CLD

 

Chronic liver disease (CLD)

• Background

  Causes

  Dietary:

  • Alcoholic liver disease (ALD).
  • Obesity: non-alcoholic fatty liver disease (NAFLD). Can be seen as the liver manifestation of metabolic syndrome, as it is often comorbid with its features, especially insulin resistance.

  Infectious:

  • Hepatitis B and C (HBV and HCV).
  • Herpesviridae: CMV, EBV.

  Autoimmune:

  • Autoimmune hepatitis (AIH).
  • Primary biliary cirrhosis (PBC).
  • Primary sclerosing cholangitis (PSC).

  Genetic:

  • Hereditary haemochromatosis (HH).
  • Alpha 1 antitrypsin deficiency (A1AD).
  • Wilson's disease.

  Drugs:

  • Methotrexate
  • Amiodarone
  • Methyldopa

  Stages

  Stages in alcoholic and fatty liver disease:

  1. Steatosis (aka fatty liver). In and of itself, it is usually benign. Either NAFLD (aka non-alcoholic steatosis) or alcoholic steatosis, the latter usually due to chronic ingestion but occasionally from acute intake.
  2. Steatohepatitis. Fatty liver plus progressive inflammation, characterised by Mallory bodies.
  3. Cirrhosis. Occurs in 5% of ALD, and 1-2% of NAFLD.
  4. Hepatocellular carcinoma (HCC).

  This process is reversible up to the cirrhosis stage, when the liver's capacity for self-repair is exceeded.

  A similar pattern is seen in some other causes of CLD, including A1AD and drug-induced.

  Epidemiology

  NAFLD (25% UK prevalence) is commoner than ALD, and the commonest cause of abnormal LFTs, but ALD is more likely to progress to advanced disease.

• Signs and symptoms

  Clinical presentations:

  • Often asymptomatic and discovered incidentally: abnormal LFTs, ↑MCV (ALD), abnormal clotting.
  • Other presentations: jaundice, pruritus, bleeding varices, ascites/oedema, hepatic encephalopathy.
  • Systemic features: anorexia, weight loss, fatigue.

  Examination findings:

  • Organomegaly: hepatomegaly in earlier stages, but later shrinks as it becomes cirrhotic. Splenomegaly due to portal hypertension.
  • Hands: leukonychia (↓albumin), clubbing, Dupuytren's contracture, palmar erythema, hyperdynamic circulation.
  • Face: xanthelasma, parotid enlargement, spider naevi.
  • Trunk: spider naevi, gynecomastia, body hair loss.

  Discriminants of cause:

  • Non-hepatic features: SOB (A1AD), arthritis (HH, HBV, AIH), sicca (PBC), bloody diarrhoea (PSC i.e. UC symptoms), skin pigmentation (PBC, HH), neuromotor and psychiatric features (Wilson's).
  • Signs of bile build up from cholestasis: pruritus and xanthelasma. Often seen in PBC.
  • Previous episodes of acute jaundice: suggests AIH or viral hepatitis.
  • Weight loss may indicate HCC, though can be a feature of cirrhosis too.

• Investigations

  Bloods

  General:

  • Liver function tests (LFTs).
  • FBC: ↑MCV (ALD; uncommon in NAFLD), ↓platelets (cirrhosis).
  • U&E: ↑urea = GI bleeding, ↑urea and creatinine = renal impairment e.g. hepatorenal syndrome.
  • Later in disease, ↓synthetic function of liver: ↑PT/INR (highly sensitive test of liver function), ↓albumin (poor prognostic sign), ↓glucose (↓gluconeogenesis).

  Investigating causes:

  • Viral serology: HBC, HCV, CMV, EBV.
  • Auto-antibodies: see autoimmune hepatobiliary disease.
  • A1AT
  • Hereditary haemochromatosis: ↑ferritin. May also be slightly elevated in ALD.
  • Wilson's: ↓serum ceruloplasmin, ↑24h urine copper, slit lamp test for Keiser-Fleischer rings.

  Enhanced liver fibrosis (ELF) test:

  • Calculates a score to determine presence of advanced liver fibrosis based on 3 biomarkers: hyaluronic acid, procollagen III amino terminal peptide, tissue inhibitor of metalloproteinase 1.
  • Recommended every 3 years for those with NAFLD to identify those at risk of cirrhosis.

  Imaging

  Abdominal US is the 1st-line imaging for anyone with abnormal LFTs. May show:

  • Bright liver: steatosis.
  • Small liver: late cirrhosis.
  • Focal liver lesions.
  • Hepatic vein thrombosis.
  • Splenomegaly: portal hypertension.
  • Gallstones

  Transient elastography (FibroScan):

  • US-based measure of liver fibrosis.
  • A non-invasive alternative to biopsy for cirrhosis diagnosis.

  Other modalities:

  • Contrast CT. Good for: varices, portal hypertension, and architecture changes (e.g. in cirrhosis).
  • MRI: best for focal lesions
  • MRCP

  Biopsy

  Indications:

  • To determine the degree of disease (e.g. steatosis or cirrhosis?), if it is unclear and clinically relevant. Often required in chronic HCV, but much less so in ALD and NAFLD.
  • Post-transplant to look for signs of rejection.
  • To investigate focal lesions if their nature is unclear from imaging.

  Weaknesses:

  • Cannot distinguishing ALD vs. NAFLD/NASH.
  • Not useful in acute failure.
  • Sampling problems, as the disease is often heterogenous.

  Complications:

  • Pain (1/3), but only severe in 1/30.
  • Major bleeding (1/200). Do a transjugular biopsy instead if there is a clotting abnormality.
  • Damage to other organs (<1/1000).
  • Death (<1/1000).

  Cirrhosis prognostic scores

  • Estimate mortality risk and thus guide transplant requirement.
  • Model for End-stage Liver Disease (MELD) score: based on BR, INR, creatinine, sodium. Slightly more accurate than Child-Pugh.
  • Child-Pugh score: based on BR, INR, albumin, ascites, hepatic encephalopathy. A OK, B intermediate, C decompensated.

• Management

  Early stages

  • NASH/NAFLD: diet, exercise, alcohol only within recommended limits, and manage metabolic syndrome if present. Pioglitazone or vitamin E if there is high ELF score, to reduce histological disease progression.
  • ALD: alcohol abstinence. See alcohol misuse.
  • Monitor for progression to cirrhosis: transient elastography every 2 years. Offer to all those with ALD, and NASH/NAFLD patients with high ELF score.

  Cirrhosis

  Monitor to prevent complications:

  • Calculate MELD score every 6 months: >12 suggests high risk of complications.
  • Hepatocellular carcinoma screening: 6-monthly US and AFP.
  • Varices detection: 3-yearly OGD.
  • Osteoporosis: screen and treat if present.
  • Ascites and SBP detection: check regularly.

  Treatment:

  • HAV and HBV immunisation to prevent viral superinfection.
  • Vitamin replacement if deficient: thiamine, B12, folate.
  • If varices found on OGD: propranolol to prevent bleeding, or endoscopic variceal band ligation (VBL) to remove them. If an upper GI bleed occurs, combine propranolol and VBL, and if rebleed occurs despite this, consider transjugular intrahepatic portosystemic shunt (TIPS).
  • Transplantation: referral should be considered when a complication develops (e.g. variceal bleed, encephalopathy, ascites), and patients are typically listed when MELD ≥15, the point at which survival with transplant is higher than without.

• Complications and prognosis

  Complications:

  • Portal hypertension.
  • Oesophageal varices and upper GI bleeds.
  • Ascites and spontaneous bacterial peritonitis.
  • Hepatorenal syndrome.
  • Acute on chronic liver failure.
  • Hepatocellular carcinoma.

  Cirrhosis is the cause of 1/20 UK deaths. 85% are due to alcoholic liver disease.

• Acute decompensated liver disease

  Definition and presentation

  • An acute deterioration in a patient with chronic liver disease, presenting with jaundice, coagulopathy, ascites (± SBP), hepatic encephalopathy (confusion, asterixis), sepsis, and/or variceal upper GI bleed.
  • Most commonly acute decompensated alcoholic liver disease.
  • The term acute on chronic liver failure is used when new/worsening organ failure (liver, kidney, brain, coagulation, circulation, respiratory) is present in a cirrhotic patient, and has a 40% mortality rate at 90 days.

  Triggers

  CRASH-CV:

  • Cancer
  • Rx: hepatotoxic drugs.
  • Alcohol (commonest).
  • Sepsis and SBP.
  • Haemorrhage (variceal).
  • Clots: portal vein thrombosis, ischaemic hepatitis.
  • Viral hepatitis.

  Note that many of these are both triggers and complications of worsening liver function.

  Management

  Screen for and treat any triggers and complications:

  • Alcohol withdrawal.
  • Volume depletion and electrolyte disturbances (esp. K+, Ca2+, Mg2+, PO43-).
  • Acute kidney injury and hepatorenal syndrome.
  • Malnutrition: thiamine IV, dietician review and possible NG feed.
  • Hepatic encephalopathy.
  • Alcoholic hepatitis.
  • Ascites and spontaneous bacterial peritonitis (SBP).
  • Infection, most commonly SBP, UTI, pneumonia, C. diff, or cellulitis.
  • Upper GI bleed.

  Transplantation may be needed but is typically reserved for those already listed before the acute decompensation.

• Alcoholic hepatitis

  Definition

  • Acute onset (<3 months) jaundice, liver failure, and systemic inflammation, due to heavy alcohol consumption, usually of long duration.
  • There may or may not be underlying cirrhosis.
  • The term is sometimes also applied to asymptomatic steatohepatitis in ALD.

  Presentation

  • Jaundice
  • Fever
  • Tender hepatomegaly.
  • Worsening of underlying cirrhosis if present: ascites, encephalopathy.

  Investigations

  • ↑WBC (neutrophils).
  • LFT: ↑AST and ↑ALT (>2 times upper limit), AST/ALT ratio >2, ↑BR.
  • ↑PT/INR.
  • Consider biopsy if diagnosis unclear.

  Management

  Prednisolone PO 4 weeks if Maddrey score ≥32 (based on PT and BR).

• Portal hypertension

  Pathophysiology

  Physical (cirrhosis) and chemical (↑endothelin) reduction in hepatic microvessel radius → ↑resistance in the portal vein.

  Complications

  • Varices
  • Splenomegaly
  • Caput medusae.

  Varices

  • Dilated submucosal veins in the lower oesophagus.
  • Propranolol can help prevent them and reduce the risk of bleeding. Variceal band ligation is an alternative.

• Ascites

  Excess fluid in the peritoneal cavity.

  Pathophysiology

  • Portal hypertension → splanchnic vasodilation due to ↑vasodilators, especially ↑nitric oxide (↑synthesis and/or ↓clearance) → renin-angiotensin-aldosterone (RAS) response → Na+ and fluid retention. This is the peripheral arterial vasodilation hypothesis.
  • ↓Albumin may also contribute due to ↓oncotic pressure.

  Causes

  • Portal hypertension: cirrhosis (commonest cause of ascites), IVC or portal vein thrombosis, portal lymphadenopathy, CHF, constrictive pericarditis, Budd-Chiari syndrome.
  • Hepatocellular carcinoma or liver mets
  • Infection and inflammation: TB, pancreatitis.
  • ↓Albumin: nephrotic syndrome, protein losing enteropathy (e.g. coeliac, IBD).
  • Myxoedema

  Investigations

  Diagnostic paracentesis – which should be performed even if coagulopathy is present – allows calculation of the serum-ascites albumin gradient (SAAG):

  • SAAG = serum albumin – ascites albumin.
  • High gradient (≥11 g/L, ≈ transudative): portal hypertension.
  • Low gradient (<11 g/L, ≈ exudative): HCC, pancreatitis, TB.

  Other tests of ascitic fluid:

  • Red and white cell count.
  • Culture if SBP suspected.
  • Glucose: ↓ in peritoneal carcinomatosis or bowel perf.
  • LDH: ↑ in SBP, ↑↑ in bowel perf.
  • Amylase: ↑ in pancreatitis.

  Management

  • Identify cause and exclude SBP.
  • Na+ and fluid restrict.
  • Diuretics: spironolactone ± furosemide.
  • Therapeutic paracentesis. Follow with volume expansion using synthetic plasma expander or human albumin solution.
  • Transjugular intrahepatic portosystemic shunt (TIPS) for refractory ascites.
  • Consider liver transplantation. Ascites is a sign of severe disease with 40% 1 year mortality.

• Spontaneous bacterial peritonitis (SBP)

  Pathophysiology

  • Portal hypertension → weakened gut mucosal defence → infection of ascitic fluid, usually with E. coli.
  • A complication of ascites, and in turn increases the risk of hepatorenal syndrome.

  Signs and symptoms

  May be asymptomatic, or present with fever, vomiting, and abdo pain.

  Diagnosis

  Ascitic fluid has >250 neutrophils/μL.

  Management

  • Antibiotics – e.g. co-amoxiclav PO, pip/tazo IV if severe – and consider lifelong prophylactic antibiotics.
  • Refer for possible liver transplantation.

• Hepatorenal syndrome

  Definition and diagnosis

  • Kidney failure without known cause in the presence of severe liver disease, the latter defined as ascitic cirrhosis or acute liver failure.
  • A diagnosis of exclusion, made when AKI doesn't respond to diuretic withdrawal and albumin, and there is no nephrotoxic use, shock, or structural kidney injury (proteinuria, abnormal US).
  • Accounts for 25% of AKI in cirrhosis patients.

  Pathophysiology

  • The RAS response seen in portal hypertension leads to regional vasoconstriction, causing renal hypoperfusion.
  • May be precipitated by SBP, paracentesis without volume expansion, or variceal bleed.

  Management

  • Terlipressin – a splanchnic vasoconstrictor – plus human albumin solution.
  • Refer for possible liver transplantation.