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Cirrhosis.
Causes
Aetiology of cirrhosis
Alcoholic cirrhosis
Postnecrotic cirrhosis or postviral cirrhosis
Hepatitis B
Hepatitis C
Delta hepatitis (hepatitis D) + hepatitis B
Chronic autoimmune hepatitis
Drug-induced cirrhosis - Methotrexate,Methyldopa, isoniazid,Phenylbutazone,Sulphonamides
Biliary cirrhosis
Primary
Secondary
Nonalcoholic fatty liver disease (NAFLD) or nonalcoholic steatohepatitis (NASH)
Cardiac cirrhosis
Haemochromatosis
Wilson's disease
Alphal-antitrypsin deficiency
Glycogen storage diseases
Galactosaemia
Intestinal bypass surgery
Hepatic outflow tract obstruction
Veno-occlusive disease
Cryptogenic (idiopathic) cirrhosis
Pathology and pathogenesis
Cirrhotic changes affect the whole liver, but not necessarily every lobule.
Widespread necrosis of liver cells.
Extensive fibrosis which distorts the hepatic architecture.
Regenerative, nodular hyperplasia of the remaining surviving liver cells leads to regenerating nodules.
Destruction and distortion of hepatic vasculature by fibrosis lead to obstruction of blood flow, which eventually leads to portal hypertension and its sequelae (gastro-oesophageal varices and splenomegaly).
Ascites and hepatic encephalopathy result from both hepatocellular insufficiency and portal hypertension. Hepatocellular damage leads to jaundice, oedema, coagulopathy and a variety of metabolic abnormalities. 4 Alcoholic cirrhosis:
Safe limits of alcohol are 200 g and 140 g of alcohol per week in males and females, respectively.
10 g of alcohol equals 30 mL of whisky, 100 mL of wine and 250 mL of beer.
Occurrence of cirrhosis six times when alcohol intake is double the safety limit.
Cirrhogenic amount of alcohol is roughly 180 gm/day for 25 years.
Classification
Micronodular cirrhosis (Laennec's cirrhosis).
Involvement of every lobule of whole liver.
Uniform, regular connective tissue septa.
Regenerating nodules of less than 3 mm diameter.
Most common cause is alcoholic cirrhosis.
Macronodular cirrhosis.
Liver surface is grossly distorted.
Connective tissue septa vary in thickness.
Regenerating nodules show marked differences in size.
Coarse, irregular nodules growing up to several centimetres.
Most common cause is chronic viral hepatitis.
Mixed cirrhosis.
Shows features of both micronodular and macronodular cirrhosis.
Clinical features
Symptoms
Low-grade fever.
Weakness, fatigue, weight loss.
Anorexia, nausea, vomiting and upper abdominal discomfort. 4 Abdominal distension due to ascites and gas.
Loss of libido.
Menstrual irregularities like amenorrhoea and irregular menses.
Haemorrhagic tendencies like easy bruising, purpura, epistaxis, menorrhagia and gastrointestinal bleeding.
Haemorrhagic tendencies are due to underproduction of coagulation factors by the liver and thrombocytopenia resulting from hypersplenism.
Symptoms of hepatic insufficiency (refer elsewhere).
Symptoms of portal hypertension and its sequelae (refer elsewhere).
Signs
Signs of hepatocellular failure
Jaundice
Palmar erythema
Flapping tremors
Parotid enlargement
Dupuytren's contracture
Gynaecomastia
Diminished body hair
Clubbing
Testicular atrophy
Spider naevi
White nails
Ascites
Features dominant in male cirrhotics
Diminished body hair
Gynaecomastia
Testicular atrophy
Features dominant in alcoholic cirrhosis
Parotid enlargement
Gynaecomastia
Spider naevi
Dupuytren's contractures (related to alcoholism) 4 Liver enlarged, normal or small in size
Features dominant in female cirrhotics 4 Menstrual irregularities
Signs of virilisation
Breast atrophy
Jaundice.
In the initial stages, jaundice is fluctuating, but later the patient becomes chronically jaundiced.
Mechanisms of jaundice in cirrhosis are the following:
1.Failure of bilirubin metabolism (mainly).
2.Intrahepatic cholestasis.
3.Haemolysis.
Diminished body hair.
Seen mainly in males, who slowly loose the male hair distribution.
Alopecia affects mainly the face, axilla and chest.
Cause of alopecia is hyperoestrogenism.
Hyperoestrogenism is due to increased peripheral formation of oestrogen resulting from diminished hepatic clearance of the precursor, androstenedione.
Hyperoestrogenism is responsible for alopecia, gynaecomastia and testicular atrophy.
Spider naevi.
Syn: spider telangiectasia; vascular spiders; spider angiomas; arterial spiders.
Thought to be due to arteriolar changes induced by hyperoestrogenism.
Seen in the territory drained by the superior vena cava (head and neck, upper limbs, front and back of upper chest).
Vary in size from 1-2 mm to 1-2 cm in diameter.
Seen as a central arteriole from which numerous small vessels radiate peripherally, resembling spider's legs. Compression of the central arteriole with a pinhead makes the whole spider disappear. Releasing compression shows filling from centre to periphery.
Conditions associated with spiders
2% of healthy individuals
Third trimester of pregnancy
Viral hepatitis
Alcoholic hepatitis
Rheumatoid arthritis
Thyrotoxicosis
Palmar erythema (liver palm).
Palmar erythema is due to increased peripheral blood flow. In cirrhosis, circulatory changes occur in the form of increased peripheral blood flow and decreased visceral blood flow, especially to the kidneys.
Seen as erythema of palm, especially thenar and hypothenar eminences.
May be seen on the sole.
Also seen in hyperdynamic circulatory states and in some normal people. Dupuytren's contracture.
Due to fibrosis of palrnar aponeurosis.
Seen as a flexion contracture of the fingers, especially ring and little fingers. 4 Clubbing and central cyanosis.
Due to development of pulmonary arteriovenous shunts leading to hypoxaemia. 4 Nail changes.
White (Terry's) nails.
Due to hypoalbuminaemia.
Nails become chalky white and brittle.
Muehrcke's nails.
Pairs of transverse white lines which disappear on applying pressure.
Lines do not move with growth of nail.
Flapping tremors.
Seen in hepatic pre-coma (for further details, refer hepatic encephalopathy). Gynaecomastia.
Seen in males (in females, there is atrophy of breasts).
Due to hyperoestrogenism.
Causes of gynaecomastia
Physiological (ageing)
Cirrhosis of liver Spironolactone Cimetidine Digoxin
Ketoconazole
Oestrogens
Klinefelter's syndrome Tumours of testes and lung
Testicular atrophy.
It is a consequence of hyperoestrogenic state.
Ascites.
Results from both hepatocellular insufficiency and portal hypertension (refer ascites).
Parotid and lacrimal gland enlargement.
Mechanism is not clear.
Seen more commonly in alcoholic cirrhosis.
Skin pigmentation.
Generalised hyperpigmentation of skin occurs due to increased melanin deposition.
Anaemia.
In cirrhosis, anaemia can occur due to various reasons:
1.Acute and chronic blood loss from var ices.
2.Nutritional deficiency of vitamin B12 and folate.
3.Hypersplenism.
4.Direct bone marrow suppression by alcohol.
5.Haemolysis due to the effect of hypercholesterolaemia on RBC membrane.
Hepatomegaly.
In early stages of cirrhosis due to any cause, liver is enlarged, firm to hard, irregular and non-tender. More common in alcoholics.
In late stages, liver shrinks in size and becomes non-palpable. This is due to progressive hepatocyte destruction and fibrosis.
Other causes of enlarged liver include primary biliary cirrhosis, primary sclerosing cholangitis, haemochromatosis and Wilson's disease.
Portal hypertension, hepatic encephalopathy and renal failure.
These are major complications of cirrhosis.
Symptoms and signs of portal hypertension and its sequelae (refer portal hypertension), hepatic encephalopathy (refer hepatic encephalopathy) and renal failure (refer hepatorenal syndrome) often coexist with cirrhosis. Other extrahepatic consequences.
Hepatopulmonary syndrome.
Results in hypoxaemia through pulmonary microvascular vasodilatation and intrapulmonary arteriovenous shunting resulting in ventilation-perfusion mismatch,
Can occur even with mild liver disease.
Symptomatic patients frequently complain of the insidious onset of progressive dyspnoea or orthodeoxia-platypnoea, a clinical syndrome characterised by dyspnoea and deoxygenation accompanying a change to sitting or standing from a recumbent position.
Can also present with cyanosis, exertional dyspnoea, clubbing, and hypoxia.
Portopulmonary hypertension characterised by an elevated mean pulmonary artery pressure, increased pulmonary vascular resistance, and normal wedge pressure in a setting of underlying portal hypertension. Dyspnoea on exertion is the most common symptom, and other symptoms include orthopnoea, fatigue, syncope, chest pain and haernoptysis.
Complications
Portal hypertension and its sequelae
Ascites
Spontaneous bacterial peritonitis
Hepatic encephalopathy
Features of poor short-term prognosis in cirrhosis
Renal failure
Portal vein thrombosis
Hepatocellular carcinoma
Haemorrhagic manifestations
Progressive jaundice (serum bilirubin more than 20 mg/dL).
Rising serum creatinine.
Prolongation of prothrombin time more than 1.5 times of control.
Hyponatraemia of less than 120 mmol/L.
Hypoalbuminaemia of less than 2.5 g/dL.
Ascites responding poorly to therapy.
Encephalopathy not associated with an extensive collateral circulation.
Investigations
1. Complete blood picture.
Anaemia.
Leucopenia and thrombocytopenia due to hypersplenism and bone marrow suppression by alcohol.
Acanthocytosis—spur-like projections on RBC.
2. Liver function tests.
Hyperbilirubinaemia of both conjugated and unconjugated types.
Serum proteins show A:G ratio reversal.
Serum albumin is decreased.
Serum globulin is increased.
Hypoalbuminaemia is due to impairment of hepatic protein synthesis.
Hyperglobulinaemia is due to non-specific stimulation of reticuloendothelial system.
Transaminases.
AST (SGOT) is raised.
ALT (SGPT) is raised, but less than 300 units.
AST/ALT ratio is more than 2 in alcoholic cirrhosis (in contrast to viral hepatitis, where the ratio is less than 2).
AST is disproportionately raised relative to ALT, as a consequence of proportionately greater inhibition of ALT synthesis by alcohol.
Alkaline phosphatase may be mildly raised.
3. Prothrombin time.
Prolonged due to reduced synthesis of clotting proteins, especially the vitamin K dependent factors.
4.Hepatitis B and C markers.
5.Blood ammonia estimation in cirrhosis is a reliable investigation, particularly in a situation where hepatic encephalopathy is suspected. The reasons for raised blood ammonia are:
Diminished hepatic clearance.
Shunting of portal venous blood around the liver to systemic circulation.
6. Respiratory alkalosis.
Due to central hyperventilation.
7. Metabolic abnormalities.
Glucose intolerance.
Hyponatraemia.
Hypokalaemia.
Hypomagnesaemia.
Hypophosphataemia.
8. Ultrasonographic examination.
Liver size and echotexture alteration.
Macronodules.
Splenic size.
Collaterals.
Ascites.
Size of the portal vein.
9.Liver biopsy confirms the diagnosis of cirrhosis.
10.Relevant investigations related to the specific aetiologies of cirrhosis in individual patients. (serum a-fetoprotein, serum transferrin saturation level, serum ferritin, ceruloplasmin, alpha 1-antitrypsin, antinuclear antibodies and anti-smooth muscle antibodies).
11.Ascitic fluid examination, barium swallow for demonstration of varices, upper gastrointestinal scopy for delineation of var ices.
Treatment
Treatment of underlying cause, removal of causative agents like drugs, alcohol, etc.
High protein diet—minimum 1 g/kg/day.
2000-3000 Kcal/day.
Diets enriched in branched chain amino acids, in patients predisposed to hepatic encephalopathy. o Multivitamin supplementation daily.
Large parenteral doses of thiamine in patients with Wernicke-Korsakoff disease.
Penicillamine inhibits the formation of cross-links in collagen. Colchicine inhibits the assembly of collagen. However, none of them have shown any benefit.
Specific treatment of complications—e.g. variceal bleeding, hepatic encephalopathy and ascites.
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