direct mechanisms of mitochondrial damage mentioned above) causes matrix expansion and mitochondrial outer membrane permeabilization and rupture with release of cytochrome c and other pro-apoptotic mitochondrial proteins from the intermembrane space into the cytosol.8 In the case of apoptosis, cytochrome C then binds to a cytoplasmic scaffold (apaf-1) and pro-caspase 9, forming a complex called apoptosome, which activates signaling procaspase 9. This, however, is an active process that requires ATP and can therefore only start if MPT did not rapidly and simultaneously occur in all mitochondria. Only if some mitochondria are left intact and continue to synthesize ATP, activated pro-caspase 9 and possibly also other pro-apoptotic mitochondrial proteins subsequently activate executioner caspase 3. Caspase 3 will then cleave specific cell proteins and further activate pro-caspases 6,7 and 2, which have their own target proteins. These processes eventually result in programmed apoptotic cell death, which is characterized by cytoplasmic and nuclear condensation and fragmentation without loss of membrane integrity. Histologically these remaining fragments are referred to as Councilman bodies. Apoptosis equals a silent cell death, where apoptotic fragments are removed by phagocytosis with little accompanying inflammation and therefore also only little secondary damage. Necrosis, in contrast, develops if the initial injury is so severe that MPT quickly occurs in all mitochondria, or if other mechanisms cause rapid severe mitochondrial ATP depletion, preventing the apoptotic pathway. This is typical for hepatotoxins that directly cause profound initial cell stress. However, in the absence of ATP also activation of the extrinsic pathway may lead to necrotic cell death. Cell swelling and lysis that follow severe disturbance of cell functions characterize necrosis. Necrotic cell lysis induces inflammatory responses including release of cytokines, which is important because these may amplify initial injury through a sensitization of surrounding hepatocytes and therefore cause further collateral damage. Finally it should be mentioned that the distinction between apoptosis and necrosis is not always clear-cut. Mixed phenomena have been described, and the same hepatotoxin may cause one or the other, or even the concomitant occurrence of both, depending on the circumstances including dose and preexisting vulnerability of hepatocytes.8 Apoptosis and necrosis may therefore also be regarded as a continuous spectrum. Furthermore some controversy exists around the exact mechanisms and triggers for hepatotoxic apoptosis including the role of MPT. In conclusion one can state that mitochondria stand in the center of life and death in hepatotoxicity: they can be targets of 16

initial direct toxicity, MPT plays a key role in the further signaling of extrinsic and intrinsic pathways, and because mitochondria generate most of the cells ATP supply and are also the main intracellular source of oxygen and nitrogen free radicals, the extent of mitochondrial impairment finally determines whether hepatocytes die by apoptosis or necrosis.8

Fig. (2). A 3-step mechanistic working model of hepatotoxicity. First, initial injury is exerted through direct cell stress, direct mitochondrial inhibition and/or specific immune reactions. Second, initial injury can lead to mitochondrial permeability transition (MPT). Direct cell stress causes MPT via the intrinsic pathway. The intrinsic pathway involves activation of intracellular stressor cascades and pro-apoptotic proteins including Bax. Alternatively MPT can be initiated through the death receptor-mediated extrinsic pathway that is activated by immune reactions and/or after sensitization to TNF and FasL binding to death receptors. Cytokines modulate the sensitivity of its activation. Third, MPT leads to necrosis or apoptosis depending on the availability of ATP. In hepatocytes activation of initiator caspase 8 through the extrinsic pathway is not sufficient to directly activate apoptosis, but amplification through pro-apoptotic factors including Bid and ceramides lead to MPT, which will then lead to the apoptotic pathway that is activated in the presence of sufficient remaining ATP production. Necrosis occurs if there is no ATP available, which is required for energy-consuming apoptotic pathways. Several highlighted amplification mechanisms (A) may play an important role at different levels for the idiosyncratic occurrence of hepatotoxicity.

Source: Russmann.8

17

A mechanistic view on risk factors From a mechanistic point of view risk factors for hepatotoxicity are of particular interest, because they are the very explanation for the rare occurrence that defines idiosyncratic DILI. Severe idiosyncratic DILI typically occurs in less than 1 in 10000 exposed patients, whereas most risk factors that have been associated with DILI have a much higher prevalence in the exposed population. In particular this is true for genetic polymorphisms, which, by definition, have a prevalence of at least 1%. Furthermore, even statistically significant relative risk estimates for such associations tend to be weak and therefore do not allow a reliable prediction of DILI in clinical practice. In perfect accordance with a complex multi-step mechanistic model of hepatotoxicity, this indicates that the presence of one single risk factor is usually not sufficient to explain the occurrence of idiosyncratic DILI, but that complex interactions of different mechanisms with several risk factors must be assumed in most cases. As mentioned above, incident environmental factors can function as triggering risk factors for DILI, particularly if they tip the balance of injurious vs. protective processes in the presence of other prevalent risk factors. Several clinical risk factors for DILI such as high age, female gender and concomitant diseases or drugs have been described. Many of those may actually be associated with altered pharmacokinetics, which are an obvious risk factor whenever toxicity is dose-dependent and altered pharmacokinetics result in elevated concentrations of parent drugs and/or their toxic metabolites. However, from a current mechanistic point of view, it is most interesting to ask where risk factors exert their effect based on a multi-step model of hepatotoxicity that differentiates specific upstream vs. Nonspecific downstream mechanisms. In addition, risk factors can also be classified as either genetic or environmental. Such a view on risk factors superimposed on the 3-stepmodel is shown in Fig. (2).8

18

Fig. (3). Risk factors for hepatotoxicity. First, risk factors can be classified into environmental vs. genetic factors. From a mechanistic point of view risk factors can further affect all different levels of events leading to the final outcome of drug-induced liver injury, which is mostly dichotomous, i.e. full recovery vs. acute liver failure. Note that risk factors affecting events downstream of initial injury are rather unspecific regarding different hepatotoxins. The figure presents a selection of well-described risk factors, but one must assume that other factors also play a role, of which many currently remain unknown.

Source: Russmann.8

Hepatocyte injury in the course of an allergic hepatitis: drug-induced liver autoimmunity The immune response to foreign antigens in the liver is generally associated with a strong and sustained CD4 and CD8 T-cell response. Immune-mediated killing of hepatocytes is mainly achieved by cytotoxic T cells. Activated CD8 T cells are recruited to or trapped in the liver irrespective of their antigen specificity. Only upon recognition of their cognate antigen, however, do these CD8 T cells undergo rapid proliferation. Proliferation presumably occurs directly in the liver in this scenario, as increased numbers of antigen-specific T cells are not detectable in draining lymph nodes during the early days after adoptive transfer. The 19

lytic activity of cytotoxic T lymphocytes (CTLs) can occur by at least two pathways. In the perforin/ granzyme-mediated pathway the pore-forming agent perforin, probably in conjunction with granzymes, induces apoptosis in target cells. In the Fas-mediated pathway, engagement of Fas and Fas ligand triggers apoptosis of the CTL-bound target cell by a death domain-initiated caspase cascade. Regardless of the initiating pathway, the downstream events that lead to apoptosis appear to be similar.1, 16 Natural killer cells and natural killer T (NKT) cells are effector cells in the liver. Natural killer cells are bone marrow-derived mononuclear cells that have markers of both T lymphocytes and macrophages. The cytoplasmic granules contain perforin and granzymes, which are involved in cell membrane attack and induction of apoptosis in target cells. As opposed to target recognition by cytotoxic T lymphocytes, recognition of target cells by natural killer cells is not restricted to MHC-antigen presentation and their major role is the defence of the liver against invading tumour cells acting by the Fas/ Fas ligand pathway, resulting in activation of the caspases cascade and apoptosis.1, 16 NKTcells are considered to be separate from natural killer cells and pit cell populations. In addition to natural killer phenotype, they present surface expression of TCR. The TCR on NKT cells interacts with CD1, as opposed to the MHC-1 or MHC-2 interaction with the TCR on T lymphocytes, and can interact with target cells without restrictions. This liver-resident, locally regenerating pool of rapid response killing cells has a significant role in defending the liver from invading tumour cells.1 Natural killer and NKT cells are likely to play a role in the progression of druginduced liver injury by secreting interferon-g, and provoking a concomitant inflammatory response (chemokine production, accumulation of neutrophils, and upregulating Fas ligand expression in the liver), thus contributing to the severity and progression of liver injury downstream of the metabolism of the drug hepatotoxicity. Nevertheless, natural killer and NKT cells have been reported to dramatically diminish in a case of fulminant drug hepatitis, suggesting that both may be involved in hepatic injury in fulminant hepatic failure.1 The role of Kupffer cells in drug hepatotoxicity is contradictory and likely to be indirect. These cells can be activated by different stimuli resulting in the release of mediators acting on hepatocytes (tumour necrosis factor a, nitric oxide, reactive oxygen species) that exert important catabolic effects on hepatocytes. Activation of Kupffer cells seems to be one of the early events in acetaminophen toxicity, yet a protective effect has also been described.1 Autoimmune hepatitis can be one of the consequences of a drug-mediated hypersensitivity reaction, in which damage to liver continues once the use of the drug has 20

been discontinued. The symptoms of drug-induced autoimmunity can resemble typical systemic autoimmune diseases (i.e. systemic lupus erythematosus) or be organ-specific autoimmune reactions (i.e. liver). If not recognized promptly, they can give rise to chronic hepatitis (resembling viral hepatitis, i.e. a-methyldopa, halothane, hydralazine and other hydrazine-containing drugs, minocycline, nitrofurantoin, and oxyphenisatin) or cholangitis (resembling primary biliary cirrhosis, i.e. chlorpromazine). Several antibiotics, notably penicillins, cephalosporins, and macrolides, may cause severe cholestasic hepatitis, but rarely, if ever, cause self-perpetuating autoimmune liver disease.1 A conceptual framework for the pathogenesis of autoimmune hepatitis points at environmental agents triggering a cascade of T-cell-mediated events directed at liver antigens in a host genetically predisposed to the disease. A T-cell-mediated immune response is thought to play a major role in the causation of autoimmune liver damage. In addition to CD4 T cells, there is growing evidence to suggest a role for CD8 T cells. The syndrome differs from typical drug hypersensitivity reactions in that drug-specific T cells or antibodies are not involved, and may even not result in immune sensitization to the drug. Certain drugs are already known to induce autoimmune hepatitis (e.g. diclofenac, methyldopa, nitrofurantoin, minocycline clometacin, and interferon) while others (rifampicin, atorvastatin/ ezetimibe) have recently been claimed to cause autoimmune hepatitis as well as other systemic manifestations, such as lupus. Many severe forms of drug-induced cholestasis persist after the drug has been discontinued, and a small number of patients who develop drug-associated cholestatic hepatitis develop progressive self-destruction of cholangiocytes. There are no clear mechanisms to explain the phenomenon by which drugs may disrupt immune tolerance to self antigens. CD4 T lymphocytes expressing the IL-2 receptor chain (CD25) appear to be central to self-tolerance maintenance, preventing the proliferation and effector function of autoreactiveTcells.1

Source: Russmann.10

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Source: Russmann.10 This case presumtively from anamnesis, physical examination and laboratory result drug allergic hepatities due to by immune mediated reaction, base on data history taking anti tuberculosis drugs, fever, anorexia, nausea, vomitte, abdominal pain,and jaundice. From laboratory result was found eosinofilia, increased of liver funtions tests, total and direct bilirubin, ANA was normal. Liver biopsy showed liver cells was still good condition, there were necrotic liver cells foccuses (degeneration of hepatocytes) and bile pigment on several liver citoplasma cells (hepatocelluler cholestasis), there was no increased of inflamatory cells with conclusion hepatic injury due to drugs induced. Limitations of this case we didnt stain with immunohistostaining, so we couldnt find immune complex. Certain drugs are already known to hepatitis drug induced by immune-mediated (e.g. diclofenac, methyldopa, nitrofurantoin, minocycline clometacin, and interferon) while others (rifampicin, atorvastatin/ ezetimibe) have recently been claimed to cause hepatitis as well as other systemic manifestations, such as lupus. Many severe forms of drug-induced cholestasis persist after the drug has been discontinued. Base on this data, we conclude this case was drugs-induced hepatities immune mediated type.

Diagnosis and treatment of drug reactions It is difficult to identify a drug reaction with certainty. However, the possibility of a drug reaction must be considered in any patient with liver dysfunction. A careful drug history should be taken, which includes the patients use of prescription, over-thecounter, herbal, or alternative medications. Injury induced by complementary and alternative medications has become more common as the use of these medications has increased. Other causes of liver dysfunction, such as viral hepatitis, biliary tract or liver disease, must be excluded by a thorough medical history taking, ultrasonography, and appropriate serologic tests. 22

Assessment of causality can be difficult; often, many agents are used simultaneously, and questions about other potential causes may be inadvertently omitted. Causality-assessment methods provide a uniform approach to determine the likelihood of drug involvement in a suspected episode of hepatitis. Included among the standard factors that should be considered are the temporal relation (whether the onset of the symptoms was between 5 and 90 days after the initial exposure); the course after the patient stopped taking the drug (improvement within weeks); the concomitant use of drugs; the exclusion of causes other than drugs (e.g. viral hepatitis); patients history with regard to previous toxic effects of the particular agent; and the response to rechallenge, if performed. In many instances, data are incomplete. Cautious rechallenge should be considered only if the diagnosis of drug-induced toxicity was highly questionable and only if no other drug is available to treat a serious problem.9 The most frequent hepatotoxic drug reactions evoke moderate-to-severe injury to hepatocytes with a clinical picture that resembles viral hepatitis, characterized by a rapid onset of malaise, anorexia, nausea, abdominal pain and jaundice in association with elevated aminotransferase levels. Each drug has its own pattern of injury. If hepatocyte injury

predominates, aminotransferase levels may be at least five times as high as normal. Elevations of alkaline phosphatase and bilirubin levels predominate in cholestatic syndromes. Signs of allergic reaction are absent in most patients. Acute liver failure may develop after a week or more of illness, particularly if the patient has continued the drug after the onset of symptoms. Death is not uncommon; elderly persons seem to be at particular risk, but specific data supporting this pattern are sparse.9 Important and specific agents with their effects on the liver. Most drugs have a signature effect, which is a specific patters of liver injury, although some drugs such as rifampicin can cause all kinds of liver injury, including hepatocellular injury, cholestasis, or even isolated hyperbilirubinemia. However, knowledge of the most commonly implicated agents and high index of suspicion are very essential in diagnosis.13, 17 Ethambutol, there are fewer reports of hepatic dysfunction with ethambutol in the treatment of tuberculosis. Abnormal liver function tests have been reported in some patients taking ethambutol; however, these patients were also taking other anti tuberculosis drugs knowns to cause liver dysfunction.10 Isoniazid, around 10-20% of patients during the first 4-6 months of therapy have a mild hepatic dysfunction shown by mild and transient increase in serum AST, ALT and bilirubin concentration. But in some patients the hepatic damage can be progressive and 23

cause fatal hepatitis. Acetyl hydrazine, a metabolite of Isoniazid is responsible for liver damage. Isoniazid should be stopped if the AST increases to over 5 times the normal value. A prospective cohort study of 11,141 patients receiving isoniazid preventive therapy reported a rate of hepatitis lower than that previously reported. Of these, 11 patients (0.10% of those starting and 0.15% of completing therapy) developed clinical hepatitis.3 Pyrazinamide, the well known adverse effect of this drug is hepatotoxicity. Hepatotoxicity is dose related and may occur any time during therapy. In the Centre for Diseases Control (CDC) update, 48 cases of hepatotoxicity were reported in association with a 2 months regimen of Rifampicin- pyrazinamide for the treatment of latent tuberculosis. Thirty-seven patients recovered and 11 died of liver failure. Of the 48 reported cases, 33 (69%) occurred in the second month of therapy.3 Rifampicin, transient abnormalities in liver function are common in the initial stages of therapy. But in some cases it may cause severe hepatotoxicity, more so in those with preexisting liver disease, forcing the physician to change tretment and opt for liver friendly treatment. Rifampicin causes transient elevations in hepatic enzymes usually within the first 8 weeks of therapy in 10 to 15% of patients, demonstrating overt rifampicin-induced hepatotoxicity. The occurence of mortality associated with hepatotoxicity has been reported to be 16 in 500,000 patients receiving rifampicin. A higher incidence of hepatotoxicity has been reported in patients receiving rifampicin with other anti tubercular agents and is estimated to be fewer than 4%.3 Patients were taking combination of anti-TB drugs. Due to this reason, it is difficult to conclude which drug was the main culprit for causing hepatitis. Although, INH is the major drug incriminated to induce hepatic injury, role of other possible hepatotoxic drugs (RMP and PZA) can also be speculated. Previous studies conducted have proven that the risk is in the order of INH + RMP>INH>PZA>RMP>E. Steele et al. also reported in their, metaanalysis that INH and RMP given together produce hepatotoxicity more than INH without RMP. Since INH, RMP and PZA are always given in combination, it is difficult to diagnose the drug causing hepatotoxicity. Hepatotoxicity can cause permanent injury and death. Early recognition of DIH with immediate withdrawal of offending agent is very important to arrest its development and allow liver to heal.18 British Thoracic Society suggests that if there is a rise in ALT and/or AST to greater than 3 times normal, or a rise in bilirubin, or if the patient showed clinical symptoms of hepatitis then drugs should be stopped and reintroduced sequentially when these parameters falls to previous levels. Within few days of cessation of drugs, liver enzymes returned to the 24

normal level. This normalization of the liver enzymes levels once the administration of the regimen has been halted proves that all signs and symptoms shown by the patient are related to the administration of anti-TB drugs.
18

Current American Thoracic Society center for

disease control recommends adequate monitoring (clinical as well as biochemical) of individuals in order to avoid unnecessary morbidity and mortality, hence decreasing the cost of illness. TB patients usually belong to poor socioeconomic status and they cannot afford regular LFTs. Close monitoring of the patients physical condition can be done in such situations. 18 In this case there was history taken anti tuberculosis drugs, specially rifampicin, isoniazid and pyrazinamid, fever, anorexia, nausea, vomitte, abdominal pain, ,from physical examination found jaundice, fever, abdominal pain, liver enlargement. From laboratory result found eosinofilia, elevation of hepatic enzymes serum AST and ALT increased until 5 and 4 times upper normal limit, and then total bilirubin concentration was 22,9 gr/dl, with direct bilirubin was 16,9 gr/dl. Screening for leptospirosis found positif of IgM leptospirosis. Screening of hepatities viral, malaria, TORCH were negative result. From liver biopsy showed liver cells architecture still good condition, there were necrotic liver cells foccuses (degeneration of hepatocytes) and bile pigment on several lever citoplasma cells (hepatocelluler cholestasis) with conclusion hepatic injury due to drugs induced hepatities, but limitation of this case we didnot stain with imunohistostaining, so we couldnt find immuno complex, and we didnt investigation of content of drugs in the blood too. Combination of leptospirosis, urinary tract infection and drug allergic presumtively increased of severity of clinical manifestasion jaundice and liver function tests from drug induced hepatities.

Therapeutic approaches Early diagnosis of drug-induced liver reactions is essential to minimizing toxicity. Monitoring hepatic enzyme level is appropriate and necessary with number of agents, especially with those that lead to overt toxicity. For drugs that produce hepatotoxicity unpredictably, biochemical monitoring is less useful. ALT (alanin aminotransferase) values are more specific than AST (aspartate aminotransferase) values. ALT values that are within the reference range at baseline and rise 2 to 3 fold should lead to enhanced vigilance in terms of more frequent monitoring. ALT values 4-5 times higher than the reference range should lead to prompt discontinuation of the drug.3, 14, 15, 19

25

Diagnosis of drug-induced hepatitis was made based on the presence of all the following criteria:20 1. Clinical features of icteric hepatitis (anorexia, nausea and jaundice). 2. Elevation of serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) above 200U/l (five times the upper limit of normal value) at the time of admission. 3. Serum total bilirubin of more than 34.2 micromol/l. 4. Absence of serological evidence of an acute infection with hepatitis A, B or C. IgM antihepatitis A virus (HAV) antibody for acute hepatitis A infection was done using enzyme linked immunosorbent assay at a local private laboratory (

No specific treatment is indicated for drug induced liver disease. Treatment is generally supportive and based on symptomatology. Other than different synthetic compounds several hundred plants have been examined for use in a wide variety of liver disorders. The first step of management of hepatotoxicity is to discontinue the suspected drug. In general, corticosteroids have no definitive role in tretment. They may suppress the systemic features associated with hypersensitivity or allergic reactions. Management of protracted drug induced cholestasis is similar to that for primary biliary cirrhosis. Cholestyramine may be used for alleviation of pruritus. Ursodeoxycholic acid may be used. Lastly, consulting a hepatologist is always helpful.3, 21 Prevention and treatment of acute hepatotoxicity caused by unpredictable (idiosyncratic) hepatotoxins: because no specific antidotal treatments exist for the forms of toxicity that are caused by drug allergy or metabolic idiosyncrasy, prevention is paramount. Severe immunologically mediated or allergic hepatitis is generally considered an indication for steroid therapy, but only anecdotal reports support its use and there is scarce evidence of its benefits. Management of acute non-immunologic hepatic injury consists of supportive and symptomatic treatment, the nature of which depends on the form injury.3, 14, 15, 19, 21

26

Fig 2. Protocol for anti-tuberculosis drugs and possible hepatotoxicity. LFTs: liver function tests; ALT: L-alanine 3 aminotransferase. Source : Saukkonen

Treatment of idiosyncratic acute hepatocellular injury; drug-induced hepatocellular jaundice has a potential case fatality rate of 10% or more. Accordingly, it warrants careful observation for evidence of impending hepatic failure. In the patient whose jaundice is not severe, whose prothrombine time is normal or negligibly prolonged and who has no clinical evidence of impending encephalopathy or coagulopathy, medical management can be simply supportive and the individual can be followed on an outpatient basis. Unless there is

evidence of impending hepatic failure, a standard diet is appropriate, with no need to modify the protein or other components. Persistent anorexia may be managed by multiple small feedings and by providing fruits, vegetables and dairy foods rather than meat. Carbonated drinks, fruits juice and hard candy are usually well tolerated even when nausea is marked. There is no need to restrict physical activity, although patients should be advised to stay within limits of fatigability. The patient with measurable prolongation of protrombin time and elevated bilirubin levels should be hospitalized (or observed very closely as an outpatient), particularly if there is persistent nausea and anorexia after the drug has been withdrawn.3, 14 Treatment of acute cholestatic injury, acute drug-induced cholestatic jaundice is rarely fatal. Over 99% of patients with cholestatic jaundice caused by erythromycin, chlorpromazine, amoxicillin-clavulanate, or anabolic steroids have survived the episode. There is no firm evidence that any therapeutic measure affect the rate of disapperance of drug-induced cholestasis. However, several anecdotal observations suggest that treatment with ursodeoxycholic acid increases the rate or retrun to normal status and in our view the effort is 27

waranted. The most important aspects of treatment of cholestatic jaundice relate to the treatment of pruritus. Cholestyramine, which can offer relief, presumably traps elements involved in the itching. Other potentially useful agents include hydroxyzine, rifampin and narcotic antagonists. There is no evidence that glucocorticoids provide symtomatic or other benefit in drug-induced cholestasis. Perhaps most important is an awareness that certain druginduced cholestatic reactions can be mistaken for syndromes of anatomic biliary obstruction calling for surgical intervention, as has been seen with erythromycin and amoxicillincalvulanate.3, 14 Management of chronic drug-induced hepatic disease; treatment of the various syndromes of chronic hepatic disease that may be drug-induced mainly involves recognition of symptoms and withdrawal of the responsible agent. The lesion and syndrome of chronic hepatitis may be caused by a number of agents and by different mechanisms. Chronic autoimun hepatitis; drug-induced chronic autoimune hepatitis may resemble, to a striking degree, the form of chronic necroinflammatory disease dubbed autoimmune in origin. This type of injury has been reported following use several agents, including nitrofurantoin, minocycline, methyldopa, diclofenac, rifampicyn and pamoline, among others. Indeed, in any form of non viral chronic hepatitis, especially with autoimmune features, a drug should be suspected as the cause. Following withdrawal, improvement should become noticeable within 1 to 4 weeks. 3 Chronic cholestasis; drug induced chronic cholestasis is usually a sequel to acute cholestatic injury with loss of portal area bile ducts Vanishing bile duct syndrome, (VBDS). Currently, there is no accepted therapy for the cholestatic process in patients with VBDS, however ursodiol has been used successfully in a few reported patients who had received amoxicillin calvulanate, chlorpromazine, prochlorpromazine (improving pruritus and liver function tess) androgens, anabolic steroids and tetracycline. This syndrome usually resolves spontaneus, although it may take several months to years and only minority of these patients develop secondary biliary cirrhosis.3 Referral to liver transplantation centre/ surgical care; no specific antidote is available for the vast majority of hepatotoxicity agents. Emergency liver transplantation has increasing utility in the setting of drug-induced fulminant hepatotoxicity. Considering early liver transplantation is important. The Model for End Stage Liver Disease score can be used to evaluate short term survival in an adult with end stage liver disease. This can help stratify candidates for liver transplantation. The parameters used are serum creatinine, total bilirubin, international normalized ratio and the cause of the cirrhosis.1 28

In this case, management for hepatities drug- induced due to anti tuberculosis drugs stopped all drugs suspected, and given urdafalk (ursodeoksikolat acid) for hepatoprotector. Icteric and elevated of liver function test in this case due to of hepatities drug-induced, made serious with comorbidity were leptospirosis and urinary tract infections. The clinis condition of patient were more better with treatment of leptospirosis and urinary tract infections , and also stopped of suspected drugs made allergy. When discharge from hospital condition of patient was more better, no fever, no nausea, no vomitted but still icteric when discharged from hospital.

Leptospirosis Leptospirosis is a zoonotic disease caused by pathogenic spirochetes of the genus Leptospira. Leptospirosis is an infectious disease of worldwide distribution. Human infection can occur either through direct contact with infected animals or much more commonly through indirect contact with water or soil contaminated by urine of infected rodents or animals.22, 23 Person-to-person transmission is extremely rare since man is a dead-end host for leptospiral dissemination. In contrast, leptospires can survive for long periods in the renal tubules of infected animals without causing illness. Most human infections occur in young adult men and children and result from occupational or environmental exposure.22, 23 The clinical manifestations is mild form leptospirosis may present as an influenza-like illness with headache and myalgia. Severe leptospirosis, characterized by jaundice, renal dysfunction, and hemorrhagic diathesis, is referred to as Weils syndrome. Incubation Period: 2-26 days (usually 7-12 days) In general, clinical manifestation can be divided into two distinct clinical syndromes. 90% of patients present with mild anicteric febrile illness; 10% are severely ill with jaundice and other manifestations (Weils disease). 22, 24 Anicteric leptospirosis is the more common and milder form of the disease, and is often biphasic. In the first or septicemic phase, patients usually present with an abrupt onset of fever, chills, headache, myalgia, skin rash, nausea, vomiting, conjunctival suffusion, and prostration. Leptospires can be isolated from blood, cerebrospinal fluid (CSF), and tissues. The fever may be high and remittent reaching a peak of 40C before defervescence. Conjunctival suffusion is characteristic and usually appears on the third or fourth day. Myalgias usually involve the muscles in the calf, abdomen, and paraspinal region and can be severe. When present in the neck, myalgias may cause nuchal rigidity reminiscent of meningitis. In the abdomen, myalgia may mimic acute abdomen, leading to confusion with 29

surgical intra-abdominal emergencies. The skin manifestations seen in mild leptospirosis include transient urticarial, macular or maculopapular, erythematous or purpuric rash. The first phase lasts 3- 9 days followed by 2-3 days of defervescence, after which the second or immune phase develops. The immune phase, is characterized by leptospiruria and correlates with the appearance of IgM antibodies in the serum. Leptospira now settle in glomeruli and are eliminated from all sites in the host except eye and perhaps brain, where they may persist for weeks or months. Fever and earlier constitutional symptoms recur in some patients, and signs of meningitis, such as headache, photophobia, and nuchal rigidity may develop. Central nervous system (CNS) involvement in leptospirosis most commonly occurs as aseptic meningitis. Complications such as optic neuritis, uveitis, iridocyclitis, chorioretinitis, and peripheral neuropathy occur more frequently in the immune phase. Prolonged or recurrent uveitis was demonstrated in 2% of patients with onset several months after symptoms of clinical leptospirosis. A rare but severe manifestation is hemorrhagic pneumonia. The illness in anicteric leptospirosis may be self-limited, lasting 4-30 days, with complete recovery as a rule. 22-24 In icteric leptospirosis (Weils syndrome) (usually caused by L. icterohaemorrhagiae), persistent high fever and jaundice may obscure the two phases. This is usually associated with hepatic dysfunction, renal insufficiency, hemorrhage and multi-organ failure (MOF). Hemorrhage can occur as petechiae, purpura, conjunctival hemorrhage and gastrointestinal hemorrhage. MOF is associated with a very high mortality. Myocarditis and hemorrhagic pulmonary infiltration are other complications, which may prove fatal. 22, 23

Source: Dutta22 The investigations with most of the routine laboratory tests show nonspecific findings. The leucocyte count can be low, normal or elevated, but is usually associated with a shift to left. Mild anemia and thrombocytopenia are common; hemolytic anemia and disseminated intravascular coagulopathy (DIC) have been described in severe cases. Thrombocytopenia is found in more than 50% of patients and is significantly associated with renal failure. Liver,

30

kidney and central nervous system involvement may be present in any combination. Liver involvement may be mild, or severe with bilirubin levels reaching very high. Serum alkaline phosphatase, lactate dehydrogenase, aspartate aminotransferase (AST) and alanine aminotransferase (ALT) may all be elevated, but serum AST is only mildly or moderately elevated (unlike in viral hepatitis). Hyperamylasemia occurs frequently in severe disease, but pancreatitis is rare. Serum creatinine phosphokinase (CPK) is usually raised due to muscular involvement.22, 23 Proteinuria, pyuria, hematuria, and hyaline or granular casts are common findings on urine analysis even in the absence of renal dysfunction. Renal functional impairment is primarily a result of tubular damage; however, hypovolemia may play a critical role in the subsequent development of renal insufficiency. In the cerebrospinal fluid (CSF), features are those of aseptic meningitis. The CSF protein level may be normal or elevated upto 300 mg/dl, while the glucose concentration is normal. Although abnormal CSF findings are reported in as many as 80% of leptospirosis cases, only half of the patients are symptomatic. Various electrocardiographic and chest x-ray abnormalities are observed in patients with leptospirosis. Arrhythmias due to significant cardiac irritability have been documented. The arrhythmias observed were atrial fibrillation, atrial flutter, atrial tachycardia and premature ventricular contractions. Echocardiograms may reveal pericarditis and small pericardial effusion, in few cases. The chest radiographic abnormalities can include pulmonary edema, diffuse pneumonitis, nonsegmental or basal linear opacities and pleural effusions.22, 23 Specific Diagnosis: Definitive diagnosis of leptospirosis depends on:22 (i) Isolation of organism (ii) Serological tests (iii) Detection of specific DNA Isolation of organism, with: a) Blood : The organism may be identified by dark field examination of the patients blood or by culture on a semisolid medium (eg. Fletchers EMJH), if taken before the tenth day of illness. Cultures take 1-6 weeks to become positive. b) Urine : The organism may be isolated from the urine on darkground microscopy tenth day onwards, and in untreated patient, may be recovered on urine culture for several months. Diagnosis is usually made by means of serologic tests, of which several are available. a) Agglutination tests (microscopic, using live organisms; and macroscopic, using killed antigen) become positive after 7-10 days of illness, peak at 3- 4 weeks, and may persist at 31

high levels for many years. Thus, to make a diagnosis, a fourfold or greater rise in titer must be documented. The agglutination tests are cumbersome to perform and require trained personnel. b) ELISA IgM and slide agglutination tests (SAT) are also available. As ELISA IgM and Slide agglutination tests (SAT) are simple, sensitive tests which measure IgM antibodies, they are used to diagnose current leptospirosis at a very early stage and a single sample is adequate. The IgM ELISA test is particularly useful in making an early diagnosis, as it is positive as early as 2 days into illness, a time when the clinical manifestation may be nonspecific. It was found to be 100% sensitive and 93% specific in one study. Dot-ELISA and dip-stick methods for detecting IgM antibodies are newer screening methods.

PCR methods (presently investigational) appear to be sensitive, specific, positive early in disease, and able to detect leptospiral DNA in blood, urine, cerebrospinal fluid (CSF) and aqueous humor. Currently major disadvantage with these tests is that these are genusspecific, not serovar specific. Specific Serovar, the investigations of choice to identify specific serovar is microscopic agglutination test (MAT) and culture isolation. However, culture growth may take several weeks. In this case, from anamnesis we found history of fever, jaoundice, headache, mialgia, heartburn, nausea, vomitte, loss of appetite, tawny-colored urine, no atralgia, no gastrocnemius pain. From physical examination founded jaundice, sclera icteric, no conjungtiva sufficion, no gastrocnemius pain. From laboratory results founded anemia, leucosyte and trobocyte were normally, IgM leptospira positif, increased of liver function tests, urinalisys and renal function were normally. Treatment of leptospirosis with various antimicrobial drugs, including penicillin and tetracyclines, show antileptospiral activity. Penicillin (e.g. 6 million units daily intravenously) is the drug of choice in severe leptospirosis and is especially effective if started within first four days of illness. Total duration of therapy should be 10-14 days. Amoxycillin and erythromycin have also been found effective in severe leptospirosis. Patient should be observed for evidence of renal failure, and treated, if necessary, with hemodialysis. Patients with Weils disease having hemorrhagic manifestation may require whole blood or platelet transfusion. Patients with MOF require to be observed in intensive care unit.22

32

Besides penicillin, doxycycline in a dosage of 100 mg twice daily for 7 days is effective in treatment of mild and moderate leptospirosis. Effective prophylaxis consists of doxycycline, 200 mg orally once weekly, during the risk of exposure.23

Source: Kobayashi Y 23 The treatment of this case, we gave amoxicillin 500 mg three times a day. The clinical manifestasion more better, but there was urynary tract infection made worse condition, and then we changed antibiotic appropriate urine culture result. The prognosis of leptospirosis depends on the severity of the disease and the associated complications. Anicteric leptospirosis usually has a good prognosis. Without jaundice the disease is almost never fatal; however, fatal pulmonary hemorrhage and myocarditis have been reported occasionally in anicteric cases. The case fatality rate for Weils disease is 15-40%, and is higher for patients over 60 years of age.22

Urinary Tract Infection Urinary tract infection was estimated that 8% of girls and 2% of boys will acquired UTIs in childhood. Girls olders than age 6 months have UTIs far more commonly than boys, whereas uncircumcised boys younger than 3 months of age have more UTIs than girls. Circumcision reduces the risk of UTI in boys. The density of distal urethral and periurethral bacterial colonization with uropathogenic bacteria correlates with the risk of UTI in children. Most UTIs are ascending infections. Specific adhesins present on fimbria of uropathogenic bacteria allow colonization of the uroepithelium in the urethra and bladder and increase th likelihood of UTI.25, 26 Pathogenesis of urinary tract infection was dysfunctional voiding, which in uncoordinated relaxation of the urethral sphincter during voiding, leads to incomplete emptying of the bladder, increasing the risk of bacterial colonization. Similarly, any condition that interferon with complete emptying of the bladder, such as constipation or neurogenic bladder, increase the risk of UTI. Poor perineal hygiene, structural abnormalities of the 33

urinary tract, catheterization, instrumentation of the urinary tract, and sexual activity increase the risk as well.25-27 The inflammatory response the pyelonephritis may produce renal parenchymal scars. Such scars in infancy and childhood were contribute to hypertension, renal disease, and renal failure later in life. The organism most commonly responsible for UTI are fecal flora, most commonly E Coli (>85%), Klebsiella, Proteus, other gram-negative bacteria, and less frequently Enterococcus or coagulase-negative staphylococci.25-27 The clinical manifestations UTI in newborn and infants have nonspecific signs, including fever, hypothermia, jaundice, poor feeding, irritability, vomiting, failure to thrive, and sepsis. Strong, foul smelling or cloudy urine may be noted. Preschool children may have abdominal or flank pain, vomiting, fever, urinary frequency, dysuria, urgency or enuresis. School-aged children commonly have classic sign of cystitis (frequency, dysuria and urgency) or pyelonephritis (fever, vomiting and flank pain). Costovertebral tenderness is unusual in young children, but may be demonstrated by school-aged children. Physical examination should include attention to blood pressure determination. Urethritis, poor perineal hygiene, herpes simplex virus, or other genitourinary infections may be apparent on examination.25, 26, 28 Laboratory finding, from collections of urine for urinalysis and culture is difficult in children due to frequent contamination of the sample. In toilet-trained, cooperative, older children, a midstream, clean-catch method is satisfactory. Although cleaning of the perineum does not improve specimen quality, straddling of the toilet to separate the labia in girls, retractions of the foreskin in boys, and collecting midstream urine significantly reduce contamination. In infants and young children, bladder catheterization or suprapubic collection is necessary in most cases to avoid contaminated samples. Bagged urine specimens are helpful only if negative.25, 26 Screening urinalysis indicates pyuria (>5 WBCs/ highpower field) in most children with UTI, but many children with pyuria do not with have UTI. White cells from urethra or vagina may be present in urine or may be in the urine because systemic infection. The leukocyte esterase test correlates with pyuria, but has a similar false-positive rate. The detection of urinary nitrite by dipstick is highly correlated with enteric organism being culture from urine. Most young children (70%) with UTI have negative nitrite test. They empty their bladders frequently, and it requires several hours for bacteria to convert ingested nitrates to nitrite in the bladder. The sensitivity of nitrite detection is highest on a first

34

morning void. Gram stain of urine correlates well with culture recovery of 105 colonyforming units (cfu)/mL or more, but this test is frequently unavailable outside hospital.25, 26 The gold standart for diganosis remains the culture of a properly collected urine specimen. Specimens that are not immediately cultured should be refrigerated and kept cold during transport. Any growth is considered significant from a suprapubic culture. Quantitative recovery of colony-forming units (cfu)/mL or more is considered significant on clean catch speciments, and 104-105 is considered significant on catheterized specimens. Usually the recovery of multiple organism indicates contamination, but some contaminated specimens yield only a single species. 25, 26 Treament may increased the risk of symtomatic UTI by eliminating nonpathogenic colonization. Screening urine cultures in nonsymptomatic children are, therefore, generally discouraged. Repeate urine cultures are often helpful in differentiating asymptomatic bacteriuria from contamination of the culture versus true UTI. Urinary fuction during UTI should be assesed by measurement of BUN and serum creatinine consentration.25, 26, 28 Imaging, because congenital urologic abnormalities increase the risk of UTI, radiologic evaluation of first UTI has been routinely recommended. These recomendation usually include routine ultrasound of the kidney and voiding cystourethrogram (VCUG). Vesicoureteral reflux (VUR) is a congenital abnormality presents in about 1% of the population. VUR is graded using the international scale (1- reflux into ureter, II- reflux to the kidney; III reflux to the kidney with dilatation of ureter only; IV reflux with dilatation ureter and mild blunting of renal calyces; V reflux with dilatation of ureter and blunting of renal calyces). Reflux is detected in 30-50% of children 1 year of age and younger. The natural history of reflux is to improve, and 80% of reflux of grades I, II or III will resolve or significantly improve within 3 years following detection. 25, 26 VCUG should be done selectively on children with a first UTI. Children with suspected urologic abnormality due to weak stream, dribbling, or perineal abnormalities should be studied with VCUG. Boys with a first UTI should be studied to detect posterior urethral valves, an important congenital abnormality that requires surgery. Children older than 3 years of age who are otherwise healthy and growing well usually can be followed clinically and do not need VCUG for a first UTI. The yield in sexually active teenagers is also very low. 25 Ultrasonographic examination of kidneys should be done in children with acute pyelonephritis who have not improved after 3-5 days of antimicrobial treatment adjusted for

35

the susceptibility of the organism. The examination is done to detect renal of perirenal abscesses or obstruction of the kidney. 25 In this case, diagnosis UTI based on history of fever, jaundice, nausea, vomitte, urinary frequency, no disuria, no urgency, no suprapubic pain. Result of urine cultur found Eschericea Coli more than 100.000 cfu/mm3. Management of UTI is influenced by clinical asessment. Very young children (younger than 3 months) and children with dehydration, toxicity, or sepsis should admited to the hospital and treated with parenteral antimicrobials. Older infants and children who are not seriously ill can be treated as outpatients. Initial antimicrobial therapy is based on prior history of infection inthe urinary tract.25, 28 Uncomplicated cystitis can be treated with amoxicilin, trimethoprim-

sulfamethoxazole, or a first generation cephalosporine. These antimicrobial are concentrated in the lower urinary tract, and high cure rates are common. There are significant differences in the rates of anti mycrobial resistance, so knowledge af the rates in the local community is important. More seriously ill children are initially treated parenterally with a third generation cephalosporin or aminoglycoside. The initial antimicrobial choice is adjusted after culture and susceptibility are known. The recomended duration of antimicrobial therapy for

uncomplicated cystitis is 7-10 days. For sexually mature teenagers with cystitis, fluoroquinolones such as ciprofloxacin and levofloxacin for 3 days are effective and cost effective. Short course therapy of cystitisis not recomended in children, because differentiating upper and lower tract disease may be difficult , and higher failure rates are reported in most studies of short therapy. 25, 28 Prophylactic selected of children with frequently recurring UTI may benefit from prophylactic antimicrobials. In children with high grade VUR, prophilactic antimicrobial may be beneficial in reducing UTI, as an alternative to surgical correction, or in the interval prior to surgical therapy. Many experts recommended surgical corrections to higher-grade reflux, particularly grade V. Trimethophrim-sulfamethoxazole and nitrofurantoin are approved for prophylaxis. The use of broader spectrum antimicrobials leads to colonization and infection with resistant strain. Children with dysfunctional voiding generally do not benefit from prophilactic antimicrobials, rather addresing the underlying dysfunctional voiding is most important.25, 28 The treatment in this case, was given amycacin that the antibiotic appropriate with urine culture result for 15 days, and then switched to oral antibiotic with cefixim. The clinis of patient showed more better, there was no fever when discharge from Kariadi Hospital. 36

Anemia is defined as decrease in hemoglobin concentration below lower limit of normal with reference to age and gender. Anemia is not a diagnosis but a finding that requires further investigation. It has direct or indirect relationship with multiple determinant factors which form the basis of investigation. Anemia is a frequent laboratory abnormality in children. Multiple causes exist, but with a thorough history, a physical examination and limited laboratory evaluation a specific diagnosis can usually be established. The use of the mean corpuscular volume to classify the anemia as microcytic, normocytic or macrocytic is a standard diagnostic approach. The most common form of microcytic anemia is iron deficiency caused by reduced dietary intake. It is easily treatable with supplemental iron and early intervention may prevent later loss of cognitive function. Less common causes of microcytosis are thalassemia and lead poisoning. Normocytic anemia has many causes, making the diagnosis more difficult. The reticulocyte count will help narrow the differential diagnosis; however, additional testing may be necessary to rule out hemolysis, hemoglobinopathies, membrane defects and enzymopathies. Macrocytic anemia may be caused by a deficiency of folic acid and/or vitamin B12, hypothyroidism and liver disease. This form of anemia is uncommon in children.29, 30 Anemia is a relatively common finding and identifying the cause is important. Event though anemia in chilhood has many causes, the correct diagnosis can usually be established with relatively little laboratory cost. Frequently the cause is identified with a careful history. The posibility of nutritional causes ahould be adressed by inquiry about dietary intake, growth and development; and symptoms of chronic disease, malabsorbtion, or blood loss. Hemolitic disease may be associated with a history of jaundice (including neonatal jaundice) or by a family history of anemia, jaundice, gall bladder diase, splenomegaly or splenectomy. The child ethnic background may suggest the posibility of certain hemoglobinopathies or of deficiencies of red cell enzymes, such as glucose-6-phosphate dehydrogenase (G6PD). The review of systems may reveal clues to a previously unsuspected systemic disease associated with anemia. The patients age is important because some causes of anemia are age related. For example, patients with iron deficiency anemia and -globin disorders present more commonly at age 6-36 months than at ohers in life.31, 32 The physical examination may also reveal clues to the cause of anemia. Poor growth may suggest chronic disease or hypotiroidism. Congenital anomalies may be associated with constitutional aplastic anemia (Fanconi anemia) or with congenital hypoplastic anemia (Diamond Blackfan anemia). Other disorder may be suggested by the finding of petechie or 37

purpura (leukemia, aplastic anemia, hemolytic uremic syndrome), jaundice (hemolysis or liver disease), generalised lymphadenopthy ( leukemia, juvenil rheumatoid arthritis, HIV infection), splenomegaly (leukemia, sikcle haemoglobin syndromes, hereditary spherocytosis, liver disease, hypersplenism), chronic or recurrent infection.32 The initial laboratory evaluation of the anemic child consists of a complete blood count (CBC) with differential and platelet count, review of the peripheral blood smear, and a reticulocyte count. The algorithm in figure uses limited laboratory information, together with history and physical examination, to reach a specific diagnosis or focus to additional laboratory investigations on a limited diagnostic category (eg. Microcytic anemia, bone marrow failure, pure red aplasia, or hemolytic disease). This diagnostic scheme depends principally on the MCV to determine whether the anemia is microcytic, normocytic or macrocytic, according to the percentile curves of Dallman and Siimes. 31, 32
Anemia

MCV Low Normal or high Reticulocyte count Low High

History, physical examination, CBC compatible with iron deficiency

Yes Response to trial of iron

No

Peripheral smear

Peripheral smear

No hemolysis Neutrophils, Yes No platelet

hemolysis Specific tests dictated by history, physical, and red cell morphology Investigate blood loss

No hemolysis

Iron deficiency

Laboratory evaluation of microcytic anemia

Low Normal/ high Bone marrow failure Pure red cell aplasia or megaloblastic anemia

Figure 3. investigation of anemia. Source: Ambrusso32

The incidence of iron deficiency in child especially at age 6-24 months still height, it remains an important cause of microcytic anemia. A trial of therapeutic iron is appropriate in such children, provided the dietary history is compatible with iron deficiency and the physical examination or CBC count does not suggest an alternative cause for the anemia. If this is not

38

the case, or if a trial of therapeutic iron fails to correct the anemia and microcytosis. Further laboratory evaluation is warranted. 31 Another key element is the use of both the reticulocyte count and the peripheral blood smear to determine whether a normocytic or macrocytic anemia is due to hemolysis. Typically hemolytic disease is associated with an elevated reticulocyte count, but some children with chronic hemolysis initially present during a period of virus induced aplasia when reticulocyte count is not elevated. Then, review of the peripheral blood smear for evidence of hemolysis (eg. Spherocytes, red cell fragmentation, sickle forms) is important in the evaluation of children with normocytic anemias and low reticulocyte counts. When hemolysis is suggested, the correct diagnosis may be suspected by specific abnormalities of red cell morphology or by clues from the history or physical examination. Autoimune hemolysis is usually excluded by direct antiglobulin testing. Review of blood counts and the peripheral blood smears of the mother and father may suggest genetic disorders such as hereditary spherocytosis. Children with normocytic or macrocytic anemias, with relatively low reticulocyte counts and no evidence of hemolysis on the blood smear, usually have anemias caused by inadequate erythropoesis in the bone marrow. The presece of neutropenia or thrombocytopenia in such children suggests the posibility of aplastic anemia, malignancy, or severe folate or vitamin B12 deficiensy, and usually dictates examination of the bone marrow. 31, 32 Pure red cell aplasia may be congenital (Diamond-Blackfan anemia), acquired and transient (transient erythroblastopenia of childhood), a manifestation of a systemic disease such as renal disease or hypotiroidism, or due to malnutrition or mild deficiencies of folate or vitamin B12. 32 The patient we gave PRC transfusion because of haemoglobin in the first time came to Kariadi Hospital just 6,4 g/dl. After transfusion, from evaluation haematology laboratorium, the haemoglobin more better was 10,5 g/dl.

Prognosis The hepatitis pattern is characterized by hepatocyte necrosis and is associated with a poor prognosis. There are three types of acute cholestatic drug-induced injury: bland cholestasis is the result of abnormal biliary secretion, and is not accompanied by significant hepatocellular damage; cholestatic hepatitis (mixed type) refers to cholestasis with concomitant hepatic parenchymal damage; and the third form of acute cholestasis is defined by the presence of bile duct injury or cholangiolitis. Medications may cause chronic 39

cholestasis through two additional mechanisms: through the obliteration of bile ducts, also known as the vanishing bile duct syndrome, or by extrahepatic biliary obstruction, known as secondary sclerosing cholangitis.5 Early diagnosis of drug-induced liver reactions is essential to minimizing toxicity. Monitoring hepatic enzyme level is appropriate and necessary with number of agents, especially with those that lead to overt toxicity.3, 14 The patient with drug induced hepatities, with complication microcytic hipochromic anemia, with comorbidity leptospirosis, urinary tract infection. Sign and simptom of drugs induced hepatities was found one month from bigining of treatment with anti tuberculosis drugs. And The first step of management of hepatotoxicity is to discontinue the suspected drug. Prognosis in this case were quo ad vitam dubia ad bonam, quo ad sanam dubia ad bonam and quo ad fungsionam dubia ad bonam.

40

CHAPTER 4 SUMMARY

A 13-years-old boy was diagnosed with drug induced hepatities, with complication microcytic hipochromic anemia, with comorbidity leptospirosis and urinary tract infection. The diagnosis was established and the therapy was given. The child has treat in the Kariadi Hospital for 32 days, with clinically condition more better. The next program was referred back to Pangkalan Bun Hospital to follow up. Parents have a significant role of this patients quality of life. They have to know about their child condition, therapy program, and the prognosis. Information about carefully with drugs because this event may be can recurrence, appropriate feeding, good hygiene and sanitation was given to the parents. Also, must be routine evaluation about the liver function to local Pediatricians.

41

PROBLEM SCHEME

DIAGNOSIS

13 years old boy, body weight 31,5 kg, height 145 cm, with chief complaint jaundice

History of illness Physical examination Laboratory Imaging : o Abdominal ultrasound Liver biopsy

(1) cholestasis; (2) increase liver function test; (3) Rough liver parenchime was posibility for drug induced hepatities; (4) liver biopsy impresion hepatic injury due to drugs drugs induced;and (5) history was imbimbing antituberculosis drugs

Drug-induced Hepatities PROMOTIVE

Education : prognosis, therapeutic and complication Nutritional Stimulation

PREVENTIVE

THERAPY

Prevent infection Vaccination Monitorng of complication Carefully for drugs consumtion

Stopped suspected drugs Fat-soluble vitamin Ursodeoxycholic acid High carbohydrate and medium chain triglyceride diet

Optimal growth and development prior to genetics potential

42

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11. Shakya R, Rao BS. Incidence of hepatotoxicity due to antitubercular medicines and assessment of risk factors. Ann Pharmacother 2004; 38(6): 1074-9. 12. Gruchalla RS. Clinical assesment of drug-induced disease. Lancet. 2000;356:1505-11 13. Walgren Jl, Michell MD, Thompson DC. Role of metabolism in drug-induced idiosyncratic hepatotoxicity. Crit. Rev. Toxicol. 2005;35:325-61 14. Tohaoglu K, Atac G, Sevim AT. The management of anti-tuberculosis drug-induced hepatotoxicity. Int J Tuberculosis Lung Dis. 2001;5:65-9 15. Deleve LD, Kaplowitz. Prevention and therapy of drug-induced hepatic injury. In: Therapy of digestive disorders: A companion to sliesenger and fordtran gastrointestinal and liver disease. WB Saunders, Philadelphia, 2000. P.334-48 16. Fauzi ARM, Shah A, Rathor MY, Satwi S. Risk Factors for Anti Tuberculous Drugs Induced Hepatitis: A Prospective Survey from a Chest Clinic in a General Hospital. Med J Malaysia Vol 59 No 1 March 2004, hal: 72-78 17. Lum GM. Urinary tract infection. In: Hay WW, Levin MJ, Sondheimer JM, Deterding RR, editors. Current diagnosis & treatment pediatrics. Mc Graw Hill Lange. New York, 2009. P.670-2 18. Conway PH. Recurrent urinary tract infections in children: risk factors and associations with prophilactic antimicrobials. JAMA 2007;298:179 19. Mak RH, Kuo HJ. Pathogenesis of urinary tract infections. An update. Curr Opin Pediatr 2006;18:148 20. Barrat TM. Pediatric Nephrology, 5th ed. Lippincott Wiliams & wilkins, 2003. 21. Hersiston ML. A practical approach to the evaluation of the anemic child. Pediatr Clin North Am 2002;49:877 22. Ambruso DR, Hays T, Goldenberg NA. Anemias. In: In: Hay WW, Levin MJ, Sondheimer JM, Deterding RR, editors. Current diagnosis & treatment pediatrics. Mc Graw Hill Lange. New York, 2009. P.806-23

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