Archive for the HCP Category

Liver transplantation (LT) is an accepted therapeutic modality for:

• End-stage liver disease (acute or chronic); and
• Selected tumors

Transplantation is indicated for patients with advanced forms of disease in whom no realistic hope for extension of life exists with other forms of medical or surgical intervention. In general, for patients with cirrhosis, one should consider referral for liver transplantation as they develop features of decompensated liver disease such as ascites, bleeding esophageal or gastric varices and hepatic encephalopathy that are not easily controlled with medical/endoscopic therapy.  The MELD-sodium is also a general guide.  Most patients who are considered for transplant have MELD-sodium values >15, but there are certainly exceptions whereby patients with lower MELD scores can be considered. This links to the OPTN (Organ Procurement and Transplantation Network) MELD exception document from 2017.

Indications for Liver Transplantation:

1. Hepatocellular Liver Disease
   • Nonalcoholic Steatohepatitis
   • Viral Hepatitis
   • Alcohol related Cirrhosis with 6 months abstinence from alcohol.
   • • Selected patients may meet criteria for the new exception pathway. Consult Transplant hepatology to discuss these cases.
   • Severe Alcoholic Hepatitis refractory to steroids
     • Selected patients may meet criteria for the new exception pathway. One of the requirements is that there can be no prior history of hospital or ER visits with intoxication or alcohol withdrawal. There are a list of other criteria. Consult Transplant hepatology to discuss these cases.
   • Hepatitis B
   • Cryptogenic Cirrhosis
2. Cholestatic Liver Disease
   • Primary Biliary Cholangitis, Primary Sclerosing Cholangitis, Secondary Biliary Cirrhosis, Idiopathic or Drug Induced Cholestasis
3. Inborn Errors of Metabolism
   • Wilson’s Disease, Alpha 1 Antitrypsin Deficiency, Hemochromatosis, Familial Amyloidosis Polyneuropathy, Other
4. Fulminant Hepatic Failure
5. Budd-Chiari Syndrome
6. Drug Toxicity leading to liver failure
7. Other
8. Selected intrahepatic malignancies – this refers to tumors originating within the liver, not metastatic disease to the liver. Involve a liver specialist with any suspected diagnosis of Hepatocellular carcinoma (HCC).
   • Listing criteria for Hepatocellular carcinoma
     • Total tumor volume (TTV) is ≤115 cm³ AND AFP ≤400 ug/mL
   • Not candidates for transplant
     • TTV >115 cm³ OR AFP >400 ug/mL
     • Metastasis outside the liver
     • HCC vascular invasion on radiological imaging
     • General contraindications for liver transplantation
   • Useful HCC information – see HCC page for more HCC details
     • TTV is calculated based on the area of any viable tumor (tumor showing enhancement).
     • Under the guidance of a liver specialist, a patient can be considered for HCC down-staging if TTV ≤250 cm³, regardless of AFP. Following down-staging, a patient can be considered for transplantation if TTV ≤115cm³ AND AFP ≤400 ng/mL for 6 months.
   • TTV calculator

Contraindications for Liver Transplantation

During the evolution of clinical transplantation internationally, and at University of Alberta Hospital, multiple patient-related factors have come to be recognized as adversely affecting patient outcome.   These factors constitute relative or absolute contraindications to transplantation.

The following factors exert a major adverse influence on the outcome of transplantation and would be absolute contraindications in most cases:

Absolute Contraindications

• Active systemic sepsis
• Systemic disease such as metastatic cancer, AIDS, mitochondrial disorders
• pneumonia, unresolved pulmonary infarction or other pulmonary infiltrates
• Severe non-correctable peripheral or cerebrovascular disease
• Severe irreversible cardiac disease (unless simultaneous liver and heart transplantation considered)
• Advanced cardiopulmonary disease
• Clear history of non-compliance
• Active alcohol or drug abuse (note: alcohol exception pathway criteria detailed above)
• Uncontrolled psychiatric disease
• Severe neurological instability or advanced neurological illness
• BMI > 45
• Age > 75 years

Hypotension/shock:

• Both circulatory and cardiac abnormalities may develop in patients with cirrhosis
• In cirrhosis/acute on chronic liver failure (ACLF) patients presenting with shock, the approach should be guided by a systematic assessment of volume status and correction of hypotension in an effort to restore adequate end organ perfusion.
• Arterial catheters are recommended to guide resuscitative efforts. Central venous access is also recommended to aid the assessment of hemodynamic status (e.g. measurement of central venous pressure (CVP)) and as a route for vasoactive medications.
• Assessment of volume status in this patient population can be particularly challenging due to ascites and edema. Dynamic measures of volume and circulatory function such as echocardiography, changes in CVP in response to fluid challenge are preferable
• In ACLF/cirrhosis patients with additional organ failures aim for a MAP > 65 mmHg
• Volume expansion with ringer’s lactate, plasmalyte or concentrated albumin (25% 100 cc prn) is appropriate with fluid choice guided by the patient’s clinical status
• With upper GI bleeding, there is evidence to support a restrictive transfusion threshold of 70 g/L. This threshold is liberalized if bleeding is massive or if there is a history of ischemic heart disease etc.
• Norepinephrine is the recommended first-line agent as it is associated with fewer adverse events. Vasopressin may be used as a second-line agent.
• In patients where adrenal insufficiency is suspected, it is our practice to empirically administer hydrocortisone 200 mg IV in 4 divided doses. Continue until resolution of shock.

Respiratory failure:

• Pulmonary complications in cirrhosis can either be directly related to cirrhosis (portopulmonary hypertension, hepatopulmonary syndrome, hepatohydrothorax) or unrelated (e.g. pneumonia)
• Tense ascites and hepatic hydrothorax may complicate mechanical ventilation.
• Use typical lung protective ventilation strategies with low tidal volume ventilation and use of positive end expiratory pressure (PEEP) to maintain oxygenation.
• In patients with unexplained hypoxia, consider diagnostic studies to evaluate for hepatopulmonary syndrome and portopulmonary hypertension (e.g. contrast echocardiography).

Neurological Dysfunction

• See Hepatic Encephalopathy section for more on the topic
• Treat possible precipitating factors for hepatic encephalopathy (HE) and evaluate the response to ammonia lowering therapies (lactulatose, PEG, rifaximin).
• Consider CT head in patients do not respond to standard treatments or where HE onset is abrupt or severe
• Consider electroencephalogram (EEG) to exclude other causes of altered mental status in patients who fail to respond to standard therapy
• Consider intubation for airway protection in patients with a GCS of ≤ 8
• In patients who require intubation/mechanical ventilation for respiratory failure, the use of short acting agents such as fentanyl (25-200 ug/hour) or propofol (50-150 mcg/kg/min) should be considered. Avoid benzodiazepines as these agents precipitate more pronounced neurocognitive impairment

 Renal Dysfunction

• See Renal Dysfunction section for more on the topic
• Hepatorenal syndrome (HRS) and its physiology of renal vasoconstriction and splanchnic vasodilatation are one of several causes of Acute Kidney injury (AKI) in cirrhosis. Other causes of AKI include hypovolemia/prerenal azotemia, intrinsic renal/parenchymal disorders (acute tubular necrosis/ATN, nephrotoxicity, interstitial nephritis, glomerulonephritis/ nephropathy), and obstructive nephropathy. Consider urinalysis, renal ultrasound, blood pressure evaluation and medication history to rule out other causes of AKI.
• Albumin (1g/kg (20-25%) on day one, then 20-60 g/day thereafter) along with vasoconstrictor therapies have been relatively well studied in the treatment of HRS, in particular, vasopressin Consider Midodrine (maximum dose 15 mg TID) and octreotide (maximum dose 200 ug sc TID) if on the ward. If no effect, then a therapeutic trial of IV norepinephrine to maintain a MAP > 75 mm Hg in the ICU can be considered.
• Intermittent or continuous renal replacement therapy (RRT) may be used in HRS as a bridge to LT. The use of RRT in patients with HRS is likely only appropriate in the setting of a patient who is listed for LT or has another indication for RRT (i.e. uremia, acidosis, hyperkalemia)

Hemostatic Disorders:

• Patients with cirrhosis are in a fragile continuum between ineffective hemostasis and inappropriate thrombosis due to decreased production of procoagulant and anticoagulant factors
• INR (international normalized ratio) does not account for deficiencies of the anti-coagulation system (especially low protein C), which may result in a hypercoagulable state not reflected in prolongation of the INR.
• Consider maintaining platelets > 50 and a fibrinogen > 1.5 g/L as targets in cirrhosis patients requiring procedures or with active bleeding
• If available, consider viscoelastic tests of whole blood (thromboelastography (TEG), thromboelastometry (ROTEM)).

Variceal Bleeding

• See Varices section for more on the topic
• Consider early intubation in cirrhosis/ACLF patients with concomitant HE, respiratory distress or large volume hematemesis (> 500 ml blood) prior to performing endoscopy. Consider octreotide infusion to improve portal inflow with early endoscopy.
• In the event of failed endoscopy, a balloon tamponade device, such as the Sengstaken-Blakemore or Minnesota tube may be used as a bridge to more definitive therapy including repeat endoscopy or transjugular intrahepatic portosystemic shunting
• Administer prophylactic antibiotics (i.e. ceftriaxone 1g IV qd) given potential reduction in rates of rebleeding and bacterial infections

Sepsis

• See Spontaneous Bacterial Peritonitis and Pleuritis section for more on the topic
• Early antibiotics in cirrhosis/ACLF patients with septic shock improves mortality
• Increasing numbers of ACLF patients are presenting with septic shock bacteremia from gram negatives (50-60%) and multidrug resistant pathogens
• If severe sepsis is suspected, a thorough evaluation should promptly be followed by antibiotic administration, since each hour delay impairs outcome
• In patients with clinical improvement within 48-72 hours and a known pathogen, immediate tailoring of antibiotics is recommended. In patients without clinical improvement empiric antifungal therapy and CT scan is warranted.

Acute-on-chronic liver failure (ACLF) prognostication

• Consider the CLIF-C ACLF score or the NACSELD scores for evaluation of ACLF with organ failure
• See: NACSELD calculator
• See: CLIF-ACLF calculator 
• CLIF-C ACLF Score 

A CLIF-ACLF score of > 70 is associated with 90% mortality at Day 28. While predicting futility in ACLF is challenging, decisions regarding ICU admission should be based on factors including:

• Goals of Care
• Candidacy for liver transplant
• Age
• CLIF-C ACLF score
• Other comorbidities/sarcopenia

Thank you to Dr. Borman for your efforts creating the content on this page!

Diagnosis

General Management

Specific Management

Risk factors and prevention

• The most important risk factor for HCC is liver cirrhosis. Hence, to prevent progression to cirrhosis, it is very important to detect chronic liver diseases in the general population early on in their natural history. Other risk factors for HCC are age, male sex, diabetes, obesity, alcohol, tobacco, and aflatoxin B1 exposure.
• Primary prevention should aim to prevent chronic liver disease by promoting a healthy diet, exercise, responsible drinking, and HBV vaccination.
• Secondary prevention should target the treatment of the etiology of the underlying liver disease, and other risk factors associated with HCC, in order to prevent disease progression and development of HCC. Coffee drinking may protect against HCC.

Note: Tertiary prevention would aim to reduce the risk of recurrence after curative treatments, but so far, there are no neoadjuvant or adjuvant therapies approved for this purpose. 

Surveillance

Who should be screened:

• Patients with cirrhosis (regardless of the etiology) who are Child Pugh A or B.
• Given limited treatment options, surveillance should only be done in Child Pugh C patients if they are eligible for liver transplantation
• Patients with HBV infection without cirrhosis belonging to one of the following groups:
  • PAGE-B score ≥10
  • Asian females >50 years
  • Asian males >40 years
  • Family history of HCC
  • Patients of African descent >20 years

Note: Patients with HCV-associated cirrhosis should continue to undergo screening even after SVR.

How to screen:

• Ultrasound surveillance with serum alpha-fetoprotein (AFP) every six months. Overall sensitivity of the ultrasound is 84%, but only 45% for early stages; the addition of AFP increases sensitivity to 63% in early stages.
• Do not use AFP alone for surveillance
• For ultrasound/AFP to be cost-effective, the adherence needs to be ≥34%, and the annual incidence of HCC should be ≥1.5% and ≥0.3% in patients with and without cirrhosis, respectively. Automated radiology recall programs are preferred to increase compliance – for Alberta, please see details for these programs in the grey bar.
• If there is a mass/nodule on the ultrasound > 1cm, patients need to undergo a dynamic imaging study (see diagnosis below).
• If there is a lesion < 1 cm, the ultrasound should be repeated at shorter intervals (e.g. every 3-4 months). If the lesion remains stable after 12 months of follow-up, the patient can return to every 6 months for surveillance. On the contrary, if the lesion grows or changes in pattern, the patient will need to undergo a dynamic imaging study (see diagnosis below).

NOTE: Ultrasound may perform sub-optimally in patients with obesity, steatosis, and/or multinodular livers. The US LI-RADS visualization score (i.e. A for minimal limitations, B for moderate limitations, and C for severe limitations) can help identify the need for an alternative screening strategy in a given patient (e.g. cross-sectional imaging).

Diagnosis

• In patients with underlying cirrhosis, imaging criteria defined by the European Association for the Study of the Liver (EASL) and Liver Imaging Reporting and Data System (LI-RADS) enable HCC diagnosis (without the need for targeted biopsy).
• A lesion >1cm showing arterial phase hyperenhancement and non-peripheral venous washout can be diagnosed as HCC; LI-RADS criteria also take into account threshold growth (>50% diameter increase in <6 months).
• In patients with cirrhosis and non-conclusive imaging findings, a multidisciplinary discussion is suggested to decide the best strategy to follow: targeted biopsy, close follow-up, or repeated imaging with an alternative method.
• Liver biopsy is mandatory in non-cirrhotic patients given the lower pre-test probability of HCC.
• If a biopsy is done, specific stains may help with the diagnosis of HCC.
• Isolated alpha-fetoprotein (AFP) elevation is not required for the diagnosis of HCC (40% of HCC do not make AFP)
• AFP should not be used on its own to diagnose HCC (mixed tumors can also produce AFP).
• AFP should be ordered if HCC is suspected as it has prognostic properties and is used to define liver transplant and systemic therapy (e.g. ramucirumab) candidacy.

Radiology findings

Staging and Treatment – the Alberta HCC Algorithm

• • Once the diagnosis of HCC is confirmed, a CT of the chest should be obtained for starting.
  • If there is any suspicion of bone metastasis (e.g. bone pain), a bone scan should also be obtained.
  • Staging and treatment allocation are based on the BCLC staging system, which takes into account the tumor burden (e.g. number, size, vascular invasion, extrahepatic spread), the underlying liver function, and the patient´s performance status (PS).
  • The BCLC comprises 5 stages:

Reproduced with permission from Dr. K. Burak. Source: HepAPPtology

Systemic therapy

Palliative care considerations for HCC

• Palliative care principles should be followed in all patients with HCC – this basic/primary palliative care can be carried out by any physician involved in the patient’s circle of care (Primary care physician, Oncologist, Hepatologist) and at a minimum includes advance care planning and goals of care discussions.
• Specialist palliative care involvement (a board certified specialist or the primary care physician if they are comfortable with palliative care) should be considered with complex palliative  care including refractory symptom burden or hospice referral that is not straight-forward.

Prognosis

Can be defined based on the stage:

• Very early and early: Median survival of more than 5 years
• Intermediate: Median survival of more than 2.5 years (16 months without treatment)
• Advanced: Median survival of more than 2 years. (7 months without treatment)
• Terminal: Median survival of 3 months.

Diagnosis and Immediate Management

Identify and treat acute precipitants.

*Do not assume that HE is the result of noncompliance to lactulose before ruling out precipitants.

	Assess for:
	Infection even if no clear signs on vitals or blood work: • Blood culture, urine culture and chest x-ray • Paracentesis if ascites
	Constipation
	New medications (sedatives, narcotics)
	GI bleeding
	Metabolic abnormalities including renal injury, hypokalemia, hypovolemia, hypoxia. In some patients diuretics may be the only precipitant.

Additional Management