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Fisiopatologia 8) CIRROSI EPATICA Antonio Nenna

CIRROSI EPATICA

La cirrosi epatica ha causa virale, alcolica o tossica (farmaci). Si hanno:


- riduzione della massa epatocellulare (distruzione del parenchima)
- riduzione della funzionalità epatica
- alterazioni del flusso ematico (ostruzione => ipertensione portale)

Indici di alterata funzionalità epatica:


- iperbilirubinemia
- ipoalbuminemia
- aumento del tempo di protrombina
- diminuzione del fibrinogeno
- aumento delle transaminasi (indicano il danno epatico, analoghe della troponina per l’IMA)

Caratteristiche del sistema portale:


- flusso portale = 1200 mL/min (25% del C.O.)
- pressione normale del sistema portale è 5-10 mmHg (7-14 cmH2O) [bassa resistenza nei sinusoidi, poiché
c’è ampio lume+ *la pressione nelle vene del circolo sistemico è 1-5 mmHg]
- gradiente venoso portale (GVP) di 5 mmHg (permette al sangue di passare dalla porta alla cava)

Le complicanze della cirrosi epatica sono:


 ipertensione portale
o ascite
per aumento della pressione nel circolo splancnico che causa trasudazione
l’ascite è un ottimo terreno di coltura => peritonite batterica spontanea, PBS1
nella cirrosi è un trasudato
il versamento è rilevabile all’EO solo se è maggiore di 500mL)
o varici gastroesofagee (emorragia digestiva superiore)2
presenti se GVP > 12 mmHg
normalmente il flusso nella v. porta è epatopeto (in). In ipertensione, il flusso è epatofugo (out)
le vene dilatate si possono ulcerare, precedute dai “segni del rosso” nella gastroscopia
le emorragie sono improvvise, drammatiche, senza dolore
o splenomegalia (per aumento della Parteria splenica) (anemia, leucopenia, piastrinopenia)
 sindrome epatorenale (IRA in cirrosi)
 encefalopatia epatica/portosistemica (l’ammoniaca del catabolismo proteico non viene smaltita come
urea, ma passa in circolo sistemico e causa il coma epatico)
 sindrome epatopolmonare
 coagulopatia
 anomalia ematologiche
 malattie ossee
 malnutrizione (per ridotta sintesi proteica)
 cancrocirrosi

1
Peritonite:
- batterica spontanea / primaria (PBS) (dovuta a infezione batterica)
- batterica secondaria (dovuta a perforazione: ulcera, cancro, appendicite, trauma)
- batterica terziaria (dovuta a dialisi peritoneale)
2
Anastomosi porto-cavali:
- vv. esofagee inferiori (varici esofagee)
- vv. ombelicali e epigastriche superiori (caput Medusae)
- vv. emorroidarie inferiori (emorroidi)
- vv. peritoneali, circolo di Retzius
Fisiopatologia 8) CIRROSI EPATICA Antonio Nenna

IPERTENSIONE PORTALE
Ipertensione portale: GVP > 5 mmHg
Complicanze dell’ipertensione portale: GVP > 10 mmHg

Ipertensione portale epatica: pre-sinusoidale (fibrosi, schistosomiasi), sinusoidale (cirrosi, epatite alcolica),
post-sinusoidale (ostruzione dei sinusoidi)
Ipertensione portale pre-epatica: trombosi della v. splenica, trombosi della v. porta, splenomegalia
Ipertensione portale post-epatica: s. di Budd-Chiari, cause cardiache (percardite essudativa)

Cause di ipertensione portale (+P):


 aumento del flusso portale (+Q) [splenomegalia ematologica]
 aumento delle resistenze (+R)
o sinusoidale [cirrosi epatica]
o pre-sinusoidale [trombosi della v. porta, anche paraneoplastica]
o post-sinusoidale [trombosi della v. sovraepatica]
 fistola arterovenosa

Segni di ipertensione portale (ECO-Doppler):


- ascite
- splenomegalia
- diametro della v. porta in espirazione > 15 mm
- gradiente porto-cavale > 5 mmHg
- rallentamento o inversione del flusso nella v. porta
- diametro della v. splenica > 12 mm
- pressione nella v. porta > 10 mmHg
- trombo (se è presente trombosi)

FASI DELLA CIRROSI


FASE 1: cirrosi compensata. L’aumento della pressione portale (fino a 10 mmHg) causa, tramite NO e glu-
cagone, vasodilatazione splancnica, che sequestra sangue causando una riduzione del volume circolante ef-
ficace; ciò fa aumentare la frequenza e l’inotropia cardiaca, facendo aumentare la gittata cardiaca; questo
ripristina un normale volume circolante efficace. E’ presente S1 vibrato (cirrosi è una sindrome ipercinetica)
FASE 2: sindrome epatorenale (IRA in cirrosi). La vasodilatazione causa attivazione massiva del sistema re-
nina-angiotensina-aldosterone (RAA), che causa vasocostrizione dell’arteria renale e aumenta la ritenzione
idrica; ciò aggrava l’ascite e porta a insufficienza renale.

ASCITE: PARACENTESI ESPLORATIVA


essudato trasudato
proteine totali + –
albumina + –
leucociti + –
coltura (peritonite batterica?)
amilasi (peritonite pancreatica?)
citologia

SAAG: gradiente di albumina siero/ascite (albumina sierica – albumina ascitica)


SAAG > 1,1 => TRASUDATO (poche proteine nell’ascite)
SAAG < 1,1 => ESSUDATO (molte proteine nell’ascite)
[infezione batterica, infiammazione (lupus, febbre mediterranea, artrite reumatoide), neoplastiche]
Fisiopatologia 8) CIRROSI EPATICA Antonio Nenna

Patologie con SAAG > 1,1 (trasudato): Patologie con SAAG < 1,1 (essudato):
- cirrosi - peritonite da tbc
- epatite alcoolica - pancreatite
- metastasi epatiche - sindrome nefrosica (proteinuria e ipoalbumi-
- CHF nemia. La bassa albumina nel sangue è responsa-
- pericardite bile del SAAG da essudato. La bassa pressione on-
- s. di Budd-Chiari (trombosi delle vv. sovraepati- cotica causa la trasudazione nel peritoneo)
che dovuta a trombofilia [protC, protS, fattV])

patologia SAAG proteine


cirrosi T –
HF T –/+
neoplasia E +
peritonite da tbc E +
peritonite piogenica E +
sindrome nefrosica E –
ascite pancreatica E +

CASO CLINICO
Donna di 42 anni, con dolore urente retrosternale e epigastrico, maggiore in posizione supina e postpran-
diale, da 4 settimane, non modificato dalla attività fisica. Il dolore dura circa 30’ ed è rimosso dagli antiacidi.
Non sono presenti fattori di rischio per la cardiopatia ischemica (fumo, alcol, diabete, iperlipidemia).
All’EO, assenza di dolore alla palpazione; presenza di flatulenze; distensione addominale poco significativa
(addome globoso), manca presenza di sangue occulto nelle feci. Diagnosi di lavoro: esofagite da reflusso.
Esame outpatient con gastroscopia e terapia sintomatica (H2-antagonisti e inibitori della pompa protonica).
La distensione è dovuta a meteorismo. Può essere presente un versamento ascitico minore di 500mL (non
rilevabile all’EO). La paracentesi esplorativa (esame del liquido ascitico) serve alla distinzione tra trasudato
(cirrosi) ed essudato (cancrocirrosi, infiammazioni). La paracentesi ha rivelato essudato (SAAG < 1,1 g/dL).
ECO e TC hanno evidenziato ascite e masse omentali. La citologia mostra adenocarcinoma papillare, dovuto
a carcinoma dell’ovaio.
Le flatulenze e il meteorismo sono dovuti alla diapedesi dei batteri aerobi della PBS dal liquido ascitico al
colon (che fermentano e producono aria), e la distensione addominale è dovuta all’ascite.

CAUSE DI DOLORE TORACICO:


- cardiopatia ischemica (IMA)
- colica biliare (dolore epigastrico o ipocondriale, irradiato sulla scapola destra e sulla spalla destra)
- reflusso gastroesofageo (dovuto a ernia iatale)
- ulcera peptica
- dolore muscoloscheletrico (aumenta con la palpazione) (sindrome di Treiz: infiammazione condrosternale)
- dolore pleurico (flogosi della pleura diaframmatica) (dolore epigastrico e retrosternale, inspiratorio, con
auscultazione di sfregamenti pleurici)
- infezione della valvola aortica (insufficienza e stenosi)
- malattia della mucosa esofagea

CAUSE DI DISTENSIONE ADDOMINALE:


- meteorismo intestinale / peritoneale => addome timpanico, peristalsi normale
- liquido ascitico peritoneale => essudato (flogosi) / trasudato (osmotico), ottusità, non saccato
- sangue in cavità peritoneale => ottusità
- ileo meccanico / ileo paralitico => occlusione intestinale (neuropatia o ostruzione) (nausea e vomito)
- masse tumorali (con o senza carcinomatosi) (visibile alla palpazione)
Fisiopatologia 8) CIRROSI EPATICA Antonio Nenna

CIRRHOSIS3

Cirrhosis is not an irreversible condition, and its recovery depends on the removal of the cause.
Cirrhosis consists of the development of fibrosis in the liver, which causes a decrease in hepatocellular
mass, in hepatocellular function and blood flow.
The induction of fibrosis occurs with activation of hepatic stellate cell, resulting in the formation of in-
creased amounts of collagen and other component of the extracellular matrix. The whole condition can be
compensated or decompensated.
Portal hypertension is a significant complicating feature and is responsible for the development of ascites
and bleeding from esophagogastric varices.
Loss of hepatocellular function results in jaundice, coagulation disorders, hypoalbuminemia and portosys-
temic encephalopathy. The complication of cirrhosis are the same, regardless of the etiology.

Causes of cirrhosis:
- alcoholism
- chronic viral hepatitis (HBV, HCV)
- autoimmune hepatitis
- non-alcoholic steatohepatitis
- biliary cirrhosis (primary, sclerosing cholangitis, autoimmune cholangitis)
- cardiac cirrhosis
- inherited metabolic liver disease (hemochromatosis, Wilson’s disease, cystic fibrosis)
- cryptogenic cirrhosis

ALCOHOLIC CIRROSIS
Excessive chronic alcohol use can cause several different types of liver disease (alcoholic fatty liver, alcohol-
ic hepatitis, alcoholic cirrhosis). Chronic alcohol use can produce fibrosis in the absence of related inflam-
mation and/or necrosis. Fibrosis can be centrolobular, pericellular or periportal. The fibrotic nodules
formed are usually < 3mm in diameter (micronodular fibrosis).
Intake of ethanol increases cellular accumulation of triglycerides by increasing fatty acid uptake and by re-
ducing fatty acid oxidation and lipoprotein secretion. Protein synthesis, glycosylation and secretion are im-
paired. Oxidative damage in hepatocytes is due to reactive oxygen species (ROS); also, acetaldehyde is a
reactive molecules which combines with protein and interferes with enzyme activities, including microtubu-
lar formation and hepatic protein trafficking.
This results in Kupffer’s cell activation (via cytokines) and production of excess collagen and extracellular
matrix. Connective tissue appears in both periportal and pericentral zones, and eventually connects portal
triads with central veins, forming regenerative nodules and losing hepatocytes.
The symptoms are: right upper quadrant pain, fever, nausea, vomiting, diarrhea, anorexia, malaise. They
also can present with ascites, edema of upper GI hemorrhage, jaundice or encephalopathy.
On physical examination, the liver and spleen may be enlarged, with the liver edge being firm and nodular.
Other frequent findings are scleral icterus, palmar erythema, spider angiomas, parotid gland enlargement,
digital clubbing and muscle wasting.
Lab tests may be completely normal in patient with early compensated alcoholic cirrhosis. In later stages,
they are anemic (from GI blood loss, nutritional deficiency, hypersplenism related to portal hyperten-
sion), platelet count is low, bilirubin is high, prothrombin time is prolonged (unresponsive to vitamin K),
aminotransferases are high (AST/ALT = 2).

3
Cirrhosis and Its Complications, Harrison, cap. 302
Fisiopatologia 8) CIRROSI EPATICA Antonio Nenna

CHRONIC VIRAL HEPATITIS (HBV, HCV)


Of the patient exposed to HCV, 80% develop chronic hepatitis, and of those, 30% develop cirrhosis over 20
years. HCV is a noncytopatic virus, and liver damage is immune-mediated. Progression of liver disease is
due to portal-based fibrosis with bridging fibrosis and nodularity developing, culminating in cirrhosis. The
liver is small and shrunken, with mixed macro- and micro-nodular points. The presentation is similar to
those of alcoholic cirrhosis. The diagnosis is based on testing for viral RNA.

AUTOIMMUNE HEPATITIS and NON-ALCOHOLIC STEATOHEPATITIS


Autoimmune hepatitis must be suspected when biopsy does not show a significant inflammatory infiltrate.
Lab test is needed for autoimmune markers (ANA, anti-nuclear antibody; ASMA, anti-smooth muscle anti-
body). Immunosuppressive therapy is beneficial.
Non-alcoholic steatohepatitis is increasingly common in developing countries, with the development of ob-
esity. They have steatosis, with liver enlargement.

BILIARY CIRRHOSIS
Cholestatic liver disease may result from necroinflammatory lesion, congenital or metabolic processes, or
external bile ducts compression. So, the bile retention is distinguished in intrahepatic and extrahepatic.
Extrahepatic tissue may benefit from surgical biliary tract decompression, whereas intrahepatic cholestasis
will not improve.
The major causes are primary biliary cirrhosis (PBS), autoimmune cholangitis, primary sclerosing cholangitis
(PSC) and idiopathic adulthood ductopenia [distinguished with blood test, history and presentation]. They
cause cholate stasis, copper deposition, xanthomatous transformation of hepatocytes, and irregular fi-
brosis, usually with chronic portal inflammation.

CARDIAC CIRRHOSIS
Patient with right CHF may develop chronic liver injury and cardiac cirrhosis. This is rare.
The elevated venous pressure transmitted via the vena cava and hepatic veins to the sinusoids of the liver,
which become dilated and engorged with blood. The liver becomes enlarged and swollen, with long-term
passive congestion and relative ischemia due to poor circulation, centrolobular hepatocytes can become
necrotic, leading to pericentral fibrosis. This fibrotic pattern can extend to the periphery of the lobule, caus-
ing cirrhosis.
Patients have signs of congestive HF and enlarged liver. Differentiation from Budd-Chiari syndrome (BCS)
can be made by seeing extravasation of the red blood cells in BCS, but not in cardiac cirrhosis.
Treatment is based on management of the underlying cardiac disease.

OTHER TYPES OF CIRRHOSIS


Hemochromatosis is an inherited disorder or iron metabolism, with progressive iron deposition in the liver,
which leads to portal-based fibrosis, progressing to hepatocellular cancer.
Wilson’s disease is an inherited disorder of copper homeostasis, leading to accumulation in the liver. The
physical examination findings include Kayser-Fleischer corneal rings.
Α1-antitripsin deficiency results in failure of secretion of this protein from the liver.

MAJOR COMPLICATIONS OF CIRRHOSIS


SPLENOMEGALY
Splenomegaly is associated with thrombocytopenia and leukopenia; upper-left quadrant pain may indicate
the severity of splenomegaly. This is usually the first sign of portal hypertension.

PORTAL HYPERTENSION
Portal hypertension is the elevation of the hepatic venous pressure gradient (HVPG) to > 5 mmHg. It is
caused by two hemodynamic processes:
- increased intrahepatic resistance to the passage of blood due to cirrhosis and nodules
- increased splanchnic blood flow secondary to vasodilatation within splanchnic vascular bed
Fisiopatologia 8) CIRROSI EPATICA Antonio Nenna

Classification of portal hypertension:


 Pre-hepatic
o portal vein thrombosis
o splenic vein thrombosis
o massive splenomegaly (Banti’s syndrome)
 Hepatic
o pre-sinusoidal
 schistosomiasis
 congenital hepatic fibrosis
o sinusoidal
 cirrhosis
 alcoholic hepatitis
o post-sinusoidal
 hepatic sinusoidal obstruction (veno-occlusive syndrome)
 Post-hepatic
o Budd-Chiari syndrome
o inferior vena cava webs
o cardiac causes
 restrictive cardiomyopathy
 constrictive pericarditis
 severe congestive heart failure

Coagulation disorder that may lead to portal vein thrombosis include: polycythemia vera, essential throm-
bocytopenia, deficiencies in proteinC-proteinS-antithrombin3-factor5Leiden.

Portal hypertension is responsible for the two major complications of cirrhosis (HVPG > 12 mmHg):
- esophageal varices (variceal hemorrhage) [cherry-red spot]
- ascites (edema)
- hypersplenism (reduction in platelet)

ASCITES
Ascites is the accumulation of fluid within the peritoneal cavity. Ascites is due to portal hypertension, ma-
lignant or infective causes.
The development of ascites in cirrhotic patients is due to: cirrhosis => portal hypertension => splanchnic va-
sodilation (NO) => + splanchnic pressure/arterial underfilling (vasoconstrictors, antinatriuretic factors, RAA
=> sodium retention => plasma volume expansion) => formation of ascites. This is also due to the lessen
oncotic pressure because of the impairment in the production of albumin (hypoalbuminemia).
Patient typically have peripheral edema and increase in abdominal girth; 1-2L of fluid are necessary to be
symptomatic. If ascetic fluid is massive, respiratory function can be compromised, and patient will complain
of dyspnea, fatigue and weakness.
In order to characterize the fluid, paracentesis is necessary (albumin content, blood cell count, cultures,
amylase). In patient with cirrhosis, the protein concentration of the ascetic fluid is low.

Serum-ascites albumin gradient (SAAG):


- SAAG > 1,1 g/dL, ascites is due to portal hypertension (cirrhosis)
- SAAG < 1,1 g/dL, ascites is due to infections or tumors

BONE DISEASE
Osteoporosis is common in patients with chronic cholestatic liver disease, due to malabsorption of vit. D
and decreased calcium ingestion
Fisiopatologia 8) CIRROSI EPATICA Antonio Nenna

SPONTANEOUS BACTERIAL PERITONITIS (SBP)


SBP is a common and severe complication, characterized by spontaneous infection of the ascetic fluid with-
out an intra-abdominal source. Bacterial translocation is the onset of the SBP, with gut flora traversing the
intestine into mesenteric lymph nodes, leading to bacteremia and seeding of the ascetic fluid. The most
common pathogens are: Escherichia coli, Streptococcus viridans, Staphylococcus aureus, Enterococcus spo-
rigenus. If more than two organisms are found, secondary bacterial peritonitis due to perforation is com-
mon. Treatment is with cephalosporin.

HEPATORENAL SYNDROME (HRS)


HRS is a form of functional renal failure without renal pathology that occurs in 10% of patients with cirrho-
sis. It is caused by renal vasoconstriction. Patient has a step-wise progressive increase in creatinine. It is
usually seen in patient with refractory ascites. Treatment include α-agonists.
HRS-Type1: reduction in creatinine clearance
HRS-Type2: reduction in GFR

HEPATIC ENCEPHALOPATHY (PORTOSYSTEMIC ENCEFALOPATHY)


Portosystemic encephalopathy is an alteration in mental status and cognitive function in presence of liver
failure. It is a requirement for the diagnosis of fulminant hepatic failure.
Gut-derived neurotoxins that are not removed by the liver (NH3) because of vascular shunting get to the
brain and cause this encephalopathy. Ammonia levels are elevated, and this impairs Krebs’cycle.
Brain edema is associated with swelling of the gray matter, and can cause cerebral herniation.
Encephalopathy can also be due to electrolyte disturbances.

ABNORMALITIES IN COAGULATION
Coagulopathy is due to decreased syntesis of clotting factors and impaired clearance of anticoagulants. Al-
so, patient may have thrombocytopenia from hypersplenism due to portal hypertension.

HEMATOLOGIC ABNORMALITIES
Anemia can be due to hypersplenism, hemolysis, iron deficiency or folate deficiency.
Macrocytosis is a common abnormality in red blood cell morphology.
Neutropenia is a result of hypersplenism.