LIVER CIRRHOSIS

Definition

Histological features of cirrhosis (3)

• Diffuse distortion of the basic architecture
• Replacement of normal liver parenchyma with scar tissue and fibrosis
• Formation of regenerative nodules

Stage 1 cirrhosis is compensated and asymptomatic, can last for 10-20 yr with almost normal life
expectancy
Stage 2 cirrhosis is the onset of first decompensation, typically development of ascites (most
common), variceal bleeding, encephalopathy, etc.

Anatomopathology
Macroscopic appearance
Consistency hard, sharp inferior edge, dysmorphia: atrophy > hypertrophic
Irregular size: micro nodules (<3mm) and macro nodules (> 3 mm) regeneration
Microscopic appearance
Mutilating fibrosis ring replacing the normal parenchyma
Regenerating nodules limited by fibrosis / diffuse lesions

Pathophysiology

Hepatic failure: Destruction of parenchymal, therefore hepatocytes by fibrosis
Metabolic: Decrease glycogenolysis and gluconeogenesis.
Synthetic: Decrease production of albumin and blood coagulation factors (prothrombin time & factor V). In addition, complement, other acute phase reactants and binding proteins for iron, copper and vitamin A are liver products
Storage: The liver is an important storage site for glycogen, triglycerides, iron, copper and lipid-soluble vitamins.
Catabolic and Neutralize: Decrease elimination of endogenous substances (Hormones: estrogen → hyperestrogenism) and drugs. Increase metabolism waste (i.e. ammonia) and exogenous toxic
Excretory: Decrease bile production → Decrease fat absorption in the small intestine; increase bilirubinemia (jaundice)

Portal hypertension: portal pressure > 15mmHg or pressure gradient between hepatic vein pressure and wedged hepatic vein pressure (corrected sinusoidal pressure) > 5 mmHg
Pathogenesis: intra-hepatic block by fibrosis; hepatic venules compression
Consequence: Ascites, splenomegaly, derivation anastomose of portal system

Etiology

Alcoholic liver disease
Last diagnosis if others etiologies not be found
Note: Average alcoholic consumption 30g/day (male); 20g/day (female)

Chronic viral hepatitis (B, B+D, C; not A or E)

Autoimmune hepatitis

Hemochromatosis

α1-antitrypsin deficiency

Primary biliary cirrhosis

Chronic hepatic congestion: Cardiac cirrhosis (chronic right heart failure, constrictive pericarditis), Hepatic vein thrombosis (Budd-Chiari)

Idiopathic

Rare: Wilson’s disease, Gaucher’s disease

Diagnosis

Clinical exam

History

• Drug abuse, transfusion (viral hepatitis)
• Alcoholic consumption
• Hepatotoxic drugs
• Past medical history of known hepatitis (viral)

2/3 of patient with cirrhosis in stage 1 (compensated) are asymptomatic

Physical exam

Liver palpation: may not be palpable if atrophy form
Hepatomegaly (Hypertrophy)
Consistency hard, sharp inferior edge
Dysmorphia, atrophy

Hepatocyte insufficiency
Spider angioma (chest, upper limbs, face)
Hyperestrogenism: Gynecomastia, amenorrhea
Nail clubbing (formerly known as Hippocratic fingers), Terry's nails (Proximal nail bed turns white)
Palmar erythema
Jaundice (Total bilirubin)
Fetor hepaticus

Portal hypertension

Splenomegaly

Ascites +/- edema

Caput medusa: epigastric, peri-umbilical

↑ Heart rate, ↓ diastolic pressure by vasodilation

Searching complication

Ascites, edema: Abd girth, flank dullness + shifting dullness, weight gain

Varices and Variceal Hemorrhage: Melena, hematemesis

Hepatic encephalopathy: Neurologic examination, confusion, asterixis

Hepatocellular carcinoma: Vital sign, Virchow's node (supraclavicular node), liver palpation

Investigation

Liver biopsy
Definitive diagnosis

Not recommended in cirrhosis that caused by viral hepatitis or associated with HIV

Not indicated if the diagnosis is almost certain

Must confirm hemostasis at optimal (Prothrombin time, partial thromboplastin time)

2 ways insertion: Trans-parietal (monitored by ultrasound), or Trans-jugular (if prothrombin time < 50% or high amount ascites)

Non-invasive method
FibroScan: non-invasive tool using elastography
FibroTest: combination of various clinical and biochemical markers that can predict degree
of fibrosis

Abdominal ultrasound with doppler

Liver dysmorphic, right lobe atrophy, hypertrophy or macro nodular

Splenomegaly, portal veins dilatation

Complication: ascites, portal thrombosis, HCC (nodule)

Confirming etiology

Alcohol: CBC (macrocytose), ↑ gamma glutamyl transferase, AST > ALT

Viral serology: HBs antigen, Hbs anti-body, Hbc antibody, HCV antibody

Autoimmune hepatitis study: IgG, ANA

others: Fe, Cu study; α1-anti trypsin

Evaluation

Blood work: fall in platelet count <150 is the earliest finding, followed many yr later with rise in INR, fall in albumin, rise in bilirubin, fall in glucose level (pre-terminal event)
Anemia: Marrow suppression, hyperslpenism, Fe and/or folate deficiency
Neutropenia: Hyperslpenism
Thrombocytopenia: Hyperslpenism, ↓ thrombopoietin production by liver, alcoholic toxic
↓ Coagulation (prothrombin time, factor V)
Serum protein electrophoresis: Polyclonal hypergamaglobulinemia

Evaluate severity and pronosis by Child-Pugh score:

Toronto's note 2014

Complication

Ascites

Increased backpressure into capillaries, as well as decreased oncotic pressure as the result of decreased albumin synthesis

In addition, increased activity of the renin–angiotensin–aldosterone system contributes to sodium and water retention

May compromise respiratory ventilation; or develop to spontaneous bacterial peritonitis

Dx: Ultrasonography is effective if fluid accumulation more than 2000ml

A serum albumin–ascites gradient (SAAG) greater than 1.1 g/dL is indicative of portal hypertension

Varices occur as a result of the development of collateral vessels that bypass the obstructed liver

Varices are common in the esophagus and somewhat less common in the stomach, duodenum, and hemorrhoidal plexus

Massive digestive hemorrhage is life threatening if rupture. Affected patients are potentially develop infective gastropathies

Dx: Best made by endoscopy. Endoscopy is essential in the acutely bleeding patient because the mortality rate is high (40%–50% for each episode of bleeding), and early treatment can be life saving

Portosystemic encephalopathy

The primary cause of hepatic encephalopathy is unclear. Elevated ammonia
levels may be found in the blood but do not clearly correlate with disease. It is essential to
rule out secondary causes of hepatic encephalopathy, which include:

• Azotemia, due to increased nitrogen load
• Increased production of ammonia or increased protein load due to constipation, increased dietary protein, or gastrointestinal bleed
• Infection, which leads to increased tissue metabolism and increased protein load
• Sedatives, whose direct depressant effect on the brain is compounded by decreased hepatic catabolism of the drugs
• Electrolyte abnormalities, including hypokalemia and alkalosis, which lead to impaired renal excretion of ammonia and to increased transfer of ammonia across the blood–brain barrier

Hepatorenal syndrome

The exact pathogenesis of this complication of cirrhosis is not known, but all data indicate that the renal failure is caused by hypoperfusion of kidneys. Occurs in patients with severe liver disease

Several factors are implicated:

• Splanchnic arterial vasodilation triggered by portal hypertension.
• Intense renal vasoconstriction
• Decreased glomerular filtration rate (GFR)
• Decreased renal blood flow

Diagnostic criteria

• Chronic or acute hepatic disease with advanced hepatic failure and portal hypertension
• Plasma creatinine > 1.5 mg/dL
• Absence of any other cause for renal disease (shock, infection, obstruction, nephrotoxins)
• Urine red blood cells < 50 cells/per high-power field, urine protein < 500 mg/day
• Lack of improvement in renal function after volume expansion with albumin and
  withdrawal of diuretics

Prognosis is poor when hepatorenal syndrome develops. Outcomes are strongly dependent on the reversal of hepatic failure, either through medical therapy or liver transplantation

Rate of recovery of kidney function after liver transplantation is unknown; however, a substantial proportion of patients do improve

Coagulation defects usually are attributable to decreased hepatic synthesis of clotting factors.
In addition, splenomegaly may contribute to thrombocytopenia
Other complication

Hepatopulmonary syndrome is a hypoxic state caused by intrapulmonary vascular shunting (effectively, a right-to-left shunt). Exercise or standing-induced hypoxia is noted, and clubbing may occur in severe cases. This syndrome is probably present in 30% of patients with cirrhosis and may be severe in 10% of patients. Treatment is with oxygen and eventual liver transplantation
Cirrhotic cardiomyopathy: ↓ Inotropic & chronotropic response, ↓ systolic and
diastolic function, prolonged QT, hyperkinetic circulation
Infection: Kuppfer cell (hepatic macrophage) dysfunction, ↓opsonic activity; vaccinate for HAV &
HBV, influenza yearly, pneumonia
Hepatocellular carcinoma: Incidence ~ 3.5%/yr (↑ risk if HBV or hemochromatosis)
Features: ↑ liver size, ascites, encephalopathy, weight loss
Screen all cirrhotic patients with US +/- α-fetoprotein, though CT/MRI more sensitive
Diabetes (15–30%): due to altered glc & insulin metabolism