Case DIH done.doc

Case Report “Drug Induced Hepatitis”

I. TABLE OF CONTENTS

II. IDENTITY...........................................................................................................................32.1 1.1 Patient...............................................................................................................................32.2 1.2 Patient’s Father.................................................................................................................42.3 1.3 Patient’s Mother................................................................................................................4

III. ANAMNESIS.....................................................................................................................53.1 HISTORY OF PRESENT ILLNESS.................................................................................................53.2 HISTORY OF PAST ILLNESS.......................................................................................................63.3 MOTHER’S PREGNANCY HISTORY............................................................................................6

3.3.1 ANTENATAL CARE....................................................................................................................63.3.2 DISEASE DURING PREGNANCY................................................................................................73.3.3 DRUGS TAKEN.........................................................................................................................7

3.4 BIRTH HISTORY........................................................................................................................73.5 POSTNATAL HISTORY...............................................................................................................73.6 HISTORY OF DEVELOPMENT....................................................................................................73.7 HISTORY OF EATING................................................................................................................8

3.7.1 BEFORE 1 YEAR OF AGE...........................................................................................................83.7.2 MORE THAN 1 YEAR OF AGE...................................................................................................8

3.8 IMMUNIZATION HISTORY........................................................................................................83.9 FAMILY HISTORY.....................................................................................................................93.10 MODE OF REPRODUCTION....................................................................................................93.11 HISTORY OF DISEASE IN THE FAMILY.....................................................................................93.12 HISTORY OF DISEASE IN OTHER FAMILY MEMBERS/AROUND THE HOME..............................9

IV. PHYSICAL EXAMINATION (30th September 2015).............................................................9

V. INVESTIGATIONS.............................................................................................................14

VI. WORKING DIAGNOSIS....................................................................................................18

VII. MANAGEMENT.............................................................................................................18

VIII. PROGNOSIS.................................................................................................................19

IX. FOLLOW UP....................................................................................................................20

XI. LITERATURE REVIEW......................................................................................................2511.1 DEFINITION.........................................................................................................................2511.2 ANATOMY...........................................................................................................................2511.3 MECHANISM OF DRUG METABOLISM..................................................................................2811.4 PATHOGENESIS...................................................................................................................2911.5 CLINICAL MANIFESTATIONS.................................................................................................34

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11.6 LABORATORY FINDINGS......................................................................................................3411.7 DIAGNOSIS..........................................................................................................................3611.8 TREATMENT........................................................................................................................4111.9 PROGNOSIS.........................................................................................................................42

XII. REFERENCES..................................................................................................................43

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CASE REPORT Department of Pediatric

II. IDENTITY

II.1 1.1 Patient

Name DZ

Date of birth, age May 8th 2014, 16 months

Gender Female

Address Jalan Permata 4, Depok, East Jakarta

Nationality Indonesia

Religion Moslem

Education -

II.2 1.2 Patient’s Father

Name Mr. F

Age 35 years old



Religion Moslem

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Education Senior High school

Job Employee

II.3 1.3 Patient’s Mother

Name Mrs. A

Age 33 years old



Religion Moslem

Education Senior High school

Job Employee

III. ANAMNESIS

Alloanamnesis from the mother on 30th September 2015.

Chief complain : Yellowing of the skin since 1 week before admission to the hospital.

Additional complain : Nausea, vomiting, lost appetite, tea-colored urine, stomachache

III.1 HISTORY OF PRESENT ILLNESS

The patient was brought by her mother to emergency unit POLRI Hospital with chief

complaint yellowing of the skin and the whites of the eyes since 1 week before admission. The

symptom occurs suddenly, not preceded by fever or anything else. The patient also lost her

appetite since 5 days ago, she felt nausea and vomited everytime she was given breastmilk or

food. In a day the patient can vomit about 3-5 times and the volume of each vomit is about

quarter glass of Aqua. Vomiting does not projectile and always preceded by nausea. Vomiting is

not accompanied by blood or phlegm. Because of the nauseous, she only eats 2-6 spoons of

porridge in a day. Usually she eats 3 times a day with a normal portion and she looks lethargic

and less active than usual because of it. According to her mother, The patient’s urine was tea-

colored and more concentrated since 3 days before admission. Any pain during urinating is

denied. The patient also complain of low grade fever and pain in her stomach. The temperature is

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slightly above normal, which is 38 degrees Celsius and subsided after Paracetamol. The

characteristic of the stomach pain is unclear, but the pain is start and stop abruptly and nothing

can make the pain goes away.

3 days before admission the patient went to the doctor in Harapan Hospital Depok, and

hospitalized for 2 days. The doctor told the mother probably her daughter is infected by hepatitis

viral and he recommend the mother to bring her daughter to the bigger hospital so they can do

more advanced examination and investigation regarding to the symptoms.

4 months ago, the patient had shortness of breath for 1 week and admitted to the nearest

clinic. Based on her chest x – ray, she was diagnosed with Lung Tuberculosis and started the

medication right away. She had been given three different drugs in fixed dose combination,

which are Isoniazid, Rifampicin and Pirazinamid. The doctor said it must be taken every day at

the same time for 6 months ahead. In the first three months, there was significant improvement

regard the patient’s symptom. Now she’s on fourth month Tuberculosis medication.

The Patient’s mother denied any diarrhea and allergy in the patient.

III.2 HISTORY OF PAST ILLNESS

DISEASES

Tuberculosis +

Bronchitis -

Pneumonia -

Pharyngitis/tonsilitis -

Pertussis -

Varicella -

Diphtheria -

Malaria -

Morbili -

Enteritis -

Bacillary Dysentry -

Dysentery Amoeba -

Typhoid -

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Worm infection -

Polio -

Brain concussion -

Fracture -

Drug reaction -

Surgery -

III.3 MOTHER’S PREGNANCY HISTORY

III.3.1 ANTENATAL CARE

Mother checked up her pregnancy to the health care center every month. There were no problems

during her pregnancy and no abnormalities with the fetus. The fetus in the womb was healthy.

III.3.2 DISEASE DURING PREGNANCY

The mother claimed that no problems during her pregnancy. No hypertension, diabetes mellitus,

bleeding, or other diseases during her pregnancy.

III.3.3 DRUGS TAKEN

The mother got vitamins and ferrous every antenatal care.

III.4 BIRTH HISTORY

Labor : Harapan Hospital Depok

Birth attendants : Obstetrician

Mode of delivery : Vaginal delivery

Gestation : 38 weeks

Fetal membrane : clear

Infant state : healthy

Birth weight : 3200 grams

Body length : 51 cm

APGAR : 9

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According to the mother, the baby started to cry after the delivery. The baby’s skin was red and

no congenital defect detected.

III.5 POSTNATAL HISTORY

Postnatal examination carried out in the hospital and conducted by doctor.

The state of the infant was healthy.

III.6 HISTORY OF DEVELOPMENT

First dentition : 6 months old

Psychomotor development

o Smile : 2 months old

o Slant : 2 months old

o Prone : 3 months old

o Sitting : 6 months old

o Crawling : 8 months old

o Standing :10 months old

o Walking : 12 months old

Conclusion: good motor developmental status

III.7 HISTORY OF EATING

III.7.1 BEFORE 1 YEAR OF AGE

Breast milk From birth until now

Formula milk Since 6 months old until now, patient consumed SGM milk

Fruit and vegetables Since 7 months old, patient consume apple, banana, spinach

Solid Foods and side

dishes

Since 1 year old, patient consume cereals, chicken, vegetable soup,

rice, meat, fish

III.7.2 MORE THAN 1 YEAR OF AGE

TYPE OF FOOD FREQUENCY AND AMOUNT

Rice/substitute +

Formula Milk +

Cereals +

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Eggs +

Tofu +

Tempe +

Meat/chicken/fish +

Fruit +

Vegetables +

III.8 IMMUNIZATION HISTORY

IMMUNIZATION FREQUENCY AGE OF IMMUNIZATION

Hepatitis B 3 times 0,1,6 months

BCG 1 times 1 month

DPT 3 times 2,4,6 months

Polio 3 times 2,4,6 months

MMR - -

III.9 FAMILY HISTORY

FAMILY DATA

INFORMATION FATHER MOTHER

Number of wedding 1 1

Age of marriage 27 years old 25 years old

State of health Healthy Healthy

III.10 MODE OF REPRODUCTION

The patient is the second child of two siblings.

NUMBER OR

CHILDREN

AGE GENDER TYPE OF

DELIVERY

1 6 years old Male Vaginal delivery

2 (patient) 16 months Female Vaginal delivery

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III.11 HISTORY OF DISEASE IN THE FAMILY

Father : healthy

Mother : healthy

III.12 HISTORY OF DISEASE IN OTHER FAMILY MEMBERS/AROUND

THE HOME

Around the house: clean

IV. PHYSICAL EXAMINATION (30th September 2015)

General condition : looks moderately ill

Awareness : compos mentis

VITAL SIGNS

Heart rate : 110 beats/minute, strong, full, regular

Respiratory rate : 26 beats/minute

Body temperature : 37,2º C

ANTHROPOMETRIC DATA

Head circumference : 47 cm

Body weight : 9,0 kg

Body height : 73 cm

Nutritional status based on NCHS (National Center for Health Statistics) year 2000:

1. Interpretation based on WHO

WFA (Weight for Age) : below percentile 50

HFA (Height for Age) : below percentile 50

2. Interpretation based on lokarya Antropometri Depkes 1974 dan Puslitbang Gizi 1978

WFA (Weight for Age) : 9,0/10,4 x 100% =86 %

HFA (Height for Age) : 73/78 x 100% = 93 %

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WFH (Weight for Height) : 9,0/9,6 x 100% = 93 %

10

Conclusion: Nutrition status is good


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SYSTEMATIC PHYSICAL EXAMINATION

SYSTEMATIC EXAMINATION RESULT OF EXAMINATION

Head

Shape and size

Large fontanel

Hair

Occipital lymph node

Normocephaly, no deformity

Closed

Black, equitable distribution, not easily removed

Non palpable

Eyes

Pallor conjunctiva

Icteric sclera

Conjuctival hyperemia

Lacrimation

Sunken eyelids

-/-

+/+

-/-

-/-

-/-

Ears

Serumen

Right and left tymphanic membrane

-/-

Intact

Nose

Secretions

Nasal flaring

-/-

(-)

Mouth

Lips

Teeth

Mucous

Tongue

Pharynx

Tonsils

Moist

No carries

Moist

Moist, no coated tongue, no tremors

No hyperemia

T1/T1

Neck No palpable enlarged lymph nodes

Thorax

Inspection Symmetric in a static and dynamic state

Suprasternal retractions (-)

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Intercostals retraction (-)

Ictus cordis is visible

Palpation Ictus cordis is palpable in the fourth intercostals

space of the left middle clavicular line

Tactile fremitus are symmetric for both lung fields

Percussion

o Top border of the heart

o Left border of the heart

o Right border of the heart

Sonor in both lung fields

o Second intercostals in left parasternal line

o Fourth intercostals in midclavicula line

o Fourth intercostals in right parasternal line

Auscultation

o Breath sounds

o Heart sounds

Vesicular breath sounds, no rhonci, no wheezing

First and second heart sounds regular, no murmur,

no gallop

Abdomen

Inspection Convex, no epigastric retraction

Post operation scar (-), hypopigmentation (+)

Palpation Supple

Tenderness (+) in all abdomen fields, Liver and

spleen not palpable, Abdominal mass (-)

Percussion Hypertymphanic, shifting dullness (-)

Auscultation Bowel sounds : normal

Vertebrae No scoliosis, kyphosis, or lordosis

No mass along the vertebrae line

Genitalia Normal

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Anus Hole intact, no mass around anus

Extremity Warm extremities

Infusion sets on the right hand

CRT < 2 seconds

Skin icteric (+), cyanosis (-), good turgor

NEUROLOGICAL EXAMINATIONS

Meningeal Signs:

o Neck stiffness : (-)

o Brudzinski I maneuver : (-)

o Brudzinski II maneuver : (-)

o Kernig maneuver : (-)

Physiological Reflex

o Biceps reflex : normoreflex/normoreflex

o Triceps reflex : normoreflex/normoreflex

o Patellar reflex : normoreflex/normoreflex

o Achilles reflex : normoreflex/normoreflex

Pathological Reflex

o Hoffman-Trommer reflex : -/-

o Babinski reflex : -/-

o Oppenheimer reflex : -/-

o Schaefer reflex : -/-

o Chaddock reflex : -/-

o Gordon reflex : -/-

V. INVESTIGATIONS

Laboratory investigation on September 27th 2015, 12.45 (Harapan Hospital Depok)

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TEST RESULT NORMAL VALUE

HEMATOLOGY

Haemoglobin 11 g/dl 13-16 g/dl

Leukocytes 11.300 U/L 5.000-10.000 U/L

Hematocrites 32 % 40-48%

Trombocytes 349.000 /ul 150.000-400.000 /ul

Erythrocytes 4,14 million/µL 4.5 – 5.5 million/µL


KIMIA KLINIK

Total Bilirubin 4,42 mg/dl <1,5 mg/dl

Direct Bilirubin 2,37 mg/dl <0,5 mg/dl

Indirect Bilirubin 2,05 mg/dl <1,0 mg/dl

SGOT/AST (37 C) 211 U/L <37 U/L

SGPT/ALT (37 C) 145 U/L <40 U/L

Random Blood Glucose 99 mg/dl <130 mg/dl

HEMATOLOGY RESULT NORMAL VALUE

ESR 15 mm/hour 0 – 20 mm/hour

Differential count

Basophil - 0 – 1

Eosinophil 2 1 - 5

Rod neutrphil 2 0 – 8

Segment neutrophil 26 50 – 70

Lymphocyte 68 20 – 40

Monocyte 2 2 – 8

Thorax X-ray on May 18th 2015

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Interpretation :

Costophrenic sinus, diaphragm, cor are normal.

Right hilus thick shape, Inflitrate in right paracardial.

Conclusion : Suspect Right lung Tuberculosis.

Laboratory investigation on September 29th 2015, 12.45 (Emergency Department POLRI Hospital)


HEMATOLOGY


Leukocytes 13.100 U/L 5.000-10.000 U/L

Hematocrites 33% 40-48%



KIMIA KLINIK




SGOT/AST (37 C) 111 U/L <37 U/L

SGPT/ALT (37 C) 122 U/L <40 U/L

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Urinalysis Results Normal Value

Colour Yellow

Clearness Clear

Reaction / pH 7,0 5 – 8.5

Specific gravity 1,010 1000 – 1,030

Protein - Negative

Bilirubin - Negative

Glucose - Negative

Ketones - Negative

Blood / Hb - Negative

Nitrite - Negative

Urobilinogen 0.1 0.1 – 1,0 IU

Leukocytes - Negative

SEDIMENT

Leukocytes 1-2 / field of view -

Erythrocytes 1-2 / field of view -

Epithelial cells + / field of view -

Cylinder - -

Crystal - -

Bacteria - -

Laboratory investigation on September 30th 2015, 12.45 (Anggrek I)


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ELECTROLYTES

Sodium 143 mmol/l 135-145 mmol/l

Kalium 4,0 mmol/l 3,8-5,0 mmol/l

Chloride 110 mmol/l 98-106 mmol/l


SEROLOGY/IMMUNOLOGY

HBs Ag Non Reactive Non Reactive

Anti HAV IgM Negative Negative

Laboratory investigation on October 2nd 2015, 12.02 (Bangsal Anggrek I)


KIMIA KLINIK




SGOT/AST (37 C) 50 U/L <37 U/L

SGPT/ALT (37 C) 66 U/L <40 U/L

VI. WORKING DIAGNOSIS

Drug Induced Hepatitis

Lung tuberculosis

VII. MANAGEMENT

Parenteral infusion KA-EN 3B 30 dpm

Injection of Cefotaxime 2 x 300 mg

Domperidone syrup 2 x 5 ml

Stop Tuberculosis drug

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VIII. PROGNOSIS

Quo ad vitam : ad bonam

Quo ad functionam : ad bonam

Quo ad sanationam : ad bonam

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IX. FOLLOW UP

Follow up on September 29th 2015, the first day of hospitalization, the 8th day of sickness

S Yellowing skin and whites of the eyes, nausea, vomiting (3 times/day), lost

appetite, stomachache, lethargic, tea-colored urine, shortness of breath (-), fever

(-)

O General condition: moderately ill

Consciousness: Compos mentis

Vital Signs

Heart rate: 112 times/minute,

strong, full, regular

Respiratory Rate: 26 times/minute

Temperature: 37.5° C

Physical examination

Sclera icteric: +/+

Thorax : vesiculer +/+, wheezing -/-. rhonki -/-, retraction (-)

Abdomen: tenderness (+), bloating (+), hepatomegaly (-), spleenomegaly (-)

A Drug Induced Hepatitis

Lung Tuberculosis

P Parenteral infusion KA-EN 3B 30 dpm



The second day of hospitalization, 9tg day of sickness, September 30th 2015

S Yellowing skin and whites of the eyes decreased, nausea, stomachache, appetite

increased, lethargic, tea-colored urine (-), vomiting (-)


Consciousness: compos mentis

Vital Signs

Heart rate: 124times/minute, strong, full, regular

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Temperature: 36,5° C


Sclera icteric: +/+



Investigation September 30th 2015, 12.45 (Anggrek I)


SEROLOGY

HBs Ag Non Reactive Non Reactive

Anti HAV IgM Negative Negative


Lung Tuberculosis




Lesicort 2 x 150 mg

The third day of hospitalization, 10tg day of sickness, October 1st 2015

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ELECTROLYTES

Sodium 143 mmol/l 135-145 mmol/l

Kalium 4,0 mmol/l 3,8-5,0 mmol/l

Chloride 110 mmol/l 98-106 mmol/l


S Yellowing skin and whites of the eyes decreased, nausea, bloating, stomachache

subsided, appetite increased, tea-colored urine (-), vomiting (-)


Consciousnes: Compos mentis

Vital Signs

Heart rate: 102 times/minute, weak, full, regular


Temperature: 36° C


Sclera icteric: +/+




Lung Tuberculosis




Lesicort 2 x 150 mg

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The fourth day of hospitalization, 11tg day of sickness, October 2nd 2015

S Yellowing skin and whites of the eyes decreased

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Awareness: Compos mentis

Vital Signs

Heart rate: 104 times/minute, weak, full, regular


Temperature: 37.5° C


Sclera icteric: +/+



Laboratory investigation on October 2nd 2015, 12.02 (Anggrek I)


KIMIA KLINIK




SGOT/AST (37 C) 50 U/L <37 U/L

SGPT/ALT (37 C) 66 U/L <40 U/L


HEMATOLOGY


Leukocytes 8.100 U/L 5.000-10.000 U/L

Hematocrites 32 % 40-48%



Lung Tuberculosis



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Lesicort 2 x 150 mg

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X. LITERATURE REVIEW

X.1 DEFINITION

Drug-induced hepatitis is the inflammation of the liver that caused by toxic exposure to certain

medications, vitamins, herbal remedies, or food supplements resulting in liver cell damage and

destruction. 2 It may present as a mild reaction or, much more seriously, as acute liver failure. 1,2,6

The toxicity occurs may be immediate or take weeks to months to develop. A large number of

drugs and chemicals can produce liver injury. The mechanism of liver injury may be direct toxic

damage to hepatocytes, but also involves a variable combination of toxicity and inflammation

with immune-mediated hepatocyte destruction. 2,7

X.2 ANATOMY

Anatomy of the Liver 4

The liver is the largest organ in the body, contributing about 2 percent of the total body weight,

or about 1.5 kilograms (3.3 pounds) in the average adult human. The basic functional unit of the

liver is the liver lobule, which is a cylindrical structure several millimeters in length and 0.8 to 2

millimeters in diameter. The human liver contains 50,000 to 100,000 individual lobules. 4

Figure 1. Schematic of liver lobule as a basic functional unit of the liver

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The liver lobule, shown in cut-away format, is constructed around a central vein that empties into

the hepatic veins and then into the vena cava. The lobule itself is composed principally of many

liver cellular plates that radiate from the central vein like spokes in a wheel. Each hepatic plate is

usually two cells thick, and between the adjacent cells lie small bile canaliculi that empty into

bile ducts in the fibrous septa separating the adjacent liver lobules. 4

In the septa are small portal venules that receive their blood mainly from the venous outflow of

the gastrointestinal tract by way of the portal vein. From these venules blood flows into flat,

branching hepatic sinusoids that lie between the hepatic plates and then into the central vein.

Thus, the hepatic cells are exposed continuously to portal venous blood. 4

Hepatic arterioles are also present in the interlobular septa. These arterioles supply arterial blood

to the septal tissues between the adjacent lobules, and many of the small arterioles also empty

directly into the hepatic sinusoids, most frequently emptying into those located about one-third

the distance from the interlobular septa. 4

In addition to the hepatic cells, the venous sinusoids are lined by two other cell types: (1) typical

endothelial cells and (2) large Kupffer cells (also called reticuloendothelial cells), which are

resident macrophages that line the sinusoids and are capable of phagocytizing bacteria and other

foreign matter in the hepatic sinus blood. 4

The endothelial lining of the sinusoids has extremely large pores, some of which are almost 1

micrometer in diameter. Beneath this lining, lying between the endothelial cells and the hepatic

cells, are narrow tissue spaces called the spaces of Disse, also known as the perisinusoidal

spaces. The millions of spaces of Disse connect with lymphatic vessels in the interlobular septa.

Therefore, excess fluid in these spaces is removed through the lymphatics. Because of the large

pores in the endothelium, substances in the plasma move freely into the spaces of Disse. Even

large portions of the plasma proteins diffuse freely into these spaces. 4

Metabolic Functions of the Liver

The liver is a large, chemically reactant pool of cells that have a high rate of metabolism, sharing

substrates and energy from one metabolic system to another, processing and synthesizing

27


multiple substances that are transported to other areas of the body, and performing myriad other

metabolic functions. For these reasons, a major share of the entire discipline of biochemistry is

devoted to the metabolic reactions in the liver. But here, let us summarize those metabolic

functions that are especially important in understanding the integrated physiology of the body. 4

1) Carbohydrate Metabolism

In carbohydrate metabolism, the liver performs the following functions

1. Storage of large amounts of glycogen

2. Conversion of galactose and fructose to glucose

3. Gluconeogenesis

2) Fat Metabolism

Specific functions of the liver in fat metabolism are the following:

1. Oxidation of fatty acids to supply energy for other body functions

2. Synthesis of large quantities of cholesterol, phospholipids, and most lipoproteins

3. Synthesis of fat from proteins and carbohydrates

3) Protein Metabolism

The most important functions of the liver in protein metabolism are the following:

1. Deamination of amino acids

2. Formation of urea for removal of ammonia from the body fluids

3. Formation of plasma proteins

4. Interconversions of the various amino acids and synthesis of other compounds

from amino acids

4) The Liver Is a Storage Site for Vitamins

5) The Liver Stores Iron as Ferritin

6) The Liver Forms the Blood Substances Used in Coagulation

7) The Liver Removes or Excretes Drugs, Hormones, and Other Substances

The active chemical medium of the liver is well known for its ability to detoxify or

28


excrete into the bile many drugs, including sulfonamides, penicillin, ampicillin, and

erythromycin. In a similar manner, several of the hormones secreted by the endocrine

glands are either chemically altered or excreted by the liver, including thyroxine and

essentially all the steroid hormones, such as estrogen, cortisol, and aldosterone. Liver

damage can lead to excess accumulation of one or more of these hormones in the

body fluids and therefore cause overactivity of the hormonal systems. Finally, one of

the major routes for excreting calcium from the body is secretion by the liver into the

bile, which then passes into the gut and is lost in the feces. 4

X.3 MECHANISM OF DRUG METABOLISM

The liver metabolizes virtually every drug or toxin introduced in the body. Hepatic metabolism

of drugs and toxins is mediated by a sequence of enzymatic reactions that, in large part,

transform hydrophobic, less soluble molecules into more nontoxic, hydrophilic compounds that

can be readily excreted in urine or bile. Relative liver size, liver blood flow, and extent of protein

binding also influence drug metabolism. 5,6,7

Metabolism of drugs occurs in 2 phases. In the phase 1 reaction, the drug is made polar by

oxidation or hydroxylation. The process involves enzymatic activation of the substrate to

reactive intermediates containing a carboxyl, phenol, epoxide, or hydroxyl group. The

cytochrome P-450 enzymes catalyze phase 1 reactions. Most of these intermediate products are

transient and highly reactive. These reactions may result in the formation of metabolites that are

far more toxic than the parent substrate and may result in liver injury. All drugs may not undergo

this step, and some may directly undergo the phase 2 reaction. 5,6,7

The phase 2 involving conjugation with with glucuronic acid, sulfate, acetate, glycine, or

glutathione that further increases solubility. Some drugs may be directly metabolized by these

conjugating reactions without 1st undergoing phase 1 activation. Subsequently, drugs with high

molecular weight may be excreted in bile, while the kidneys excrete the smaller molecules. 5,6,7

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Figure 2. Drug Metabolism Pathways

X.4 PATHOGENESIS

Depending on the drug, the patterns of drug-induced liver injury may include one or more

of the following: hepatocellular necrosis, cholestasis, steatosis, steatohepatitis, fibrosis, and

vascular lesions. These patterns of injury are similar to those that occur in other types of liver

disease, requiring careful analysis to confirm the cause of the injury. 7

The pathophysiologic mechanisms of hepatotoxicity are still being explored and include both

hepatocellular and extracellular mechanisms. The following are some of the mechanisms that

have been described 7 :

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Figure 3. Mechanisms of Liver Injury 7

1) Disruption of the hepatocyte: Covalent binding of the drug to intracellular proteins can

cause a decrease in ATP levels, leading to actin disruption. Disassembly of actin fibrils at

the surface of the hepatocyte causes blebs and rupture of the membrane.

2) Disruption of the transport proteins: Drugs that affect transport proteins at the

canalicular membrane can interrupt bile flow. Loss of villous processes and interruption

of transport pumps such as multidrug resistance–associated protein 3 prevent the

excretion of bilirubin, causing cholestasis.

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3) Cytolytic T-cell activation: Covalent binding of a drug to the P-450 enzyme acts as an

immunogen. Covalent binding of the heme-containing cytochrome P-450 enzyme to the

drug, thus creating nonfunctioning adducts. Activating T cells and cytokines and

stimulating a multifaceted immune response.

4) Apoptosis of hepatocytes: Activation of the apoptotic pathways by the tumor necrosis

factor-alpha receptor of Fas may trigger the cascade of intercellular caspases, which

results in programmed cell death.

5) Mitochondrial disruption: Certain drugs inhibit mitochondrial function by a dual effect

on both beta-oxidation energy production by inhibiting the synthesis of nicotinamide

adenine dinucleotide and flavin adenine dinucleotide, resulting in decreased ATP

production.

6) Bile duct injury: Toxic metabolites excreted in bile may cause injury to the bile duct

epithelium. 7

Drug toxicity mechanisms 2,3

Chemical hepatotoxicity can be (1) predictable or (2) idiosyncratic. Predictable hepatotoxicity

implies a high incidence of hepatic injury in exposed individuals, with dose dependence. 2,3 It is

understandable that only a few drugs in clinical use fall into this category. These agents may

damage the hepatocyte directly through alteration of membrane lipids (peroxidation) or through

denaturation of proteins; such agents include carbon tetrachloride and trichloroethylene. 2,3

Indirect injury can occur through interference with metabolic pathways essential for cell integrity

or through distortion of cellular constituents by covalent binding of a reactive metabolite;

examples include the liver injury produced by acetaminophen or by antimetabolites such as

methotrexate or 6-mercaptopurine. 5

Idiosyncratic hepatotoxicity is infrequent and unpredictable but accounts for the majority

of adverse reactions. The likelihood of injury is not dose dependent and may occur at any time

during exposure to the agent. Idiosyncratic drug reactions in certain patients may reflect aberrant

pathways for drug metabolism, possibly related to genetic polymorphisms, with production of

32


toxic intermediates. Duration of drug use before liver injury varies (weeks to <1 yr) and the

response to re-exposure may be delayed. Examples include isoniazid, valproate, phenytoin, and

HMG-CoA reductase inhibitors (statins). 2,3,7

An idiosyncratic reaction can also be immunologically mediated as a result of prior

sensitization (hypersensitivity); extrahepatic manifestations of hypersensitivity can include fever,

rash, arthralgia, and eosinophilia. Duration of exposure before reaction is generally 1–4 wk, with

prompt recurrence of injury on re-exposure. Studies indicate that arene oxides, generated through

oxidative (cytochrome P450) metabolism of aromatic anticonvulsants (phenytoin, phenobarbital,

carbamazepine), may initiate the pathogenesis of some hypersensitivity reactions. Arene oxides,

formed in vivo, may bind to cellular macromolecules, thus perturbing cell function and possibly

initiating immunologic mechanisms of liver injury. 2,3,7

Patterns of Hepatic Drug Injury

The pathologic spectrum of drug-induced liver disease is extremely wide, is rarely specific, and

can mimic other liver diseases. Predictable hepatotoxins such as acetaminophen produce

centrilobular necrosis of hepatocytes. Steatosis is an important feature of tetracycline

(microvesicular) and ethanol (macrovesicular) toxicities. A cholestatic hepatitis can be observed,

with injury caused by erythromycin estolate and chlorpromazine. Cholestasis without

inflammation may be a toxic effect of estrogens and anabolic steroids. Use of oral contraceptives

and androgens has also been associated with benign and malignant liver tumors. Some

idiosyncratic drug reactions can produce mixed patterns of injury, with diffuse cholestasis and

cell necrosis. Several antineoplastic drugs and some herbal remedies have produced hepatic

veno-occlusive disease. Chronic hepatitis has been associated with the use of methyldopa and

nitrofurantoin. Some herbal supplements are associated with hepatic failure. 2,3,7

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DISEASE DRUG

Centrilobular necrosis Acetaminophen

Halothane

Microvesicular steatosis Valproic acid

Acute hepatitis Isoniazid

General hypersensitivity Sulfonamides

Phenytoin

Fibrosis Methotrexate

Cholestasis Chlorpromazine

Erythromycin

Estrogens

Veno-occlusive disease Irradiation plus busulfan

Cyclophosphamide

Portal and hepatic vein thrombosis Estrogens

Androgens

Biliary sludge Ceftriaxone

Hepatic adenoma or hepatocellular carcinoma Oral contraceptives

Anabolic steroids

Table 1. Patterns of Hepatic Drug Injury

34


X.5 CLINICAL MANIFESTATIONS

Drug-induced chronic hepatitis is clinically and histologically indistinguishable from chronic

viral hepatitis or autoimmune hepatitis, and hence serologic markers of viral infection are critical

for making the distinction. 1.2,5

Clinical manifestations can be mild and nonspecific, such as fever and malaise. Fever, rash, and

arthralgia may be prominent in cases of hypersensitivity. 1.2,5 In ill, hospitalized patients, the signs

and symptoms of hepatic drug toxicity may be difficult to separate from the underlying illness.

The differential diagnosis should include acute and chronic viral hepatitis, biliary tract disease,

septicemia, ischemic and hypoxic liver injury, malignant infiltration, and inherited metabolic

liver disease. 2,8

X.6 LABORATORY FINDINGS

Initial testing should include complete blood cell count, basic metabolic profile, hepatic function

panel and urinalysis. Patients with a hepatocellular process generally have a disproportionate

elevation in serum aminotransferase levels compared with alkaline phosphatase levels, while

those with cholestasis have the opposite findings. 10

Hepatic function tests and their interpretations are as follows:

Bilirubin (total) - To diagnose jaundice and assess severity

Bilirubin (unconjugated) - To assess for hemolysis

Alkaline phosphatase - To diagnose cholestasis and infiltrative disease

AST/serum glutamic oxaloacetic transaminase (SGOT) - To diagnose hepatocellular

disease and assess progression of disease

ALT/serum glutamate pyruvate transaminase (SGPT) - ALT relatively lower than AST in

persons with alcoholism

Albumin - To assess severity of liver injury (HIV infection and malnutrition may

confound this.)

Gamma globulin - Large elevations suggestive of autoimmune hepatitis, other typical

increase observed in persons with cirrhosis

35


Prothrombin time after vitamin K - To assess severity of liver disease

Antimitochondrial antibody - To diagnose primary biliary cirrhosis

ASMA - To diagnose primary sclerosing cholangitis 1.2,6

The laboratory features of drug- or toxin-related liver disease are extremely variable.

Hepatocyte damage can lead to elevations of serum aminotransferase activities and serum

bilirubin levels and to impaired synthetic function as evidenced by decreased serum coagulation

factors and albumin. Hyperammonemia can occur with liver failure or with selective inhibition

of the urea cycle (sodium valproate). Toxicologic screening of blood and urine specimens can

aid in the detection of drug or toxin exposure. Percutaneous liver biopsy may be necessary to

distinguish drug injury from complications of an underlying disorder or from intercurrent

infection. 1.2,6

Slight elevation of serum aminotransferase activities (generally <2–3 times normal) may

occur during therapy with drugs, particularly anticonvulsants, capable of inducing microsomal

pathways for drug metabolism. 1.2,6

Liver biopsy reveals proliferation of smooth endoplasmic reticulum but no significant liver

injury. 1.7 Liver test abnormalities often resolve with continued drug therapy. There are instances

where biopsy can be strongly recommended such as to help discern between autoimmune

hepatitis and DILI. Current diagnostic algorithms for autoimmune hepatitis (AIH) include

histology. AIH is typically responsive to immunosuppressive therapy, but commitment to

therapy is often long term and has risks and side effects. Therefore, a biopsy is recommended if

AIH remains on the differential and certainly if immunosuppressive therapies are contemplated. 7

Imaging studies

Imaging studies are used to exclude causes of liver pathology, after which a diagnosis can be

made. 1.2,6

36


Ultrasonography: Ultrasonography is inexpensive compared with CT scanning and MRI

and is performed in only a few minutes. Ultrasonography is effective to evaluate the gall

bladder, bile ducts, and hepatic tumors.

CT scanning: CT scanning can help detect focal hepatic lesions 1 cm or larger and some

diffuse conditions. It can also be used to visualize adjacent structures in the abdomen.

MRI: MRI provides excellent contrast resolution. It can be used to detect cysts,

hemangiomas, and primary and secondary tumors. The portal vein, hepatic veins, and

biliary tract can be visualized without contrast injections. 1.2,6

Procedures

Liver biopsy: Histopathologic evaluation remains an important tool in diagnosis. A liver biopsy

is not essential in every case, but a morphologic pattern consistent with the expected pattern

provides supportive evidence. A liver biopsy should be considered if autoimmune hepatitis

remains a competing etiology and if immunosuppressive therapy is contemplated. 1.2,6

X.7 DIAGNOSIS

When a single agent is involved, the diagnosis may be relatively simple, but with multiple

agents, implicating a specific agent as the cause is difficult. To facilitate the diagnosis of drug-

induced hepatic injury, several clinical tools for causality assessment have been developed to

assist the clinician. 2,6

History: History must include dose, route of administration, duration, previous

administration, and use of any concomitant drugs, including over-the-counter

medications and herbs. Knowing whether the patient was exposed to the same drug

before may be helpful. The latency period of idiosyncratic drug reactions is highly

variable; hence, obtaining a history of every drug ingested in the past 3 months is

essential. 2,6

o Onset: The onset is usually within 5-90 days of starting the drug.

37


o Exclusion of other causes of liver injury/cholestasis: Excluding other causes of

liver injury is essential.

Dechallenge: A positive dechallenge is a 50% fall in serum transaminase levels within 8

days of stopping the drug. A positive dechallenge is very helpful in cases of use of

multiple medications. 2,6

Track record of the drug: Previously documented reactions to a drug aid in diagnosis. 2,6

Rechallenge: Deliberate rechallenge in clinical situations is unethical and should not be

attempted; however, inadvertent rechallenge in the past has provided valuable evidence

that the drug was indeed hepatotoxic. 2,6

38

DRUG INDUCED HEPATITIS


Figure 4. A way to diagnose Drug Induced Hepatitis

39


Differential diagnoses 6

Acute viral hepatitis

Autoimmune hepatitis

Nonalcoholic steatohepatitis (NASH)

Shock liver/cardiovascular causes, especially right-sided heart failure

Cholecystitis

Cholangitis

Budd-Chiari syndrome

Alcoholic liver disease

Cholestatic liver disease

Pregnancy-related conditions of liver

Malignancy

Wilson disease

Hemochromatosis

Coagulation disorders

Drug Examples

1. Aspirin 1,2

Aspirin liver toxicity is dosage related and usually occur in juvenile rheumatoid arthritis with

high dosage of aspirin. The hepatotoxicity occur with the sign of serum aspirin concentration

>2,5 mg/dL and often increasing the transaminase enzyme concentration, elevated aspartate

concentration and/or alanine aminotransferase and eosinophilia. Symptoms like anorexia, nausea,

vomit, abdominal pain and hepatomegaly could be found. In the over dosage and progressive

cases, icteric visible and mononuclear cell infiltration and necrotic cell could be seen on biopsy.

Hepatitis can occur in children ingesting doses at or above 30.9 mg/dL. Reye syndrome is

another form of pediatric salicylate-induced hepatic disease.

40


2. Acetaminophen1,2

The acetaminophen toxicity can be predicted. The hepatotoxicity

occur by the high dosage of administration of acetaminophen. Its

metabolite, N-acetyl-p-benzoquinoneimine (NAPQI) cause the

liver damage. In a normal condition, NAPQI rapidly binds with

the glutathione in the liver to become non-toxic state. But in high

dosage, the increased NAPQI production is imbalance with the

glutathione concentration that caused NAPQI to form a

macromolecule with hepatocyte and resulting in liver cell

necrosis.

Toxic dose of acetaminophen is >160 mg/kg/day. For children,

do not exceed 10-15 mg/kg/dose of acetaminophen, and do not

exceed five doses or 2.6 grams in 24 hours.

Figure 6. Hepatocellular Necrosis caused by

Acetaminophen Overdose

3. Tuberculosis Drugs 1,2,10

41

Figure 5. Signs and Symptoms of Acetaminophen Overdose and Metabolism


Isoniazid

Approximately 7%, Isoniazid causing liver disorder in child.

10-20% of cases experienced liver function disorder on long-term usage with dosage of 10

mg/kg/day, but when using the dosage of 3-5 mg/kg/day this cases will decreased up to 2%. The

toxic effect of this drug is caused by the metabolism of acetylate that become isoniazid acetyl

and hydralazine acetyl.

Isoniazid is cleared mostly by the liver, primarily by acetylation by N-acetyl transferase 2 (NAT-

2). Acetyl-isoniazid is metabolized mainly to mono-acetyl hydrazine (MAH) and to the nontoxic

diacetyl hydrazine, as well as other minor metabolites. Reactive metabolites of MAH are

probably toxic to tissues through free radical generation.

Figure

7. Mechanism

How Isoniazid

causes Hepatic

Necrosis

Rifampicin

Rifampicin secreted by bile duct. This drug causes both conjugated and unconjugated

hyperbilirubinemia. Conjugated hyperbilirubinemia probably is caused by rifampin inhibiting the

major bile salt exporter pump. Rare hepatocellular injury appears to be a hypersensitivity

reaction, and it may be more common with large, intermittent doses.

Pyrazinamide

Pyrazinamide may exhibit both dose dependent and idiosyncratic hepatotoxicity. Daily doses of

pyrazinamide at 40 to 50 mg/kg commonly caused hepatotoxicity. Pyrazinamide alters

nicotinamide acetyl dehydrogenase levels in rat liver, which might result in generation of free

radical species.

42


4. Halotane 1,2

Halotane is the example of idiosyncratic drug hepatotoxicity. The incidence is 1:82.000 children

who got halothane anesthesia. The mechanism of liver injury that caused by halothane is not

well known. But it may associated with the allergic factor. The multiple usage if halothane

causing centrolobular liver damage. Halotane induced hepatitis usually showed clinical

manifestation after 1-2 weeks after the usage and reused in 3 months.

X.8 TREATMENT

There is no specific therapy for drug-induced hepatitis. Treatment of drug- or toxin-related liver

injury is mainly supportive. Contact with the offending agent should be avoided. Corticosteroids

may have a role in immune-mediated disease.

N-acetylcysteine therapy, by stimulating glutathione synthesis, is effective in preventing

hepatotoxicity when administered within 16 hr after an acute overdose of acetaminophen and

appears to improve survival in patients with severe liver injury even up to 36 hr after ingestion.

Orthotopic liver transplantation may be required for treatment of drug- or toxin-induced hepatic

failure.

X.9 PROGNOSIS

There is no specific therapy for drug-induced hepatitis. Treatment of drug- or toxin-related liver

injury is mainly supportive. Contact with the offending agent should be avoided. Corticosteroids

may have a role in immune-mediated disease.

N-acetylcysteine therapy, by stimulating glutathione synthesis, is effective in preventing

hepatotoxicity when administered within 16 hr after an acute overdose of acetaminophen and

appears to improve survival in patients with severe liver injury even up to 36 hr after ingestion.

Orthotopic liver transplantation may be required for treatment of drug- or toxin-induced hepatic

failure.

43


44


XI. REFERENCES

1. Bradley, John S., John D. Nelson, and David W. Kimberlin. Nelson's Pediatric

Antimicrobial Therapy. 2012-2013. Elk Grove Village, IL: American Academy of

Pediatrics, 2012.

2. Mehta, Nilesh MD dkk. Drug-Induced Hepatotoxicity. Department of Gastroenterology

and Hepatology. 2010

3. Drug-Induced Hepatotoxicity http://emedicine.medscape.com/article/169814-overview

4. Hall, John Edward., and Arthur C. Guyton. Guyton and Hall Textbook of Medical

Physiology. Philadelphia, PA: Saunders, 2011.

5. Hinson, Jack A., Dean W. Roberts, and Laura P. James. Mechanisms of Acetaminophen-

Induced Liver Necrosis. Handbook of experimental pharmacology 196 (2010): 369–

405. PMC. Web. 23 May 2015. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2836803/

6. Kasper, Dennis L., and Tinsley Randolph Harrison. Harrison's Principles of Internal

Medicine. New York: McGraw-Hill, Medical Pub. Division, 2005.

7. Kumar, Vinay, Ramzi S. Cotran, and Stanley L. Robbins. Robbins Basic Pathology.

Philadelphia, PA: Saunders, 2003.

8. Laura P. James, Philip R. Mayeux, and Jack A. Hinson. ACETAMINOPHEN-INDUCED

HEPATOTOXICITY. Drug Metab Dispos December 2003 31:1499-1506; published

online November 18, 2003, doi:10.1124/dmd.31.12.1499 http://dmd.aspetjournals.org/

9. http://www.urmc.rochester.edu/encyclopedia/content.aspx?

ContentTypeID=85&ContentID=P00668

10. Saukkonen JJ, Cohn DL, Jasmer RM et al. An official ATS statement: hepatotoxicity of

antituberculosis therapy. Am. J. Respir. Crit Care Med. 2006; 174: 935–52.

11. https://www.thoracic.org/statements/resources/mtpi/hepatotoxicity-of-antituberculosis-

therapy.pdf

http://gi.org/guideline/diagnosis-and-management-of-idiosyncratic-drug-induced-liver-

injury/ , downloaded on 13th June 2014.

45

http://gi.org/guideline/diagnosis-and-management-of-idiosyncratic-drug-induced-liver-injury/

http://gi.org/guideline/diagnosis-and-management-of-idiosyncratic-drug-induced-liver-injury/

https://www.thoracic.org/statements/resources/mtpi/hepatotoxicity-of-antituberculosis-therapy.pdf

https://www.thoracic.org/statements/resources/mtpi/hepatotoxicity-of-antituberculosis-therapy.pdf

http://www.urmc.rochester.edu/encyclopedia/content.aspx?ContentTypeID=85&ContentID=P00668

http://www.urmc.rochester.edu/encyclopedia/content.aspx?ContentTypeID=85&ContentID=P00668

http://dmd.aspetjournals.org/

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2836803/

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