SIROSIS HEPATIS

Sigit Widyatmoko Fakultas Kedokteran UMS

Normal Liver

Introduction
Cirrhosis is common end result of many chronic liver disorders. Diffuse scarring of liver follows hepatocellular necrosis of hepatitis. Inflammation healing with fibrosis Regeneration of remaining hepatocytes form regenerating nodules. Loss of normal architecture & function.

Introduction
Irreversible chronic injury of the hepatic parenchyma, include extensive fibrosis in

association with the formation of regenerative nodules Result from hepatocyte necrosis, collapse of supporting reticulin network, with subsequent connective tissue deposition, distortion of the vascular bed, and nodular regeneration of remaining liver parenchyma.

 Clinical features of cirrhosis derive from the morphologic alterations and often reflect the severity of hepatic damage rather than the etiology of the underlying liver disease Classification:
Alcoholic
Cryptogenic and post hepatitis Biliary

Cardiac
Metabolic, inherited, and drug related

Definition:
1. Diffuse disorder of liver characterised by;
2. Complete loss of normal architecture, 3. Replaced by extensive fibrosis with, 4. Regenerating parenchymal nodules.

Classification
Morphologic classification: less useful
Micronodular cirrhosis: uniform nodules < 3 mm
Macronodular cirrhosis: nodular variation > 3 mm Mixed cirrhosis

Etiologic classification: preferred

The most useful clinically

The two most common cause of cirrhosis: alcohol use and viral hepatitis

 Pembagian lain:
Sirosis kompensata

Sirosis dekompensata: ikterus, perdarahan varises,

asites, ensefalopati hepatikum, karsinoma hepatikum

Perubahan kompensata menjadi dekompensata:

5-7% pertahun Survival menurun jauh:

Sirosis kompensata: 12 tahun

Sirosis dekompensata: 2 tahun

Epidemiologi
Prevalensi di Indonesia antara 3,6-8,4% pada pasien bangsal Jawa dan Sumatera atau rata-rata 47,4% dari seluruh pasien penyakit hati yang dirawat Pria : wanita 2,1 : 1 Usia rata-rata= 44 tahun

Normal Liver Histology

CV

PT

Cirrhosis

Fibrosis

Regenerating Nodule

Etiology of Cirrhosis
Alcoholic liver disease 60-70%

Viral hepatitis
Biliary disease

10%
5-10%

Primary hemochromatosis 5%
Cryptogenic cirrhosis 10-15%

Wilsons, 1AT def

rare

Alcoholic Liver Injury:

Ethyl alcohol : Common cause of

acute/Chronic liver disease Alcoholic Liver disease - Patterns

Fatty change, Acute hepatitis (Mallory Hyalin) Chronic hepatitis with Portal fibrosis Cirrhosis, Chronic Liver failure

All reversible except cirrhosis stage.

Alcoholic Liver Injury

May be clinically silent, and many cases (10-40%) are discovered incidentally at laparotomy Occuring usually > 10 years of excessive alcohol use

Increased peripheral release of fatty acids. Inflammation, Portal bridging fibrosis Stimulates collagen synthesis fibrosis. Micronodular cirrhosis.

Alcoholic Liver Damage

Mallorys hyalin: eosinophilic fibrillar material seen in ballooned hepatocytes

Alcoholic Fatty Liver

Alcoholic Fatty Liver

Alcoholic Fatty Liver

Cirrhosis in Alcoholism

Alcoholic Cirrhosis

Cirrhosis

Nodules of fatty and regenerating liver cells separated by scars (cirrhosis)

Pathogenesis:
Hepatocyte injury leading to necrosis.
Alcohol, virus, drugs, toxins, genetic etc..

Chronic inflammation - (hepatitis). Bridging fibrosis.

Regeneration of remaining hepatocytes Proliferate as round nodules.

Loss of vascular arrangement results in

regenerating hepatocytes ineffective.

Cirrhosis Features:
Liver Failure
Parenchymal regeneration Portal obstruction, Porta systemic shunts

Portal hypertension, Splenomegaly

Jaundice, Coagulopathy, hypoproteinemia,

toxemia, Encephalopathy,

Micronodular cirrhosis

Micronodular cirrhosis:

Macronodular Cirrhosis

Clinical Features
Hepatocellular failure.
Malnutrition, low albumin & clotting factors,

bleeding. Hepatic encephalopathy.

Portal hypertension.
Ascites, Porta systemic shunts, varices,

splenomegaly.

Bleeding in Liver disease:

vitamin K in liver gamma-

carboxyglutamic acid for coagulation factors II, VII, IX, and X. Liver disease factor VII is the first to go so the defect will appear initially in the extrinsic pathway, i.e., abnormal PT. When severe it affects both pathways.

Cirrhosis Clinical Features

Gynaecomastia in cirrhosis

Porta-systemic anastomosis: Prominent abdominal veins.

MRI Cirrhosis

Complications:
Congestive splenomegaly. Bleeding varices. Hepatocellular failure. Hepatic encephalitis / hepatic coma. Hepatocellular carcinoma.

Impaired Metabolic and Endocrine Functions

Hyperglycemia - portal to systemic shunting, which decreases the efficiency of postprandial glucose extraction from portal blood by hepatocytes. mesa@food

Hypoglycemia - hepatocyte destruction and impaired glycogenolysis and gluconeogenesis

Impaired Metabolic and Endocrine Functions

Impaired protein synthesis1
Albumin low oncotic pressure
Angiotensinogen low blood pressure Insulin-like growth factor 1, thyroid hormone binding proteins poor growth and metabolism

Impaired protein processing

Oxidative deamination, transamination, urea cycle buildup of toxic biological compounds such as ammonia

Impaired Metabolic and Endocrine Functions

Disruptions in the entero-hepatic circulation of bile
Cholestasis impairs dietary absorption of lipids and fat-soluble vitamins A, D, E, K

Inhibited excretion of bilirubin jaundice, buildup of bile acids pruritus

Impaired Metabolic and Endocrine Functions

Decreased synthesis of sex hormone binding globulin, decreased hepatic clearance of unbound sex hormones, increased peripheral aromatization of androgens to estrogens feminization (testicular atrophy, gynecomastia, loss of male-distribution body hair), pituitary and gonadal suppression1

Hematologic Derangements
Thrombocytopenia impaired liver production of thrombopoietin, increased destruction due to hypersplenism from splenic vein engorgement

Gastrointestinal Varices
Varices are a direct consequence of portal hypertension, and patients are at risk with portal pressures greater than 10 mmHg Esophageal varices are present in 30% of patients with compensated cirrhosis and 60% of patients with decompensated cirrhosis11 Each episode of bleeding carries a 20% mortality rate12

Untreated patients have a 70% rebleeding risk within one year13

Varicose veins in the esophagus

Gastrointestinal Varices
All patients should undergo screening upper endoscopy when cirrhosis is first diagnosed. Those without varices should undergo repeat endoscopy every 3 years if liver function is stable, or once a year if there are any signs of deterioration. Screening endoscopy can be stopped once patients are on beta blockers.

Gastrointestinal Varices
Primary Prophylaxis
No definitive data to support treatment of small varices Medium to large varices should be treated with nonselective beta blockers, which can reduce portal pressure by an average of 15 20%, and can decrease overall upper gastrointestinal bleeding by 40%; Endoscopic band ligation is recommended for those unable to tolerate beta blockers The dose of beta blocker should be titrated up to produce a 25% reduction in the patients baseline heart rate, or until a resting heart rate of 5560 beats per minute is reached

Gastrointestinal Varices
Acute variceal bleed - high risk of death within weeks from uncontrolled bleeding, early rebleeding, infection, or renal failure
Treatment should be initiated immediately with resuscitation, prophylactic antibiotics, vasoactive drugs (eg, octreotide for 48 hours 5 days), and endoscopic therapy

Ascites
Pathogenesis : sinusoidal portal hypertension increased hepatic lymph production collection of lymph fluid in the peritoneal cavity when drainage mechanisms are overwhelmed Aliran darah melalui v porta sirkulasi spanknik dan sistemik vasodilatasi ret Na dan air + aktivasi SSP ( aliran darah ginjal dan LFG ) air mengumpul

Any patient with new onset ascites should have a diagnostic paracentesis for cell count with diff, protein, albumin

 SAAG (serum albumin ascites albumin) > 1.1g/dL is consistent with portal hypertension or hipoalbuminemia (nonperitoneal SAAG < 1,1 : penyakit peritoneum atau eksudat 4 tingkatan asites:
Hanya dapat dideteksi dengan px seksama Deteksi lebih mudah dengan jumlah sedikit Tampak jelas tetapi tidak terasa keras Asites mulai terasa keras

Komplikasi asites terdapat pada 10% pasien CH

Survival pasien menurun: 50% dalam 5 th

Ascites in Cirrhosis

Ascites

ascites accumulation of fluid in the abdominal cavity

Ascites in Cirrhosis

Ascites
Treatment
Dietary sodium restriction 1-2g/day (effective in 20% of patients)
No need for fluid restriction Diuretic therapy with spironolactone plus furosemide in ratio of 100mg to 40mg, max 400mg/160mg21, 22 Note: loop diuretics may worsen hyponatremia and cause hepatic encephalopathy by increasing renal ammonia production

In patients with poor response, check 24 hour urine sodium for compliance (should be less than prescribed daily sodium limit)

Spontaneous Bacterial Peritonitis

Cairan dalam perut merupakan tempat ideal pertumbuhan kuman Mekanisme: pertumbuhan bakteri dan tranlokasi melalui dinding usus yang permeabilitasnya SBP occurs in up to 30% of patients with ascites Diagnosis - > 250 PMNs per mm3 of fluid

 Bakteri utama gram negatif, tetapi juga ditemukan Stafilokokus aureus

Klinis: demam, menggigil, nyeri abdomen, diare, asites memburuk

SBP is associated with the development of hepatorenal syndrome in about 30% of patients. The risk can be decreased by intravenous albumin infusion at a dose of 1.5mg/kg at the time of SBP diagnosis and 1.0mg/kg after 48 hours.

Spontaneous Bacterial Peritonitis

Upper GI bleed carries a high risk of SBP, even in patients who do not have ascites, and prophylactic antibiotics are warranted x 7 days
Norfloxacin 400mg PO BID
Ofloxacin 400mg IV daily

Hepatic Encephalopathy
Pathogenesis unclear, ammonia hypothesis states that ammonia is directly neurotoxic, but there is no correlation between severity of encephalopathy and ammonia level Wide range of clinical manifestations, from reversal of sleep-wake cycle, mood disturbance, psychomotor impairment, visual impairment, to decreased attention May see characteristic hand flap (asterixis)

Pathogenesis of Hepatic Encephalopathy

BRAIN Porta systemic shunts
LIVER

Toxic N2 metabolites From Intestines

Faktor Pencetus
Peningkatan amniogenesis: perdarahan

saluran cerna, sembelit, dehidrasi, infeksi, asupan protein meningkat Penurunan fungsi hepatoselular: dehidrasi, hipotensi, sepsis, hipoksia, anemia, karsinoma Peningkatan pintas portokaval: trombosis vena porta, pintasan pintasan transjugular intrahepatik portosistemik

 Pemakaian obat psikoaktif: golongan

benzodiazepin, etanol, antimual, antihistamin Faktor pencetus lain: pemberian produk darah yang disimpan

Hepatic Encephalopathy
Treatment
Look for triggers: gastrointestinal bleeding, hypovolemia, hypoglycemia, hypokalemic metabolic alkalosis, infection, constipation, hypoxia, sedatives
Non-absorbable disaccharides (lactulose, starting at 30g BID, titrated to 2-3 loose BMs daily) to increase ammonia clearance Non-absorbable antibiotics (neomycin, rifaximin) to decrease intestinal ammonia production

Probiotic: improves hepatic encephalopaty by decrease ammonia concentration

 L-ornithine-L-aspartate: decreased ammonia

concentration dose dependent

Consider liver transplantation, encephalopathy mostly

reversible, but minimal symptoms may persist after transplantation

Hepatorenal Syndrome
Pathogenesis renal vasoconstriction from low renal perfusion Type 1 rapidly progressive, doubling of serum creatinine to > 2.5mg/dL in < 2 weeks; frequently develops from Type 2 after a precipitating event such as infection, GI bleed, surgery, acute hepatitis. Without treatment, type 1 HRS has a median survival of 2 weeks Type 2 - moderate and steady decline in renal function with creatinine >1.5mg/dL, dominant feature is refractory ascites. Median survival is 6 months

Hepatorenal Syndrome
Diagnosis
Rule out other causes of renal failure
Urine studies consistent with prerenal etiology (low FENa and FEUrea) No improvement in renal function after empiric fluid challenge of at least 1.5 L Proteinuria < 500mg/day Renal ultrasound without evidence of obstructive uropathy or parenchymal disease

Hepatorenal Syndrome
Treatment
Midodrine, alpha adrenergic agonists, in combination with albumin infusion or octreotide, are beneficial in almost two thirds of patients with HRS
Liver transplantation is the only definitive treatment Patients transplanted less than 30 days after initiation of dialysis have a good chance of renal recovery after transplant

Hepatocellular Carcinoma
Annual incidence 1.4% in patients with compensated cirrhosis and 4% in patients with decompensated cirrhosis Screening should be done with AFP and ultrasound every 6 months Patients with HCC amenable to liver transplant are exempt from MELD calculation and have priority on the transplant list

 Hepatitis dapat terjadi kanker hati dengan atau tanpa sirosis terlebih dahulu

Hepatoma lebih banyak ditemukan pada hepatitis C

Sirosis hepatoma: 2-4% pertahun tergantung

penyebabnya Pada hepatitis B: HBeAg (+) paling berisiko

Hepatocellular Carcinoma