Flashcards in Hepatology - Presenting problems in liver disease Deck (27):
What is acute liver failure?
This is a rare condition in which hepatic encephalopathy results from a sudden impairment of hepatic function. In a patient whose liver was previously normal, the level of injury needed to cause liver failure is very high. In those with pre-existing chronic liver disease, the additional acute insult needed is much less. Although a liver biopsy may be useful, it is the presence or absence of features suggestive of chronic liver disease that helps. Acute viral hepatitis is the most common cause worldwide, with paracetamol toxicity most common in the UK. Acute liver failure can occur occasionally from other drugs, mushroom poisoning, pregnancy, Wilson's disease or following shock, alcohol and sepsis.
How should acute liver failure be assessed?
Hepatic encephalopathy is THE cardinal feature of acute liver failure. It starts with mild, episodic reduced concentration and alertness, progressing to restlessness, aggressive outbursts, drowsiness and coma. Cerebral oedema may cause increased ICP leading to unequal or abnormally reacting pupils, fixed pupils, hypertensive episodes, bradycardia, hypoventilation, profuse sweating, myoclonus or decerebrate posturing. Papilloedema is a rare sign and occurs late.
Examination shows jaundice which develops rapidly, but is absent in Reye's syndrome and death occasionally occurs in fulminant acute liver failure before jaundice develops. Hepatomegaly is unusual; if found with sudden onset ascites it suggests venous outflow obstruction (Budd-Chiari syndrome). Splenomegaly is uncommon.
How is acute liver failure classified?
Hyperacute = <7 days, cerebral oedema
- usually viral or paracetamol poisoning
Acute = 8-28 days, cerebral oedema
- cryptogenic or drugs
Subacute = 29 days to 12 wks, oedema uncommon
- cryptogenic or drugs
What investigations should be performed to determine the underlying cause of acute liver failure?
Toxicology screen - blood and urine
IgM anti- HBc, HBsAg
Anti-HEV, HCV, CMV, HSV, EBV serology
Caeruloplasmin, serum copper, urinary copper, slit lamp eye examination
Autoantibodies: ANF, ASMA, LKM, SLA
USS of liver and Doppler of hepatic veins
PT quickly becomes prolonged as coagulation factor synthesis fails, and is an extremely useful test that should be performed twice daily. Plasma aminotransferase activity rises to 100-500 times normal after paracetamol OD, but falls as liver damage progresses and is not helpful in determining progress. Child Pugh score is most helpful in acute liver disease.
What adverse prognostic factors are associated with acute liver failure?
- pH <7.3 at or beyond 24 hrs following OD, or
- serum creatinine >300 + PT > 100secs + encephalopathy grade 3 or 4
Non paracetamol OD:
- PT > 100secs, or
- factor V level <15% and encephalopathy grade 3 or 4, or
- any 3 of: bilirubin > 300; PT >50secs; jaundice to encephalopathy time > 7 days; age <10 or >40
How should acute liver failure be managed?
Treat patient on HDU or ITU as soon as progressive prolongation of PT or hepatic encephalopathy is identified, so that prompt treatment of complications (hypoglycaemia, infections, renal failure, metabolic acidosis) can be performed. Treatment is supportive. NAC in paracetamol poisoning, liver transplantation is an option depending on prognosis. 1 year survival is around 60%.
How should an isolated increase in serum bilirubin be investigated?
Check conjugated bilirubin and exclude haemolysis. If these come back normal then reassure the patient. The likely cause is Gilberts syndrome.
How should a patient with a raised GGT be investigated further?
- NAFLD/ incr. BMI - stage disease/ diet and exercise
- Drug toxicity - review current medication
- Alcohol excess - alcohol abstinence
A patient is found to have ALP (or transaminases) raised <2 x normal. Do they need further investigation?
Take an alcohol history and recommend alcohol abstinence if appropriate. Stop hepatotoxic drugs, weight loss if BMI >25 and re check LFTs in 3-6 months.
If the LFTs are persistently abnormal then screen for chronic liver disease.
How should a patient with ALP/ transaminases raised >2 x normal be investigated further?
Screen for chronic liver disease:
- HBsAg, HCVAb
- alpha 1 anti-trypsin
- autoimmune profile
- ferritin, caeruloplasmin
On USS, if there are dilated bile ducts then consider MRCP or ERCP. If there aren't any then arrange a liver biopsy to determine underlying cause.
When can jaundice be detected?
Jaundice is usually detected clinically when the plasma bilirubin exceeds 40umol/L.
Outline how bilirubin is metabolised?
Bilirubin in the blood is almost always all unconjugated and, because it is not water soluble, it is bound to albumin and does not enter the urine. Unconjugated bilirubin is conjugated by glucuronyl transferase into water soluble conjugates, which are exported into the bile.
Colonic bacteria convert conjugated bilirubin into stercobilinogen in the large intestine. A portion of this is lost to the stool in the form of stercobilin. Some of the stercobilinogen is reabsorbed in the blood as urobilinogen which can undergo enterohepatic circulation or be excreted in the kidneys are urobilinogen.
What are the causes of pre-hepatic jaundice?
This is caused by either haemolysis or by congenital hyperbilirubinaemia, and is characterised by an isolated raised bilirubin level. In haemolysis, destruction of red blood cells or their marrow precursors causes increased bilirubin production. Jaundice due to haemolysis is usually mild because a healthy liver can excrete a bilirubin load six times greater than normal before unconjugated bilirubin accumulates in the plasma. This does not apply to new borns. Gilbert's syndrome is the only common form of non-haemolytic hyperbilirubinaemia. It is a familial autosomal dominant mutation that reduces expression of 5" UDP glucuronyl transferase. This decreases bilirubin conjugation and causes isolated accumulation of unconjugated bilirubin in the blood. It needs no treatment.
What causes hepatocellular jaundice?
Results from an inability of the liver to transport bilirubin into the bile, as a consequence of liver disease. In hepatocellular jaundice, the concentrations of BOTH unconjugated and conjugated bilirubin in the blood increase, perhaps because of the variable way in which bilirubin transport is disturbed. Parenchymal disease causing jaundice, usually also elevates transaminase levels. Acute jaundice with an alanine aminotransferase >1000 suggests hepatitis A or B, drug toxicity or hepatic ischaemia. USS and biopsy are frequently needed for precise diagnosis.
What causes obstructive or cholestatic jaundice?
Cholestatic jaundice may be caused by:
i) Failure of hepatocytes to initiate bile flow
ii) Obstruction of the bile ducts or portal tracts
iii) Obstruction of bile flow in the extrahepatic bile ducts between the porta hepatis and the ampulla of Vater
Without treatment cholestatic jaundice tends to progress because conjugated bilirubin is unable to enter the bile canaliculi and passes back into the blood, and also because there is failure of clearance of unconjugated bilirubin arriving at liver cells.
Abdominal pain suggests choledocholithiasis, pancreatitis or choledochal cyst. Jaundice is progressive in cancer and fluctuating in sclerosing cholangitis, pancreatitis and stricture.
List some causes of hepatomegaly?
MC malignant cause in Western countries is liver metastasis, whereas primary liver cancer complicating chronic viral hepatitis is more common in the Far East. Cirrhosis can be associated with either hepatomegaly (particularly if due to alcohol or haemochromatosis) or reduced liver size in advanced disease.
In right heart failure, the liver is smooth, firm and has a tender edge. May be pulsatile.
Other causes include: abscesses, glandular fever, malaria, haematological malignancy, PBC, sarcoidosis, amyloidosis
What are ascites?
Free fluid of accumulation in the peritoneal cavity, and is usually due to malignant disease, cirrhosis or heart failure. However, primary disorders of the peritoneum and visceral organs can produce ascites, and these need to be considered, even in a patient with chronic liver disease.
Other causes include: hypoproteinaemia (nephrotic syndrome, malnutrition), pancreatitis, lymphatic obstruction, TB, hepatic venous occlusion (ie. Budd-Chiari, veno-occlusive disease), Meig's syndrome (rare), hypothyroidism (rare)
How should ascites be clinically assessed?
Small volumes are asymptomatic, but ascites >1L causes abdominal distension, fullness in the flanks, shifting dullness on percussion and a fluid thrill. Other signs include everted umbilicus, divarication of the recti, scrotal oedema, and dilated abdominal veins (with portal hypertension)
What is the pathophysiology of ascites?
Splanchnic vasodilatation, mediated mainly by nitric oxide, causes a fall in systemic arterial pressure as cirrhosis advances. This leads to activation of the RAAS, secondary aldosteronism, increased sympathetic nervous activity, increased atrial natriuretic peptide and altered activity of the kallikrein-kinin system. These systems tend to normalise arterial pressure but produce salt and water retention. The combination of splanchnic vasodilatation and portal hypertension alter intestinal capillary permeability, promoting fluid accumulation within the peritoneum.
Portal hypertension, and reduced albumin production by the liver (decreases oncotic pressure) also contributes to fluid transudation and ascites formation.
How should a patient who presents with ascites be investigated?
USS is the best method for detecting ascites. Paracentesis may point to the underlying cause:
- cirrhosis: clear, straw coloured or light green
- malignant: bloody
- infection: cloudy
- biliary communication: heavy bile staining
- lymphatic obstruction: milky white (chylous)
Measurement of total protein and serum-ascites albumin gradient (SAAG) distinguished transudate from exudate. Cirrhosis typically causes a transudate (total protein <25g/L with few cells). A SAAG of >11g/L is 96% predictive that ascites is due to portal hypertension. Venous outflow obstruction due to cardiac failure or hepatic venous outflow obstruction can also cause transudative ascites (SAAG >11g/L) but, unlike in cirrhosis, total protein is usually >25g/L. Exudative ascites suggests infection, malignancy, hepatic venous obstruction, pancreatic ascites or rarely hypothyroidism. Ascites amylase activity >1000U/L identifies pancreatic ascites and low glucose suggests malignancy or TB. PML count of >250 strongly suggests infection.
How are ascites managed?
Be careful with treating ascites, as over treatment can lead to electrolyte and imbalance and precipitate hepatic encephalopathy.
1) Sodium restriction - restrict to 100ml/day is normally adequate. Avoid sodium rich drugs (e.g. many antibiotics, antacids) and those promoting sodium retention (e.g. steroids, NSAIDs)
2) Diuretics - most patients require diuretics in addition to sodium restriction. Spironolactone is the drug of choice but may cause gynaecomastia. Some patients will also require loop diuretics, e.g. furosemide
3) Paracentesis - large volume paracentesis with i.v. albumin can be used as first line treatment of refractory ascites or when other treatments fail
4) TIPS - can relieve resistant ascites, but does not prolong life and may aggravate encephalopathy
What is hepatorenal syndrome? How many types are there?
Around 10% of patients with advanced cirrhosis and ascites develop the hepatorenal syndrome, which is mediated severe renal vasoconstriction due to underfilling of arterial circulation. There are 2 types:
Type 1 - progressive oliguria, a rapid rise in serum creatinine and a very poor prognosis. There is usually no proteinuria, urine sodium excretion is <10mmol/day and urine/ plasma osmolarity ratio is >1.5. Treatment consists of albumin infusions in combination with terlipressin and is effective in about two thirds of patients. Haemodialysis should not be routinely because it does not improve symptoms
Type 2 - usually occurs in patients with refractory ascites, is characterised by moderate and stable increase in serum creatinine and has a better prognosis
What is spontaneous bacterial peritonitis?
SBP may present with abdominal pain, rebound tenderness, absent bowel sounds and fever in a patient with obvious cirrhosis and ascites. Abdominal signs are mild or absent in about 1/3, in whom hepatic encephalopathy and fever dominate. The source of the infection cannot usually be determined, but E.coli is the most frequently identified organism in ascitic fluid. SBP needs to be differentiated from other abdominal emergencies, and the finding of multiple organisms on culture should arouse suspicion of a perforated viscus.
Treatment is with broad spectrum antibiotics like cefotaxime. Recurrence is common and may be reduced by prophylactic quinolones such as norfloxacin and ciprofloxacin.
What causes hepatic encephalopathy?
A neuropsychiatric condition caused by liver disease that progresses from confusion to coma. Confusion needs to be differentiated from delirium tremens and Wernicke's encephalopathy and come from subdural haematoma, which can occur in alcoholics after a fall. Liver failure and portosystemic shunting of blood are two important factors underlying hepatic encephalopathy. The "neurotoxins" thought to be causing encephalopathy are nitrogenous substances produced by bacterial action in the gut, which are normally metabolised by the healthy liver. Ammonia has long been considered an important factor but there is also much interest on gamma aminobutyric acid.
What are the different grades of hepatic encephalopathy?
Mental impairment increases as the condition becomes more severe:
Grade 1 = poor concentration, slurred speech
Grade 2 = drowsy but easily rousable, lethargic
Grade 3 = marked confusion, sleepy but responds to pain and voice, drowsy, disorientated
Grade 4 = unresponsive to voice, unconscious
Precipitating factors include trauma, drugs, infection, protein load (including GI bleeding) and constipation. Convulsions sometimes occur. Examination shows:
- flapping tremor (asterixis)
- inability to perform simple mental arithmatic
- constructional apraxia
- bilateral extensor planar responses
EEG shows diffuse slowing or normal alpha waves with eventual development of delta waves.
How should hepatic encephalopathy be managed?
Treat precipitating causes and to suppress production of neurotoxins by bacteria in the bowel. Lactulose (15-30mL 3 times daily) is a disaccharide that is taken orally and produces an osmotic laxative effect. It reduces the colonic pH, thereby limiting ammonia absorption and promotes the incorporation of nitrogen into bacteria. Rifamixin is a non absorbed antibiotic that acts by reducing the bacterial content of the bowel. Dietary protein restriction is no longer recommended.