Liver Cirrhosis

• The term CIRRHOSIS was first coined by Laennec in 1826
• Many definitions but common theme is injury, repair, regeneration, and scarring
• NOT a localized process; involves entire liver
• Primary histologic features:
  1. Marked fibrosis
  2. Destruction of vascular & biliary elements
  3. Regeneration
  4. Nodule formation

Cirrhosis is a pathological diagnosis. It is characterized by widespread fibrosis with nodular regeneration. Its presence implies previous or continuing hepatic cell damage.

Defined as diffuse scarring/fibrosis of liver characterized by hepatic necrosis, formation of regenerative nodules, and loss of lobular and vascular architecture of the liver.

It is not a specific disease, but the end result of several diseases causing liver injury.

Many of the causes of chronic hepatitis end up in cirrhosis.

• Alcohol
• Chronic infections: hepatitis B, C, B+D
• Chronic biliary obstruction: Primary biliary cholangitis (PBC), Primary sclerosing cholangitis (PSC), stricture, stones, cystic fibrosis, congenital biliary atresia, cysts
• Metabolic/genetic errors:Fe, Cu, α1-AT, lipids
• Autoimmune
• Cardiovascular: heart failure, pericarditis, Budd-Chiari syndrome
• Drugs and chemicals
• NASH (Nonalcoholic steatohepatitis)
• Cryptogenic
• Combined

• Diffuse liver injury leading to necrosis.
  • (Alcohol, virus, drugs, toxins, genetic, etc.)
• Chronic inflammation & healing (hepatitis).
• Bridging fibrosis – loss of architecture.
• Regeneration ➔ nodules.
• Obstruction to blood flow & shunts.
• Portal hypertension ➔ splenomegaly, varices.
• Liver failure – Debilitation, Jaundice, Ascites, Edema, Bleeding, Jaundice.
• Hormone imbalance – spider naevi, testicular atrophy, etc.

WHO divided cirrhosis into 3 categories based on morphological characteristics of the hepatic nodules:

1. Micronodular
2. Macronodular
3. Mixed

Micronodular Cirrhosis

• Nodules are less than 3 mm in diameter
• Relatively uniform in size
• Distributed throughout the liver
• Rarely contain portal tracts or efferent veins
• Liver is of normal size or mildly enlarged
• Reflect relatively early disease

Macronodular & Mixed Cirrhosis

• Nodules are greater than 3 mm in diameter and vary considerably in size
• Usually contain portal tracts and efferent veins
• Liver is usually normal or reduced in size
• Mixed pattern if both types of nodules are present in equal proportions

• Primary event is injury to hepatocellular elements
• Triggering inflammatory response with cytokine release-toxic substances
• Destruction of hepatocytes, bile duct cells, vascular endothelial cells
• Repair through cellular proliferation and regeneration
• Formation of fibrous scar
• Stellate cell is activated in response to injury and leads to expression of fibril-forming collagen
• Above process is also influenced by Kupffer cells which activate stellate cells by eliciting production of cytokines
• Sinusoidal fenestrations are obliterated because of collagen
• Prevents normal flow of nutrients to hepatocytes and increases vascular resistance
• Initially, fibrosis may be reversible if inciting events are removed
• With sustained injury, process of fibrosis becomes irreversible and leads to cirrhosis

Portal Hypertension (PH)

• Portal vein pressure above the normal range of 5 to 8 mm Hg
• Portal vein - Hepatic vein pressure gradient greater than 5 mm Hg (>12 clinically significant)
• Represents an increase of the hydrostatic pressure within the portal vein or its tributaries

Pathophysiology of PH

• Cirrhosis results in scarring (perisinusoidal deposition of collagen)
• Scarring narrows and compresses hepatic sinusoids (fibrosis)
• Portal vein thrombosis, or hepatic venous obstruction also cause PH by increasing the resistance to portal blood flow
• Progressive increase in resistance to portal venous blood flow results in PH
• As pressure increases, blood flow decreases and the pressure in the portal system is transmitted to its branches
• Results in dilation of venous tributaries
• Increased blood flow through collaterals and subsequently increased venous return cause an increase in cardiac output and total blood volume and a decrease in systemic vascular resistance
• With progression of disease, blood pressure usually falls

Region	Name of clinical condition	Portal circulation	Systemic circulation
Esophageal	Esophageal varices	Esophageal branch of left gastric vein	Esophageal branches of Azygos vein
Rectal	Haemorrhoids	Superior rectal vein	Middle rectal veins and inferior rectal veins
Paraumbilical	Caput medusae	Paraumbilical veins	Superficial epigastric vein
Retroperitoneal	(no clinical name)	Right colic vein, middle colic vein, left colic vein	Renal vein, suprarenal vein, paravertebral vein, and gonadal vein
Intrahepatic	Patent ductus venosus	Left branch of portal vein	Inferior vena cava

• When compensated, cirrhosis may not manifest with any appreciable clinical feature
• In decompensated state, there are florid clinical signs of defective synthetic liver function leading to features of hypoproteinaemia, bleeding diathesis, and gallstones.
• The diffuse fibrosis and nodules distort hepatic angioarchitecture leading to structural obstruction of the hepatic sinusoids with development of portal hypertension and its sequelae.
• Inability of the cirrhotic liver to metabolize biomolecules lead to accumulation of metabolites giving rise to features like gynaecomastia (oestrogen) and other feminization features (loss of axillary and pubic hair).

CLINICAL FEATURES

Mainly due to Hypoproteinaemia, Feminisation and Portal HT

• Peripheral oedema
• Fatigue, weakness
• Ill-health
• Nausea, vomiting, and loss of appetite
• Loss of libido
• Weight loss, muscle wasting
• Fluffy hair
• Leuconychia
• Sparse axillary hair
• Parotid fullness
• Jaundice, dark urine
• Bloody, black stools or unusually light-colored stools
• Generalized itching
• Testicular atrophy
• Palmar erythema
• Dupuytren’s contracture
• Female pattern pubic hair
• Liver palms
• Gynecomastia
• Menstrual changes in women
• Spider naevi, caput Medusae
• Vomiting of blood
• Abdominal swelling
• Swollen feet or legs
• Spider angioma
• Finger clubbing
• Splenomegaly
• Terry's nails
• Muerch’s nail
• Hepatomegaly/shrunken liver
• Ascites
• Caput medusae
• Paper money skin
• Sleep disturbances, confusion, disorientation, tremor, asterixis

• Hepatic encephalopathy
• Coagulopathy
• Portal hypertension
• Varices/Haemorrhage
• Hepatorenal syndrome
• Hepatopulmonary syndrome
• Spontaneous bacterial peritonitis
• Anaemia
• Hypersplenism
• Portal vein thrombosis
• PLCC (Primary liver cell carcinoma)

• Liver biopsy
• Viral screening
• Alpha-fetoprotein
• LFT (Liver Function Tests)
• PT/PTTK/INR
• FBC (Full Blood Count)
• ESR (Erythrocyte Sedimentation Rate)
• CXR (Chest X-ray)
• Abdominal USS (Ultrasound Scan), CT Scan, MRI Scan
• Non-invasive tests of fibrosis - Fibroscan, fibrotest

Biochemistry can be surprisingly normal but some abnormality will often be present with slightly raised transaminases and alkaline phosphatases. In severe cases, all liver enzymes will be abnormal. Low sodium and albumin are also seen.

Coagulopathy is a very sensitive indicator of liver dysfunction and is reflected in the prolonged prothrombin time.

Immunologic function test Serological markers:

• Viral hepatitis markers (HBsAg, Anti-HCV, HBV DNA)
• Antinuclear antibody (ANA)
• Anti-smooth muscle antibody
• Anti-mitochondrial antibody (AMA)

• Liver diseases:
• Chronic hepatitis
• Primary carcinoma of the liver
• Schistosomiasis
• Clonorchis sinensis
• Hepatic hydatidosis
• Ascites and enlarged abdomen:
• Tuberculous peritonitis
• Constrictive pericarditis
• Chronic glomerulonephritis
• Ovarian cysts
• Primary

• Removal of the etiological factors:
• Can stop or delay further progression
• May lead to regression
• May reduce complications

Prevention and treatment of complications

• Cirrhotic ascites
• Rest
• Diet
• Treatment:
• Bed rest
• Salt restriction
• Diuretics: spironolactone, furosemide; under regular check-up (body weight, electrolytes, renal function)
• Refractory ascites:
• Large-volume paracentesis
• TIPS- Transjugular intrahepatic portosystemic shunt
• Peritoneovenous shunting
• Spontaneous bacterial peritonitis (SBP):
• Features: fever, sepsis, hypotension, fast deterioration of liver function, azotemia, encephalopathy, death
• Diagnostics: PMN count in the ascites > 250/μl; culture
• Treatment: antibiotics; paracentesis
• Hepatorenal syndrome:
• Features: renal failure with severe liver disease without an intrinsic abnormality of the kidney
• Cause: reduction in RBF, GFR (vasoconstrictors!)
• Diagnostics: urine Na < 10 mM, oliguria without volume depletion
• Treatment: prevention of hypovolemia, hypotension; terlipressin; TIPS
• Prognosis: lethal if the liver disease is untreatable
• Bleeding esophageal and gastric varices:
• Features: hematemesis, melena, shock
• Diagnostics and treatment: stabilizing BP, replacing fluid and blood, somatostatin
• Endoscopic sclerotherapy or band ligation or balloon tamponade
• TIPS, P-C shunting
• Prevention: propranolol
• Liver transplantation

Child-Pugh

• The Child-Pugh classification is a useful guide to determine the functional capacity/prognosis in the liver.
• A, B, and C.
• Class C has the worst prognosis.
• A has the best.

Child-Pugh score
Parameters	Score 1	Score 2	Score 3
Encephalopathy (grade)	0	1 – 2	3 – 4
Ascites	Absent	Mild	Moderate
Bilirubin (mg/dl)	< 2	2 – 3	> 3
Albumin (g/dl)	> 3.5	2.8 - 3.5	< 2.8
PT (sec. prolonged)	< 4	4 – 6	> 6
OR INR	< 1.7	1.7 - 2.3	> 2.3

In cholestatic liver disease, bilirubin is scored as:

• < 4mg/dl (1 point)
• 4 - 10mg/dl (2 points)
• > 10mg/dl (3 points)

Class A = 5-6, Class B = 7-9, Class C = 10-15

• Health education
• Healthy and adequate diet
• Avoidance of alcohol
• Avoidance of potentially hepatotoxic drugs
• HBV vaccinations
• Follow up HBV carriers
• Treat unresolved acute hepatitis
• Drug monitoring