09. End Stage Liver Disease

Definition: the common endpoint of multiple diseases in which progression to liver failure is irreversible.

Etiology

The vast majority of cases are due to alcohol and chronic viral hepatitis, but other etiologies include autoimmune, cardiac, metabolic (hemochromatosis, Wilson’s, α-1-antitrypsin), biliary (primary biliary cholangitis, primary sclerosing cholangitis), vascular (Budd-Chiari, veno-occlusive disease), & nonalcoholic fatty liver disease (NAFLD).

Evaluation

  • Clinical history: alcohol use, intravenous drug use, high risk sexual behaviors, known viral hepatitis, personal or family history of other liver diseases that can result in cirrhosis.
  • Signs: jaundice, spider angiomas, scleral icterus, palmar erythema, asterixis, caput medusae, ascites, splenomegaly, peripheral edema.
  • Laboratory: hypoalbuminemia, elevated INR, thrombocytopenia, hyperbilirubinemia, macrocytic anemia (in cases of alcohol use).
  • Radiology: suggestive findings include nodular liver surface, shrunken liver (+/- enlarged caudate lobe), and signs of portal hypertension (e.g., splenomegaly, varices, enlarged portal vein diameter >1 cm, ascites).
  • Biopsy-proven cirrhosis.

Management

Primarily based on limiting progression of disease and managing symptoms and complications of ESLD.

  • Treatment of underlying etiology (e.g., hepatitis C, hepatitis B, autoimmune hepatitis, primary biliary cholangitis, iron overload).
  • Alcohol abstinence and limited use of hepatotoxic medications (such as acetaminophen and herbal medications).
  • Vaccination against hepatitis A and B if no documented immunity.
  • Management of complications per below.
  • Definitive treatment is liver transplant.

Prognosis

Depends on severity of disease (calculate Child-Pugh score):

Child-Pugh Score

Points scored

1

2

3

Encephalopathy grade

None

1-2 (mild confusion/lethargy)

3-4 (marked confusion/coma)

Bilirubin, mg/dl

<2

2-3

>3

*For PBC or PSC

<4

4-10

>10

Ascites

None

Mild-moderate

Severe or refractory

Albumin, mg/dl

>3.5

2.8-3.5

<2.8

INR

<1.7

1.7-2.3

>2.3

 

Total points

Classification

1 and 2 year survival

5–6

 

Class A

100%, 85%

 

7–9

 

Class B

80%, 60%

 

10–15

 

Class C

45%, 35%

 
  • MELD (Model for End-Stage Liver Disease), initially developed to predict death within 3 months of TIPS procedure, is useful in prognosis. Uses total bilirubin, INR, and creatinine. 
    • MELD-sodium is used to prioritize for liver transplant organ allocation (calculators available online).
    • MELD range: 6 (normal) to 40.

Complications of ESLD

1. Hepatic encephalopathy: as many as 50-70% of patients with cirrhosis may have some degree of hepatic encephalopathy, which is primarily thought to be related to ammonia accumulation. Hepatic encephalopathy is a clinical diagnosis and monitoring of serum ammonia is usually not indicated.

  • Precipitants of encephalopathy include: infection, GI bleed, sedatives (benzodiazepines, alcohol, opioids, etc.), volume depletion, renal insufficiency, constipation, worsening hepatic function, hypokalemia, alkalosis, development or worsening of hepatocellular carcinoma, portosystemic shunts (including TIPS), vascular (portal vein thrombosis), & medication discontinuation (e.g. lactulose). Dietary protein is NOT a significant contributor to encephalopathy and should not be restricted.

Grade

Findings

0

None

1

Daytime somnolence, nighttime insomnia, mild forgetfulness, slight asterixis

2

Lethargy, disinhibition, disorientation, asterixis, hyperactive reflexes

3

Somnolence, aggressive behavior, asterixis, hyperactive reflexes

4

Comatose, decerebrate posturing, dilated pupils, asterixis, and reflexes absen
  • Management of hepatic encephalopathy: 
    • Stabilize patient: address airway if mental status is impaired, vital signs, consider NGT and empiric antibiotics.
    • Treatment is aimed at decreasing ammonia production and absorption from the gut:
      • Lactulose 10-20 grams (15-30 mL) orally BID or TID, titrating to 3 loose bowel movements per day. Can use NGT or enemas depending on mentation.
      • Rifaximin (a non-absorbed oral antibiotic active against gut flora) was recently approved for treatment of encephalopathy. Dose is 550 mg PO BID (or 400 mg TID). Can be used as first-line therapy, but cost generally dictates trying lactulose first. Rifaximin can be used in combination with lactulose.
      • Zinc sulfate 220 mg PO daily can be used in zinc-deficient patients with cirrhosis to treat refractory cases.
    • Diagnose and treat the underlying cause of exacerbation.
    • Dietary protein restriction is not recommended and can actually exacerbate encephalopathy by leading to skeletal wasting and reduction in muscle-mediated ammonia metabolism.

2. Ascites: in ESLD, this is due to splanchnic vasodilatation, portal hypertension and decreased serum oncotic pressure from hypoalbuminemia.

  • Multiple etiologies may cause ascites (see table below).
  • New-onset ascites should always be investigated with a diagnostic paracentesis.
    • Always send fluid for albumin and total protein, as well as cell count and culture to rule out SBP; immediate bedside inoculation of culture medium recommended.
    • Optional tests include gram stain, glucose, LDH, and amylase.
    • Depending on the setting, consider sending cytology, AFB, ADA, TG, total bilirubin.
    • Calculate the SAAG, or serum ascites-albumin gradient, by subtracting the ascites albumin from the serum albumin. A high gradient (>1.1) means there is portal hypertension.

High gradient (≥1.1 g/dl)

Low gradient (<1.1 g/dl)
  • Cirrhosis 
  • Alcoholic hepatitis
  • CHF (R-sided)
  • Constrictive pericarditis
  • Massive liver metastases
  • Fulminant hepatic failure
  • Budd–Chiari syndrome
  • Portal vein thrombosis
  • Veno–occlusive disease
  • Fatty liver of pregnancy
  • Myxedema
  • Schistosomiasis
  • Kwashiorkor
  • Mixed (high + low gradient etiologies)
  • Peritoneal carcinomatosis
  • Peritoneal TB
  • Pancreatic ascites
  • Biliary ascites
  • Nephrotic syndrome
  • Serositis
  • Bowel obstruction/infarction       

 
  • Management of cirrhotic ascites:
    • Sodium restricted diet (<2 grams per day).
    • Only fluid restrict patients with hyponatremia (Na ≤125).
    • Start diuretics for patients not controlled with dietary sodium restriction. Start with spironolactone 100 mg PO daily and furosemide 40 mg PO daily and increase in a 5:2 spironolactone to furosemide ratio as needed. Diuresis should be monitored by weight loss and should not exceed 0.5 kg per day in patients without peripheral edema or 1 kg per day in patients with peripheral edema. This represents the maximal amount of fluid that the peritoneum can resorb in a day; greater diuresis increases the risk of volume depletion or hepatorenal syndrome.
    • Goal is reversal of the urine Na and K ratio – that is, the urine should contain more sodium than potassium; this suggests a therapeutic diuretic dose. If Na/K ratio >1 and patient is not losing weight, suspect >2g/day Na intake.
    • Repeat large-volume paracentesis (LVP) may be necessary in patients refractory to diuretics.
      • 6-8g IV albumin (given as 25% albumin) per liter ascites removed for LVP should be administered.
    • TIPS should be considered in patients with refractory ascites and relatively preserved liver function (low MELD) and no contraindications, as TIPS has a survival benefit compared with serial LVP.

3. Spontaneous bacterial peritonitis:

  • Classically, SBP presents as a patient with pre-existing ascites who develops abdominal pain, fever, decreased bowel sounds, worsened hepatic encephalopathy, and hypotension. However, fever is present only 70% of the time, abdominal pain 60%, and encephalopathy only 50%. One in ten patients with SBP will have no symptoms at all. Therefore, have a low threshold for performing diagnostic paracentesis on patients with ascites due to cirrhosis.
  • Indications for diagnostic paracentesis: new ascites, established ascites with clinical deterioration (fever/SIRS or abdominal pain or encephalopathy), established ascites and admission to hospital (even if reason for admission is unrelated to ascites).
  • Contraindications for diagnostic paracentesis: DIC (i.e. virtually no contraindication).
  • Risk factors include low-protein ascites, bilirubin >2.5 mg/dl, GI bleed, urinary tract infection, catheterization, and a prior episode (over 40% will have SBP again in 6 months).
  • Diagnosis is based on paracentesis cell count and differential:
    • PMN >250/mm3: the sensitivity and specificity of this value is above 90%. Traumatic taps generate 1 WBC per 250 RBCs, and 1 lymphocyte per 750 RBCs. WBC greater than 10,000 is suggestive of secondary peritonitis.
    • Gram stains rarely yield organisms (<5%), but when positive are diagnostic and can quickly rule-in bowel perforation when polymicrobial.
  • Treat empirically with a third generation IV cephalosporin and narrow according to culture results. The most common organisms are Enterobactereciae, Streptococcus pneumoniae, and Enterococcus. Anaerobes rarely cause SBP. Treatment duration is 5 days of IV antibiotics, with longer duration if symptoms persist. Repeat paracentesis is not routinely indicated but should be considered if patient does not clinically improve.
    • Consider using broader antimicrobial coverage in patients who have a history of drug-resistant bacterial infections.
  • Give albumin on day 1 (1.5 g/kg of 25% albumin) and day 3 (1 g/kg of 25% albumin) to reduce risk of hepatorenal syndrome.
  • In high-risk patients (ascites total protein <1.0 or prior SBP), initiate SBP prophylaxis after initial antibiotic course is completed. Typical choices are ciprofloxacin 500mg PO daily, TMP-SMX DS 1 tab PO daily five days per week, and norfloxacin 400 mg po daily.
  • Prognosis: 1-2 year mortality is 25%.

4. Esophageal varices: see section GI Bleed.

5. Hepatocellular carcinoma: usually managed in the outpatient setting. If patient is suspected of having HCC during an admission, work up includes 4-phase liver CT or MRI, and AFP.

  • Treatment options:
    • Ablation: microwave/radiofrequency ablation (MWA/RFA) or percutaneous ethanol injection (PEI).
    • Transcatheter therapies: trans-arterial chemoembolization (TACE), trans-arterial bead embolization (TABE), radioembolization with yttrium-90.
    • Surgical resection: usually restricted to patients with solitary tumor and no cirrhosis or Child’s A cirrhosis without portal hypertension (e.g., normal bilirubin and platelets >100,000).
    • Systemic chemotherapy: tyrosine kinase inhibitors (e.g., sorafenib, lenvatinib), immunotherapy (e.g., nivolumab), clinical trial agents.
    • Stereotactic body radiation therapy (SBRT).
    • Liver transplantation.
  • Patients with early stage unresectable HCC are evaluated by a standard transplant criteria known as the Milan criteria.

Milan Criteria

Stage

Number of nodules

Size of Nodules

T1

1

≤5 cm

 

T2

 

2 or 3

 

≤3 cm each

 

No vascular invasion and no extrahepatic spread

 
  • Some transplant programs will consider transplant in certain patients outside the Milan criteria – e.g., UCSF. Absolute contraindications include obvious portal vein invasion or distant metastatic disease (e.g., lung, bone).
  • Don’t “rule out” transplant until a hepatologist rules out transplant.

6. Coagulopathy: patients with ESLD often have coagulopathy and thrombocytopenia (secondary to decreased liver synthetic function and splenomegaly, respectively).

  • Coagulopathy (as measured by the INR) does not necessarily imply an increased risk of spontaneous bleeding, which is rare in patients with ESLD. Profound thrombocytopenia is more of a clinical concern.
  • Coagulopathy and thrombocytopenia only need to be corrected if there is concern for clinical bleeding (GI or otherwise) or an invasive procedure is planned (e.g., liver biopsy, central line placement).
  • If indicated, correct elevated INR with FFP. You may also try vitamin K 10mg PO qday x 3 days. Recombinant Factor VIIa or prothrombin complex (Kcentra) is rarely indicated and should be considered only in patients with life-threatening bleeding or when an urgent invasive procedure is needed.
  • ESLD patients may have multiple disease processes occurring, so maintain suspicion for additional treatable causes of bleeding, such as DIC and uremic platelets.

7. Hepatorenal syndrome (HRS): renal failure due to renal vasoconstriction resulting from profound splanchnic and systemic vasodilatation. Other causes of renal failure must first be ruled out.

  • HRS is a diagnosis of exclusion as a cause of AKI in patients with cirrhosis. Patients with cirrhosis with AKI should have diuretics held and undergo a volume challenge with 1g/kg of IV albumin (using 25% albumin).
  • Type 1 HRS is often a consequence of SBP or other acute precipitant (e.g., GI bleeding, sepsis) and involves rapid (i.e., less than 2 weeks) rise in creatinine (>50% drop in CrCl to less than 20mL/min or >2-fold increase in creatinine to greater than 2.5 mg/dL) and decrease in urine output. Median survival is less than one month without treatment.
    • HRS-AKI is proposed as an updated definition: an absolute increase in sCr ≥0.3mg/dL within 48 hours and/or UOP <0.5 mL/kg in ≥6 hours, or percent increase in sCR >50% from baseline.  
  • Type 2 HRS is HRS that does not meet criteria for type I: slower progression and less severe renal impairment. It is principally characterized by ascites that is resistant to diuretics and mild elevations in creatinine.
    • HRS-NAKI is proposed as an updated definition and includes HRS-AKD (eGFR<60mL/min for <3 months) and HRS-CKD (eGFR<60mL/min for >3 months).
  • Treatment of HRS type I typically involves midodrine (oral α-1 agonist) to decrease systemic vasodilation, octreotide (inhibitor of endogenous vasodilator release) to decrease splanchnic vasodilation and IV albumin for intravascular volume expansion.
  • Terlipressin (vasopressin analog) is an effective alternative that is being considered for approval in the US.

8. Acute Liver Failure (aka Fulminant Hepatic Failure): see section Acute Liver Failure.

 

European Association for the Study of the Liver. EASL Clinical Practice Guidelines for the management of patients with decompensated cirrhosis. J Hepatol (2018), https://doi.org/10.1016/j.jhep.2018.03.024

European Association for the Study of the Liver. EASL clinical practice guidelines on the management of ascites, spontaneous bacterial peritonitis, and hepatorenal syndrome in cirrhosis. J Hepatol. 2010;53(3):397‐417. doi:10.1016/j.jhep.2010.05.004

Hepatic Encephalopathy in Chronic Liver Disease: 2014 Practice Guideline by the European Association for the Study of the Liver and the American Association for the Study of Liver Diseases. J Hepatol (2014), http://dx.doi.org/10.1016/j.jhep.2014.05.042