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Quick overview of liver disease

Signs and symptoms of liver disease

  • Non-specific symptoms
    • Malaise
    • Fatigue
    • Nausea
    • RUQ abdominal pain
    • Weight loss
  • Hepatosplenomegaly
  • Signs of portal hypertension
    • Esophageal varices
    • Caput medusae
    • Hemorrhoids
  • Ascites
  • Jaundice
  • Hepatic encephalopathy

Ascites

  • Paracentesis
    • Use volume expanders such as albumin if > 5 L of volume is removed during a paracentesis
      • Large paracentesis is considered something in the range of removing 5-10 liters over the course of 6-8 hours
      • If a large paracentesis is performed then for every 1 liter of ascitic fluid removed, 6–8 g of albumin should be infused intravenously
    • SAAG is the best test to determine whether ascites is from portal hypertension or from another cause (such as right sided heart failure, nephrotic syndrome, tuberculosis)
      • Serum ascitic albumin gradient
      • If the gradient > 11 g/L = ascites from portal hypertension
    • Send ascitic fluid for analysis for SBP if the patient is suspicious for SBP
      • Fever
      • Hepatic encephalopathy
      • Shock
    • If paracentesis fails to provide symptomatic relief then consider TIPS and eventual liver transplant or palliative care
  • Evidence based offloading of fluid
    • Spironolactone first
    • If needed you can add furosemide
    • If spironolactone is given with furosemide, ensure they are given in a 50/20 ratio
      • E.g. spironolactone at 50 mg PO daily with furosemide 20 mg PO daily
      • If you need to increase the dose of spironolactone, increase the furosemide so that the ratio is maintained
      • E.g. spironolactone at 100 mg PO daily and furosemide at 40 mg PO daily

Hepatic Encephalopathy

  • Triggers
    • Anything that acutely increases protein levels in the serum such as
      • GI bleeding
      • High protein load
    • Constipation
    • Spontaneous bacterial peritonitis (SBP)
    • Hypokalemia
    • Medications
      • Benzodiazepines
      • Opioids
      • Alcohol
      • Non-compliance with lactulose or rifaximin
    • Dehydration
    • Portosystemic shunt (TIPS procedure)
      • TIPS also have a high occurence off stenosing (75 %)
      • Therefore, they are seen as more temporary measures while the patient is on the transplant list
    • Portal vein thrombosis
  • Treatment
    • Generally no protein restriction
    • Lactulose is a laxative
      • Lactulose is converted to lactic acid in the gut where it acidifies the contents of the lumen
      • NH3 is converted to NH4 which cannot be absorbed and is excreted in the feces
      • Goal of treatment is to induce 3-4 BM per day
    • Rifaximin is added to lactulose if patient has recurrent hepatic encephalopathy on lactulose
    • Liver transplant if patient continues to have recurrent hepatic encephalopathy

Spontaneous bacterial peritonitis

  • Patients with cirrhosis are at risk for SBP (infection of ascitic fluid without an obvious infectious foci) due to
    • Cirrhotic patients are on PPIs for GI bleeding
    • Immunosuppressed due to cirrhosis
    • Decreased gut motility due to cirrhosis
  • Diagnosis (keeping it simple)
    • Diagnostic paracentesis
      • PMN
        • > 250 = SBP
        • < 250 with 1 species on culture + symptoms = SBP
        • > 2 species on culture = unlikely SBP, maybe secondary peritonitis
      • SAAG
        • Tells you if the ascites is from portal hypertension, or some other cause
        • > 11 = portal hypertension
      • Check G.L.P. (if more than 2 are positive, suggestive of SBP)
        • Glucose > 2.8 mmol/L
        • LDH > 225 IU/L
        • Protein (total) > 10 g/L
  • Risk for hepatorenal syndrome
    • Patients with SBP are at risk for hepatorenal syndrome (due to the cirrhotic liver unable to clear NO which is a vasodilator that causes primarily vasodilation of the splanchnic circulation)
    • Give albumin 1.5 g/kg for 48 hours and then 1 g/kg on day 3 if they show signs of impending renal failure such as
      • BUN > 11 mmol/L
      • Creatinine > 88 umol/L
      • Bilirubin > 68 umol/L
    • MAXIMUM of 100 g/day of albumin
  • Treat infection with 3rd generation cephalosporins

Liver transplantation

  • MELD score (model of end stage liver disease)
    • Score of 10 or higher should be considered for liver transplantation
    • Prognosis of 33 % of death in the next year

https://www.mdcalc.com/meld-score-model-end-stage-liver-disease-12-older

Viral hepatitis (A for acute, B for bad, C for chronic/curable)

Hepatitis A (acute)

  • Transmission route: fecal-oral route
    • Person to person contact
    • Ingestion of contaminated food or water
  • Diagnosis
    • Elevated AST and ALT
    • HAV IgM is present during acute infection
    • HAV IgG then appears and remains detectable for life providing life long immunity
  • Prognosis
    • Almost all hepatitis A patients recover within 6 months – NO CHRONIC DISEASE
    • 20 % need hospitalization
    • Low mortality in healthy people under the age of 60

Hepatitis E (similar to hepatitis A except…)

  • Transmission route: fecal-oral route
    • Person to person contact
    • Ingestion of contaminated food or water
  • Diagnosis
    • Elevated AST and ALT
    • HEV IgM is present during acute infection
    • HEV IgG then appears and remains detectable for life providing life long immunity
  • Prognosis
    • Recovery is also possible, NO CHRONIC DISEASE
    • HEV in pregnancy can lead to fulminant hepatitis (unfortunately no hepatitis E vaccine is available)

Hepatitis B

  • Transmission route: blood-borne illness
    • Childbirth
    • Blood transfusion
    • IV drug use (most common mode of transmission in the developed world)
    • Risky sexual behaviours
  • Diagnosis
    • Check out our article on how to review hepatitis B serology here
    • Surface antigen (HBsAg): Indicates current infection (acute or chronic)
      • If you’re looking for active Hep B infection, then you can look for the Hep B surface antigen in the blood stream
      • If it’s positive then they have Hep B at that moment
    • Antibody against surface antigen (anti-HBs): Indicates immunity (vaccination or past infection)
      • Where anti-HBs indicates presence of antibody to surface antigen
    • Antibodies against the core antigens of the hepatitis B virus
      • anti-HBc IgG: Indicates either past or current infection
      • anti-HBc IgM: Indicates acute infection
  • Prognosis
    • Only 20 % of cases move from acute to chronic hepatitis
    • Chronic HBV infection can lead to
      • Cirrhosis
      • Hepatocellular carcinoma

Hepatitis C

  • Transmission route: blood-borne illness
    • Childbirth
    • Blood transfusion (very common prior to 1990)
    • IV drug use (most common mode of transmission in the developed world)
    • Risky sexual behaviours
  • Diagnosis
    • Requires 2 types of tests
      • HCV antibody testing – positive test indicates current or prior infection
      • HCV RNA testing – positive confirms an active or current infection
  • Prognosis
    • Curable
    • 80 % of patients infected with HCV will become chronically infected
    • Acute and chronic infection is usually asymptomatic and patients do not seek medical attention in the early stages of the disease
    • There is no lasting immunity against Hep C – you can get reinfected
    • Patients with hepatitis B are vulnerable to developing hepatitis D (which needs the hepatitis B surface antigen in order to enter into hepatocytes)

Protection after infection or vaccination (if available):

  • Hepatitis A
  • Hepatitis E
  • Hepatitis B

There is no lasting protection after infection with hepatitis C!

Blood borne viral hepatitis:

  • Hepatitis B
  • Hepatitis C
  • Hepatitis D

Fecal-oral transmission:

  • Hepatitis A
  • Hepatitis E

MNEMONIC (mouth at the top, faeces come out the bottom, blood is in the middle):

  • ORAL — BLOOD — FECAL
  • A — BCD — E

Autoimmune hepatitis

  • Etiology
    • Associated with autoimmune disease (e.g. thyroid disease, diabetes)
    • Genetic predisposition
  • Diagnosis
    • Elevated transaminases
    • Autoantibodies
      • Antinuclear antiboides (ANA)
      • Anti-smooth muscle antibodies (SMA)
    • Liver biopsy
  • Prognosis
    • Combination prednisone and azathioprine can induce remission and maintenance therapy is required to maintain remission
    • 90 % survival rate
    • 20 % relapse rate

Steatohepatitis

Alcoholic fatty liver disease

  • How is ethanol metabolized?
    • Ethanol is metabolized to acetaldehyde in three ways
      • Alcohol dehydrogenase
        • Most of the ethanol is metabolized via this route
        • Requires NAD+ as a cofactor which gets converted to NADH
      • CYP2E1
      • Catalase
    • Acetaldehyde is then metabolized to acetate via the enzyme acetaladehyde dehyrogenase
      • Also requires NAD+ as a cofactor which gets converted to NADH
  • Pathophysiology
    • When alcohol is consumed, you are in a temporary state of increased fatty acid synthesis
    • NADH and acetate inhibit fatty acid degradation
    • Therefore, even in alcoholic hepatitis, it still results in a fatty liver
    • The metabolism of ethanol into acetaldehyde also results in the formation of free radicals which can result in damage to hepatocytes
    • The acetaldehyde that accumulates in chronic overconsumption of alcohol can bind to compounds in the cell forming acetaldehyde adducts which are recognized as foreign by neutrophils – the ensuing inflammatory response results in further hepatocyte collateral damage
  • Diagnosis
    • Liver function tests
    • AST/ALT ratio > 2
    • Elevated GGT
    • Ultrasound and CT to assess for inflammation and fat deposition
  • Treatment
    • Management of cirrhosis
    • Symptomatic management
    • Lifestyle changes

Non-alcoholic fatty liver disease (NAFLD) and Non-alcoholic steatohepatitis (NASH)

  • Etiology
    • Metabolic syndrome
    • Insulin resistance / Diabetes
    • Total parenteral nutrition (due to high proportion of carbohydrates)
  • Pathophysiology
    • Non-alcoholic fatty liver disease generally starts with fat deposition in hepatocytes, this is referred to as steatosis
    • Patients who have insulin resistance are more likely to develop steatosis as a consequence of
      • Increased fat storage
      • Decreased fatty acid oxidation
      • Decreased secretion of fatty acids into the bloodstream
      • Increased synthesis and uptake of free fatty acids from the blood
    • The fat in the hepatocytes promotes the degradation of hepatocytes due to the formation of fatty acid radicals
    • As cells die, the inflammatory response is promoted – at this point the simple steasosis has evolved into steatohepatitis (NASH)
    • If inflammation is chronic then the stellate cells of the liver begin to lay down fibrotic tissue – at this point the steatohepatitis has evolved into fibrosis
    • If fibrosis continues unimpeded then the patient may develop cirrhosis
  • Diagnosis
    • Generally speaking, NAFLD is a diagnosis of exclusion
    • Elevated transaminases
    • Ultrasound and CT can used to look for signs of inflammation and fat deposition
    • Biopsy to confirm
  • Treatment
    • Management of cirrhosis
    • Symptomatic management
    • Lifestyle changes

Hereditary liver disease

Hemochromatosis

  • Hemochromatosis is a disease in which there is the abnormal deposition of iron in multiple organs
  • 2 types
    • Primary hemochromatosis is genetically linked and is due to excessive absorption of iron in the small intestine
    • Secondary hemochromatosis is due to endogenous or exogenous iron overload as can be seen in certain hemoglobinopathies such as thalassemia or multiple iron transfusions
  • Clinical features
    • Bronzing of the skin
    • Diabetes
    • Liver disease
    • Heart failure from cardiomyopathy
  • Diagnosis
    • Ferritin will be high, but it is non-specific as it is an acute phase reactant
    • Initial screen should definitely include transferrin saturation
      • > 45% is suggestive of iron overload
    • Genetic testing
    • Liver biopsy (may be deferred if genetic testing confirms diagnosis)
  • Treatment
    • Phlebotomy to reach target ferritin levels
    • Iron chelation with deferoxamine

Alpha-1 antitrypsin deficiency

  • Alpha-1 antitrypsin (AAT) deficiency is a congenital disorder where there is the accumulation of defective AAT in the liver
  • Neutrophil elastase is a protease which if found in excess in the lung can lead to early onset emphysema; it’s activity is controlled by alpha-1 antitrypsin which is produced in the liver
  • Clinical features
    • Hepatitis and liver cirrhosis due to the accumulation of defective alpha-1 antitrypsin enzyme in the liver
    • Emphysema due to uninhibited neutrophil elastase activity in the lungs
  • Diagnosis:
    • Genetic testing
    • Chest x-ray or CT showing signs of emphysema
    • Serum antitrypsin levels
    • Liver biopsy showing signs of cirrhosis
  • Treatment
    • Avoid risk factors for worsening lung or liver function
    • Replace antitrypsin
    • Liver transplantation

Wilson disease

  • Wilson disease is an autosomal recessive disorder involving the impaired biliary excretion of copper leading to copper accumulation and consequent deposition in the liver and other organs
  • Clinical features
    • Asymptomatic elevation of transaminases
    • Signs of liver failure
    • Neuropsychiatric changes as the patient ages
    • Kayser-Fleischer rings
  • Diagnosis
    • Slit lamp exam showing Kayser-Fleischer rings
    • Decreased ceruloplasmin (copper carrier in blood)
    • 24-hour urinary copper excretion
    • Liver biopsy
  • Treatment
    • Low copper diet
    • Copper chelating agents (penicilamine)