Paper Tutorial Block 11 Oktober, 2013

LEARNING UNIT 6

LIVER DAMAGE

Disusun oleh :

Nama : Bulan Putri Pertiwi

Stambuk : G 501 11 009

Kelompok : 6 (Enam)

PROGRAM STUDI PENDIDIKAN DOKTER

FAKULTAS KEDOKTERAN DAN ILMU KESEHATAN

UNIVERSITAS TADULAKO

PALU

2013

LEARNING OBJECTIVES

1. Hubungan alkohol dengan terjadinya sirosis?

Jawab:

Alcoholic hepatitis is a syndrome of progressive inflammatory liver injury associated

with long-term heavy intake of ethanol. The pathogenesis is not completely understood.[1]

Patients who are severely affected present with subacute onset of fever, hepatomegaly,

leukocytosis, marked impairment of liver function (eg, jaundice, coagulopathy), and

manifestations of portal hypertension (eg, ascites, hepatic encephalopathy, variceal

hemorrhage). However, milder forms of alcoholic hepatitis often do not cause any

symptoms.

Although the association of alcohol and liver disease has been known since antiquity, the

precise mechanism of alcoholic liver disease remains in dispute. Genetic, environmental,

nutritional, metabolic, and immunologic factors, as well as cytokines and viral disease

have been invoked.

Ethanol metabolism

Most tissues of the body, including the skeletal muscles, contain the necessary enzymes

for the oxidative or nonoxidative metabolism of ethanol. However, the major site of

ethanol metabolism is the liver. Within the liver, 3 enzyme systems—the cytosolic

alcohol dehydrogenase (ADH) system, microsomal ethanol-oxidizing system (MEOS),

and peroxisomal catalase system—can oxidize ethanol.

Cytosolic ADH uses nicotinamide adenine dinucleotide (NAD) as an oxidizing agent.

ADH exists in numerous isoenzyme forms in the human liver and is encoded by 3

separate genes, designated as ADH1, ADH2, and ADH3. Variations in ADH isoforms

may account for significant differences in ethanol elimination rates.

The microsomal ethanol-oxidizing system (MEOS) uses nicotinamide adenine

dinucleotide phosphate (NADPH) and molecular oxygen. The central enzyme of MEOS

is cytochrome P-450 2E1 (CYP2E1). This enzyme, in addition to catalyzing ethanol

oxidation, is also responsible for the biotransformation of other drugs, such as

acetaminophen, haloalkanes, and nitrosamines. Ethanol upregulates CYP2E1, and the

proportion of alcohol metabolized via this pathway increases with the severity and

duration of alcohol use.

Peroxisomal catalase uses hydrogen peroxide as an oxidizing agent.

The product of all 3 reactions is acetaldehyde, which is then further metabolized to

acetate by acetaldehyde dehydrogenase (ALDH). Acetaldehyde is a reactive metabolite

that can produce injury in a variety of ways.

Genetic factors

Although the evidence to prove a genetic predilection to alcoholism is adequate, the role

of genetic factors in determining susceptibility to alcoholic liver injury is much less clear.

Most people who are alcoholics do not develop severe or progressive liver injury.

Attempts to link persons who are susceptible with specific human leukocyte antigen

(HLA) groups have yielded inconsistent results, as have studies of genetic

polymorphisms of collagen, ADH, ALDH, and CYP2E1.

Similar conclusions were reached in a meta-analysis of 50 studies pertaining to the

association of alcoholic liver disease and genetic polymorphism.[3]Nonetheless, the fact

remains that only a small fraction of even heavy alcoholics develop severe liver disease

(ie, cirrhosis). Thus, future case-control studies investigating the genetic basis of alcohol-

induced liver disease are urgently needed.

The genetic factor that most clearly affects susceptibility is sex. For a given level of

ethanol intake, women are more susceptible than men to developing alcoholic liver

disease (see Epidemiology).

Malnutrition

Most patients with alcoholic hepatitis exhibit evidence of protein-energy malnutrition

(PEM). In the past, nutritional deficiencies were assumed to play a major role in the

development of liver injury. This assumption was supported by several animal models in

which susceptibility to alcohol-induced cirrhosis could be produced by diets deficient in

choline and methionine. This view changed in the early 1970s after key studies by Lieber

and DeCarli performed in baboons demonstrated that alcohol ingestion could lead to

steatohepatitis and cirrhosis in the presence of a nutritionally complete diet. [4] However,

subsequent studies have suggested that enteral or parenteral nutritional supplementation

in patients with alcoholic hepatitis may improve survival.

Toxic effects on cell membranes

Ethanol and its metabolite, acetaldehyde, have been shown to damage liver cell

membranes. Ethanol can alter the fluidity of cell membranes, thereby altering the activity

of membrane-bound enzymes and transport proteins. Ethanol damage to mitochondrial

membranes may be responsible for the giant mitochondria (megamitochondria) observed

in patients with alcoholic hepatitis. Acetaldehyde-modified proteins and lipids on the cell

surface may behave as neoantigens and trigger immunologic injury.

Hypermetabolic state of the hepatocyte

Hepatic injury in alcoholic hepatitis is most prominent in the perivenular area (zone 3) of

the hepatic lobule. This zone is known to be sensitive to hypoxic damage. Ethanol

induces a hypermetabolic state in the hepatocytes, partially because ethanol metabolism

via MEOS does not result in energy capture via formation of ATP. Rather, this pathway

leads to loss of energy in the form of heat. In some studies, antithyroid drugs, such as

propylthiouracil (PTU), that reduce the basal metabolic rate of the liver have shown to be

beneficial in the treatment of alcoholic hepatitis.

Generation of free radicals and oxidative injury

Free radicals, superoxides and hydroperoxides, are generated as byproducts of ethanol

metabolism via the microsomal and peroxisomal pathways. In addition, acetaldehyde

reacts with glutathione and depletes this key element of the hepatocytic defense against

free radicals. Other antioxidant defenses, including selenium, zinc, and vitamin E, are

often reduced in individuals with alcoholism. Peroxidation of membrane lipids

accompanies alcoholic liver injury and may be involved in cell death and inflammation.

Steatosis

Oxidation of ethanol requires conversion of NAD to the reduced form NADH. Because

NAD is required for the oxidation of fat, its depletion inhibits fatty acid oxidation, thus

causing accumulation of fat within the hepatocytes (steatosis). Some of the excess NADH

may be reoxidized in the conversion of pyruvate to lactate. Accumulation of fat in

hepatocytes may occur within days of alcohol ingestion; with abstinence from alcohol,

the normal redox state is restored, the lipid is mobilized, and steatosis resolves.

Although steatosis has generally been considered a benign and reversible condition,

rupture of lipid-laden hepatocytes may lead to focal inflammation, granuloma formation,

and fibrosis, and it may contribute to progressive liver injury. Nonoxidative metabolism

of ethanol may lead to the formation of fatty acid ethyl esters, which may also be

implicated in the pathogenesis of alcohol-induced liver damage.[5]

Formation of acetaldehyde adducts

Acetaldehyde may be the principal mediator of alcoholic liver injury. The deleterious

effects of acetaldehyde include impairment of the mitochondrial beta-oxidation of fatty

acids, formation of oxygen-derived free radicals, and depletion of mitochondrial

glutathione. In addition, acetaldehyde may bind covalently with several hepatic

macromolecules, such as amines and thiols, in cell membranes, enzymes, and

microtubules to form acetaldehyde adducts. This binding may trigger an immune

response through formation of neoantigens, impair function of intracellular transport

through precipitation of intermediate filaments and other cytoskeletal elements, and

stimulate hepatic stellate cells to produce collagen.

levels of acetaldehyde in the liver represent a balance between its rate of formation

(determined by the alcohol load and activities of the 3 alcohol-dehydrogenating enzymes)

and its rate of degradation by ALDH. ALDH is downregulated by long-term ethanol

abuse, with resultant acetaldehyde accumulation.

Role of the immune system

Active alcoholic hepatitis often persists for months after cessation of drinking. In fact, its

severity may worsen during the first few weeks of abstinence. This observation suggests

that an immunologic mechanism may be responsible for perpetuation of the injury. levels

of serum immunoglobulins, especially the immunoglobulin A (IgA) class, are increased

in persons with alcoholic hepatitis. Antibodies directed against acetaldehyde-modified

cytoskeletal proteins can be demonstrated in some individuals. Autoantibodies, including

antinuclear and anti–single-stranded or anti–double-stranded DNA antibodies, have also

been detected in some patients with alcoholic liver disease.

B and T lymphocytes are noted in the portal and periportal areas, and natural killer

lymphocytes are noted around hyalin-containing hepatocytes. Patients have decreased

peripheral lymphocyte counts with an associated increase in the ratio of helper cells to

suppressor cells, signifying that lymphocytes are involved in a cell-mediated

inflammatory process. Lymphocyte activation upon exposure to liver extracts has been

demonstrated in patients with alcoholic hepatitis. Immunosuppressive therapy with

glucocorticoids appears to improve survival and accelerate recovery in patients with

severe alcoholic hepatitis.

Cytokines

Tumor necrosis factor-alpha (TNF-alpha) can induce programmed cellular death

(apoptosis) in liver cells. Several studies have demonstrated extremely high levels of

TNF and several TNF-inducible cytokines, such as interleukin (IL)–1, IL-6, and IL-8, in

the sera of patients with alcoholic hepatitis. Inflammatory cytokines (TNF, IL-1, IL-8)

and hepatic acute-phase cytokines (IL-6) have been postulated to play a significant role in

modulating certain metabolic complications in alcoholic hepatitis, and they are probably

instrumental in the liver injury of alcoholic hepatitis and cirrhosis, as shown in the

images below.

Ethanol (ETOH) and cytokine production. CYP = cytochrome P; IL = interleukin; NF-κB = nuclear factor-kappa B; ROS = reactive oxygen species; TNF = tumor necrosis factor.

Mechanisms of cytokine injury. IL = interleukin ; NO = nitric oxide; O2- = superoxide anion; OH- = hydroxyl radical; PMN = polymorphonuclear lymphocyte; TNF = tumor necrosis factor.

Role of concomitant viral diseaseAlcohol consumption may exacerbate injury caused by other pathogenic factors, including hepatitis viruses. Extensive epidemiologic studies suggest that the risk of cirrhosis in patients with chronic hepatitis C infection is greatly exacerbated by heavy alcohol ingestion. Possible mechanisms include the impairment of immune-mediated viral killing or enhanced virus gene expression due to the interaction of alcohol and hepatitis C virus.

Acetaminophen-alcohol interactionsLong-term alcohol abuse has been established as potentiating acetaminophen toxicity via induction of CYP2E1 and depletion of glutathione. Alcoholic patients may develop severe, even fatal, toxic liver injury after ingestion of standard therapeutic doses of acetaminophen.[6]

http://emedicine.medscape.com/article/170539-overview#aw2aab6b2b2

Alcoholic Hepatitis  Author: Sandeep Mukherjee, MB, BCh, MPH, FRCPC; Chief Editor: Julian Katz, MD 

Updated: Aug 20, 2012

Most people who drink large amounts of alcohol harm their livers in some way, but not all of these

people get cirrhosis of the liver. Women who are heavy drinkers are at higher risk than men.

People who have hepatitis B or hepatitis C are more likely to suffer liver damage from alcohol.

http://www.webmd.com/digestive-disorders/cirrhosis-liver

2. Penatalaksanaan Hepatitis B dan sirosis?

Jawab:

Management sirosisSpecific medical therapies may be applied to many liver diseases in an effort to diminish symptoms and to prevent or forestall the development of cirrhosis. Examples of such treatments include the following:

Prednisone and azathioprine - For autoimmune hepatitis Interferon and other antiviral agents - For hepatitis B and C Phlebotomy - For hemochromatosis Ursodeoxycholic acid - For primary biliary cirrhosis Trientine and zinc - For Wilson disease

Once cirrhosis develops, treatment is aimed at the management of complications as they arise. Examples include the following:

Hepatorenal syndrome - Kidney function usually recovers when patients with cirrhosis and hepatorenal syndrome undergo liver transplantation; patients with early hepatorenal syndrome may be salvaged by aggressive expansion of intravascular volume with albumin and fresh frozen plasma and by avoidance of diuretics

Hepatic encephalopathy - Pharmacologic treatment includes the administration of lactulose and antibiotics

Ascites - Treatment can include sodium restriction and the use of diuretics, large-volume paracentesis, and shunts (peritoneovenous, portosystemic, transjugular intrahepatic portosystemic)

Liver transplantation

Patients should be referred for consideration for liver transplantation after the first signs of hepatic decompensation.

In a recent review, Lewis and Stine provided recommendations, including the following, on the safe use of medications in patients with cirrhosis[1, 2] :

Lower medication doses should generally be used, particularly in patients with significant liver dysfunction

Opioid analgesics, anxiolytics, and sedatives, which can precipitate hepatic encephalopathy, should be used cautiously

Nonsteroidal anti-inflammatory drugs (NSAIDs), which can cause renal failure and gastrointestinal (GI) bleeding in patients in cirrhosis, should not be used

If used at low doses (2-3 g or less, daily) for short periods, paracetamol (acetaminophen) can be used safely as a first-line pain treatment

Statins are safe to administer to patients with cirrhosis. Proton-pump inhibitors and histamine-2 blockers should be used only for valid indications, since they

may lead to serious infections in patients with cirrhosis

Cirrhosis  Author: David C Wolf, MD, FACP, FACG, AGAF; Chief Editor: Julian Katz, MD   more...

 

Updated: Aug 5, 2013

http://emedicine.medscape.com/article/185856-overview#aw2aab6b3

http://www.dexa-medica.com/images/publish_upload080711257643001215763044FA

%20MEDICINUS%208%20MEI%202008%20rev.pdf

Rebecca L.Corey, 2008; terj. DLyrawati, 2011 1

Farmakoterapi Hepatitis B dan C: Up-date Rebecca L. Corey, PharmD., BCPS

http://lyrawati.files.wordpress.com/2008/07/farmakoterapi-hepatitis-b-dan-c.pdf

Lok AS, McMahon BJ. Chronic hepatitis B.Hepatology. 2007 Feb;45(2):507-39. Erratum in:

Hepatology. 2007 Jun;45(6):1347.

http://ojs.unud.ac.id/index.php/eum/article/download/5108/3898

3. Patofisiologi Hepatitis B?

Jawab:

Virus Hepatitis B adalah suatu virus DNA dengan struktur genom yang sangat

kompleks. Virus Hepatitis B berupa virus DNA sirkoler berantai ganda, termasuk family

Hepadnaviradae, yang mempunyai tiga jenis antigen. Ketiga jenis antigen tersebut yaitu

Antigen Surface Hepatitis (HbsAg) yang terdapat mantel (envelope virus), antigen ”cor’’

Hepatitis B (HbcAg) dan antigen ’’e’’ Hepatitis B (HbeAg) yang terdapat pada

nucleocapsid virus. Ketiga jenis antigen ini dapat merangsang timbulnya antibodi spesifik

masing – masing yang disebut anti HBs, anti HBc dan anti HBe.

Bagian virus Hepatitis B terdiri dari selubung luar HbsAg, inti pusatnya (HbcAg),

pembawa sifat (DNA), dan enzim pelipat ganda DNA (DNA polimerase) dan serpihan

virus (HbeAg). HbsAg terdiri dari 4 sub tipe penting yang mempunyai subdeterminan

yang sama yaitu a dan 4 subdeterminan yang berlainan, yaitu d, y, w dan r.

Semua partikel virus Hepatitis B bersifat imonogenik dan mampu merangsang

pembentukan antibodi. Bila seseorang terinfeksi virus Hepatitis B, maka tubuh penderita

terdapat antigen yang berasal dari partikel virus dan antibodi humoral yang dibentuk

untuk melawan antigen tersebut. HbsAg telah diidentifikasi dalam darah dan produk

darah, saliva, cairan serebrospinal, peritoneal, pleural, cairan sinovial, cairan amnion,

semen, sekresi vagina, dan cairan tubuh lainnya. Penularan melalui perkutaneus meliputi

intra vena, intra muscular, subcutan atau intra dermal. Penularan non perkutaneus melalui

ingesti oral telah dicatat sebagai jalur pemajanan potensial tetapi efisiensinya cukup

rendah. Di lain pihak dua jalur penularan non perkutaneus yang dianggap memliki

dampak terbesar adalah hubungan seksual dan perinatal. Penularan perinatal terutama

ditemukan pada bayi yang dilahirkan carrier HbsAg atau ibu yang menderita Hepatitis B

selama kehamilan trimester ketiga atau selama periode awal pasca partus. Meskipun kira-

kira 10% dari infeksi dapat diperoleh in utero, bukti epidemiologik memberi kesan bahwa

hampir semua infeksi timbul kira-kira pada saat persalinan dan tidak berhubungan

dengan proses menyusui. Pada hampir semua kasus, infeksi acut pada neonatus secara

klinis asimtomatik, tetapi anak itu kemungkinan menjadi seorang carrier HbsAg.

Penyebaran perinatal merupakan masalah yang besar di negara–negara dimana

terdapat prevalensi infeksi virus Hepatitis B yang tinggi dengan prevalensi HbsAg yang

tinggi. Hampir semua bayi yang dilahirkan dari ibu HbsAg positif akan terkena infeksi

pada bulan kedua dan ketiga dari kehidupannya. Peranan adanya HbsAg pada ibu sangat

dominan untuk penularan. Sebaiknya walaupun ibu mengandung HbsAg positif namun

bila HbsAg dalam darah negatif maka daya tularnya menjadi rendah. Masa masuknya

virus kedalam tubuh sampai timbulnya gejala (masa inkubasi) bervariasi mulai dari 45-

180 hari dan rata-rata 60-90 hari.

Kemungkinan Hepatitis B menjadi kronik, bervariasi tergantung usia terinfeksi

virus Hepatitis B. Infeksi pada saat kelahiran umumnya tanpa manifestasi klinik tapi 90%

kemunkinan kasus menjadi kronik, di lain pihak apabila infeksi Hepatitis B terjadi pada

usia dewasa muda maka akan timbul manifestasi klinik risiko berkembang menjadi

kronik hanya 1%.

Kurang dari 10% infeksi Hepatitis virus akut pada anak-anak dan 30% - 50%

pada orang dewasa terdeteksi secara klinis. Penderita umumnya mengalami gejala klinis

nafsu makan menurun, nyeri perut, mual, muntah dan kadang – kadang disertai nyeri

sendi dan rash dan sering berlanjut ke jaundice.

Virus hepatitis B masuk ke dalam tubuh secara parenteral, dari peredaran darah

partikel Dane masuk ke dalam hati dan terjadi proses replikasi virus. Selanjutnya sel-sel

hati akan memproduksi dan mensekresi partikel Dane utuh, partikel HbsAg bentuk bulat

dan tubuler dan HBeAg yang tidak ikut membentuk partikel virus. Virus hepatitis B

smerangsang respon imun tubuh, yang pertama kali adalah respon imun non spesifik

karena dapat terangsang dalam waktu beberapa menit sampai beberapa jam dengan

memanfaatkan sel-sel NK dan NKT. Kemudian diperlukan respon imun spesifik yaitu

dengan mengakstivasi sel limfosit T dan sel limfosit B. aktivasi sel T, CD8 + terjadi

setelah kontak reseptor sel T dengan komplek peptide VHB-MHC kelas I yang ada pada

permukaan dinding sel hati. Sel T CD8 + akan mengeliminasi virus yang ada di dalam sel

hati terinfeksi. Proses eliminasi bisa terjadi dalam bentuk nekrosis sel hati yang akan

menyebabkan meningkatnya ALT.

Aktivasi sel limfosit B dengan bantuan sel CD+ akan mengakibatkan produksi

antibody antara lain anti-HBs, anti-HBc, anti-HBe. Fungsi anti-HBs adalah netralisasi

partikel virus hepatitis B bebas dan mencegah masuknya virus ke dalam sel, dengan

demikian anti-HBs akan mencegah penyebaran virus dari sel ke sel.

Bila proses eliminasi virus berlangsung efisien maka infeksi virus hepatitis B

dapat diakhiri tetapi kalau proses tersebut kurang efisien maka terjadi infeksi virus

hepatitis B yang menetap. Proses eliminsai virus hepatitis B oleh respon imun yang tidak

efisien dapat disebabkan oleh faktor virus atau pun faktor pejamu.

Faktor virus antara lain : terjadinya imunotoleransi terhadap produk virus hepatitis

B, hambatan terhadap CTL yang berfungsi melakukan lisis sel – sel terinfeksi, terjadinya

mutan virus hepatitis B yang tidak memproduksi HBeAg, integarasi genom virus

hepatitis B dalam genom sel hati.

Faktor pejamu antara lain : faktor genetik, kurangnya produksi IFN, adanya

antibodi terhadap antigen nukleokapsid, kelainan fungsi limfosit, respons antiidiotipe,

faktor kelamin dan hormonal.

Salah satu contoh peran imunotoleransi terhadap produk virus hepatitis B dalam

persistensi virus hepatitis B adalah mekanisme persistensi infeksi virus hepatitis B pada

neonatus yang dilahirkan oleh ibu HBsAg dan HBeAg posistif, diduga persistensi infeksi

virus hepatitis B pada neonatus yang dilahirkan oleh ibu HBeAg yang masuk ke dalam

tubuh janin mendahului invasi virus hepatitis B, sedangkan persistensi pada usia dewasa

diduga disebabkan oleh kelelahan sel T karena tingginya konsentrasi partikel virus.

4. Jelaskan jenis dan epidemiologi hepatitis?

Jawab:

Hepatitis A B C D E

Famili Picornaviridae Hepadnaviridae

Flaviviridae - Caliciviridae

Envelope - (HBs Ag) Ya Ya (HBs Ag)

-

Genom ssRNA dsDNA ssRNA ssRNA ssRNA

Stabilitas Tahan panas&asam

Asams EterS AsamS PanasS

Transmisi Fecal-oral Parenteral Parenteral Parenteral Fecal-oral

Prevalensi Tinggi Tinggi Moderat Rendah, regional

Regional

Fulminat Jarang Jarang Jarang Sering Pada

disease kehamilan

Chronic disease

- Sering Sering Sering -

Oncogenic - Ya Ya ? -

a. Hepatitis A, disebabkan oleh virus Hepatitis A (HAV) yang merupakan virus

RNA dari family enterovirus yang berdiameter 27 nm.

b. Hepatitis B, disebabkan oleh virus Hepatitis B (HBV) yang merupakan virus

DNA yang berkulit ganda yang berukuran 42 nm.

c. Hepatitis C, disebabkan oleh virus Hepatitis C (HCV) yang merupakan virus

RNA kecil terbungkus lemak yang berdiameter sekitar 30 sampai 60 nm.

d. Hepatitis D, disebabkan oleh virus Hepatitis D (HDV) yang merupakan virus

RNA detektif yang membutuhkan kehadiran hepatitis B yang berdiameter 35 nm.

e. Hepatitis E, disebabkan oleh virus Hepatitis E (HEV) yang merupakan virus RNA

rantai tunggal yang tidak berselubung dan berdiameter kurang lebih 32 sampai 34

nm.

f. Hepatitis F, baru ada sedikit kasus yang dilaporkan. Saat ini para pakar belum

sepakat hepatitis F merupakan penyakit hepatitis yang terpisah.

g. Hepatitis G, adalah gejala serupa Hepatitis C, seringkali infeksi bersamaan

dengan Hepatitis B dan/atau C. Tidak menyebabkan Hepatitis fulminant ataupun

hepatitis kronik. Penularan melalui transfuse darah jarum suntik.

Dra. Susi Irawati, Apt., Ph.D Hepatitis Virus

DAFTAR PUSTAKA

Alexandria, 2011. Biliary Atresia. National Digestive Diseases Information Clearinghouse. [Online] Available at: < http://digestive.niddk.nih.gov/ddiseases /pubs/atresia/BiliaryAtresia_508.pdf> [Diakses pada 27 September 2013].

Dorland, 2010. Kamus Kedokteran Dorland Edisi 31. EGC, Jakarta.

Hernofialdi, dkk., 2007. Ikterus Obstruktif. Majalah Kedokteran Andalas No.2 Vol.31. [Online] Available at: <http://repository.unand.ac.id/376/1/ikterus-obstruktif. doc> [Diakses tanggal 27 September 2013].

Newman, J., 2009. Menyusui dan Sakit Kuning. [Online] Available at: < http://www.nbci.ca/index.php?option=com_content&view=article&id=355:breastfeedin> [Diakses pada 27 September 2013].

Soetikno, R.D., 2012. Atresia Biliaris. [Online] Diakses pada: <http://pustaka.unpad.ac.id/wp-content/uploads/2012/05/pustaka_unpad_atresia _biliaris.pdf> [Diakses tanggal 27 September 2013].

Stark et al, 2006. The Apgar Score. Pediatrics Official Journal of The American Academy of Pediatrics. [Online] Diakses pada: <http://pediatrics.aappublications.org/ content/117/4/1444.full.html> [Diakses tanggal 26 September 2013].

Sudoyo, A.W., 2009. Buku Ajar Ilmu Penyakit Dalam Edisi V Jilid I. Interna Publishing, Jakarta.