Etiology management specific to cirrhosis

Hepatitis C

• Some Hepatitis C patients can now be treated by Primary Care (after seeking advice from hepatology, infectious diseases or gastroenterology – as required by insurance provider). See the following link to the Alberta Health Services Hepatitis C Virus Primary Care Pathway
• Successful treatment is associated with reductions in morbidity, all-cause and liver-related mortality and an improved quality of life in the majority of patients.
• Historically, many sub-populations of patients required special management protocols, but that is no longer the case. Careful attention to co-morbidities (especially active Hepatitis B), drug-drug interactions and determining the presence or absence of decompensated cirrhosis should now be the focus of a pre-treatment clinical assessment.
• Suggested treatment regimens change regularly depending upon the available evidence. The most widely used pangenotypic agents are safe, well tolerated and highly efficacious. See infectiousdiseaseadvisor.com OR hcvguidelines.org for a link to suggested treatment regimens and associated evidence.
• Special treatment considerations in patients with decompensated cirrhosis–
  • Patients with a MELD score of >20 and/or a GFR of <30 who are candidates for liver transplantation should have treatment decisions supervised by a transplant center. In most cases these patients should be treated after transplant to optimize the chance of viral clearance
  • Protease-inhibitor based regimens including Maviret® (glecaprevir and pibrentasvir) and Vosevi® (sofosbuvir, velpatasvir, voxilaprevir) are contraindicated.

Non alcoholic fatty liver disease (NAFLD)

• The mainstays of NAFLD treatment are optimal management of metabolic disease, weight loss, dietary support, statin use when appropriate (statins are not contraindicated), and liver-fat specific interventions when evidence suggests benefit.
• Aim for a dietitian supervised 7-10% weight loss using a 500-1000 kcal energy deficit. A Mediterranean style diet has been associated with reductions in liver fat. Processed foods and fructose-containing beverages and foods should be avoided.
• Patients with cirrhosis and NAFLD are at risk of muscle mass loss if weight loss is carried out without appropriate dietary counselling and concurrent increases in physical activity.
• Patients should be encouraged to participate in 150 minutes per week of moderate intensity activity (aerobic + resistance training). Both of these modalities reduce steatosis.
• Statins may be used to reduce LDL-cholesterol and prevent cardiovascular risk. Of note, with worsening liver function, there is an increase in a membrane transporter in the hepatocytes that modulates statin uptake (SLCO1B), resulting in higher serum statin levels and increased rates of myopathy and hepatotoxicity. See Child Pugh calculator link here.
  • In patients with Child Pugh A disease, statins CAN BE USED at regular doses.
  • In patients with Child Pugh B disease, one agent has the most evidence to support safety – Rosuvastatin at a dose of 5 mg. Monitor CK levels and symptoms to detect adverse events.
  • In patients with Child Pugh C disease, statins are unlikely to have benefit and very likely to cause harm – they should be DISCONTINUED.
• Atorvastatin should NOT be used in cirrhosis
• Vitamin E can be considered at a dose of 400 IU/day in select patients without cardiovascular disease
• Bariatric surgery can be considered in selected patients (BMI >35) with compensated cirrhosis. In the setting of decompensated cirrhosis or portal hypertension, the risks are very high and surgery should not be considered until at or after transplant.
• There are many novel agents under investigation that act along the entire pathway that contributes to steatohepatitis.

Hemochromatosis

• Can occur as a primary or secondary condition. The most common cause of primary hemochromatosis is an alteration in the HFE gene, but other genetic mutations can also lead to primary disease.
• In patients of European ancestry, the most common cause of hemochromatosis is a mutation in the HFE gene.
  • • Among individuals of European ancestry, the carrier frequency of the most significant mutation (C282Y) is ~1/10.
    • Clinical manifestations of iron overload can be variable even in patients with C282Y homozygosity, as there is incomplete penetrance.
• The goal of treatment is to prevent organ dysfunction and improve organ function by reducing excess iron. All contributing factors (i.e. alcohol use, HCV infection) should be screened for and addressed as these can increase iron stores.
• Phlebotomy is the mainstay of therapy for patients with iron overload. It is associated with improvements in survival, hepatic fibrosis (with reduction in the size of varices), cardiomyopathy and hypogonadism. It does not improve joint pain.
• Phlebotomy schedules can be tailored to the individual, and can be done weekly to every two weeks if tolerated (hemoglobin >110 g/dL, hemodynamic stability). Each unit of blood removes 200-250 mg of iron. Target ferritin values of 50-100 ng/mL. Once this value is reached, maintenance is required at approximately 1 unit of blood very 2-4 months. Of note, patients with cirrhosis are more likely to become anemic with phlebotomy.
• Patients who do not tolerate phlebotomy should be considered for chelation therapies.
• Q 3 monthly labs to check CBC, ferritin, iron saturation, reticulocyte count
• Dietary restriction of iron is not required. Patients should avoid supplements that contain additional iron. Patients should avoid vitamin C supplements. Uncooked seafood should be avoided given the risk of vibrio vulnificus infection (a bacteria that thrives on iron).
• Relatives of any person with genetic hemochromatosis should be considered for testing, usually in a sequential pattern.

Hepatitis B

• Decision-making around Hepatitis B treatment is based upon considering the individual’s hepatitis B status, degree of liver fibrosis, and projected natural history with and without treatment. It is important to recognize there is a limitation in the evidence base around the optimal time to start and stop treatment so collaborative decision making is very important.
• Scenarios where treatment initiation is widely accepted include: patients with active disease who are developing progressive fibrosis, patients with advanced liver disease especially decompensation, patients with high viral load where the goal is to prevent vertical transmission, patients about to undergo immunosuppression, and patients who develop hepatocellular cancer.
• Note, in the setting of acute on chronic liver failure or decompensated cirrhosis with a detectable HBV DNA level, antiviral therapy should also be started as it results in clinical and biochemical improvement in 40-50% of cases. ~ 1/3 of these patients can be delisted for liver transplantation.
• The most commonly used treatments in cirrhosis are Entecavir, Tenofovir disoproxil fumarate (TDF) or Tenofovir alafenamide (TAF). Tenofovir should be avoided with renal dysfunction. There have been rare reports of lactic acidosis in patients with severe liver dysfunction who are started on Entecavir.
• In patients on treatment, monitor HBV DNA and ALT levels every 3 months until aviremia is achieved. Then testing can be extended to every 6 monthly. Patients on Tenofovir also require q 3-6 monthly monitoring of renal function and serum phosphate levels.
• Patients with cirrhosis or HCC should continue to receive treatment indefinitely or until HBsAg loss.

Autoimmune hepatitis

• The management of autoimmune hepatitis is best performed in a specialized hepatology clinic.
• Initial therapy requires the assessment for potential contraindications to therapy (Prednisone, Azathioprine) especially evaluation for any active infection.
• It is most common to give a combination of Prednisone and Azathioprine in the early phases of management:
  • Start with Prednisone alone x 2 weeks and then add on Azathioprine starting at week 3.
  • Prednisone dose is 0.5 mg/kg body weight/day tapering down by 10 mg per week until at 20 mg and then by 2.5-5 mg every 2-4 weeks until off.
  • Azathioprine dose starts at 50 mg per day for weeks 3 and 4 (provided the serum bilirubin is below 100 umol/L) increasing to 1-2 mg/kg body weight per day by week 5 if tolerated.

• Maintenance therapy can consist of a single agent or a combination of immunosuppressives.

Primary biliary cholangitis

• All patients should receive ursodeoxycholic acid (UDCA) at a dose of 13-15 mg/day (either as a single daily dose or in divided doses if there are concerns about tolerability.
• UDCA is generally well tolerated with minimal side effects (rarely weight gain, hair thinning, diarrhea, flatulence have been reported).
• Patients should continue UDCA for life, even in the absence of biochemical improvements, as this is associated with prolonged LT-free survival.
• Biochemical response should be assessed at 1 year with lack of response defined by the ALP >1.67 x ULN and/or bilirubin >1.0 x ULN.
• Risk factors for an inadequate biochemical response are early age at diagnosis (<45 years), male sex, and advanced fibrosis at presentation.
• Patients with a lack of response to UDCA require the addition of second line therapy including obeticholic acid (licensed) and bezafibrate (off-label).
  • Adjunctive treatment for incomplete responders consists of obeticholic acid (OCA) as the first option (use only in Child Pugh A disease), with bezafibrate (400 mg daily) and clinical trials as alternatives.
  • Obeticholic acid can be dosed at 5 mg po daily increasing to 10 mg po daily at six months depending upon tolerance.  Side effects include pruritus and elevations in the serum cholesterol.
  • Bezafibrate is dosed at 400mg daily. Side effects include GI upset and increased ALT.
• Patients should be monitored q 6-12 monthly with bilirubin, ALP, AST, albumin, platelet count and transient elastography.
• Patients should be evaluated for associated disease related symptoms and complications (pruritus, sicca complex, fatigue, osteoporosis, fat soluble vitamin deficiency)
• Prognosis can be estimated using risk scores such as the GLOBE score (https://www.globalpbc.com/globe). Patients with risk scores >0.30 have significantly shorter transplant-free survival than matched healthy individuals (P < .0001).

Primary sclerosing cholangitis

• The role of ursodeoxycholic acid (UDCA) remains unclear.
  • It is known that high dose (20-25mg/kg/d) UDCA is harmful. A UDCA trial for 6-12 months at a low dose (13-15 mg/kg per day in divided doses) can be considered with continuation of therapy if the ALP decreases by at least 40% or there is symptomatic improvement.
• The role of cholangiocarcinoma screening remains unclear. Notably, many centers carry out annual screening with ultrasound or MRCP ± measurement of a serum CA 19-9 (Bowlus CL et al. 2019). Given the lack of data it is reasonable to forego routine screening. If a dominant stricture is suspected, the patient should be referred to a tertiary care center with expertise in investigating these cases.
• All patients with PSC should have an annual ultrasound to screen for gallbladder carcinoma (this will be captured in q 6 monthly HCC surveillance in patients with cirrhosis).
• 90% of patients with PSC have IBD. If colitis has been established, surveillance colonoscopy is required q 1-2 yearly. Those patients without IBD require colonoscopy q 3-5 yearly with biopsies to look for previously undiagnosed colitis.
• A bone density evaluation should be carried out at diagnosis and q 2-3 yearly
• Prognosis can be estimated using risk scores such as the PRESTO (https://rtools.mayo.edu/PRESTO_calculator/)