liver biopsy is not always needed to make the diagnosis of cirrhosis
diagnosis can be established through clinical, laboratory, and/or imaging findings
platelet <160 x 10^3 /uL has a positive likelihood ration of 6.3
Definitive diagnosis of cirrhosis as well as portal hypertension and etiology
trans-jugular liver biopsy with portal pressure measurements
will demonstrate presence/lack of cirrhosis and whether portal hypertension is cardiac or liver in origin
hepatic venous pressure gradient (HPVG) = wedge pressure - free hepatic pressure
HPVG > 5 mmHg = portal hypertension
in cardiac hepatopathy there is portal hypertension but HPVG is normal
Decompensated cirrhosis, defined by presence of...
ascites
associated with poor quality of life, increased morbidity/mortality, and poor long term outcomes
after first episode of ascites survival is 85% during the first year, 56% at 5y without liver transplant
results from increased renal sodium retention due to high activity of the renin-angiotensin-aldosterone system which results from high splanchnic vasodilation and portal hypertension
variceal bleeding
can occur at an annual rate of ~5-15%
most important predictor of bleed is variceal size>decompensated cirrhosis and presence of red wale signs on EGD
hepatic encephalopathy
jaundice
Median survival ~1.5 yr
Refer to a transplant center after first episode of decompensation regardless of MELD score given poor survival
Compensated cirrhosis, does not have any of the above findings
median survival ~12 yr
palmar erythema
spider angiomata
thrombocytopenia
splenic sequestration
reduced activity of hematopoietic growth factor thrombopoietin
cirrhotic coagulopathy
bone marrow suppression by viral infections or medications
SBP
abdominal pain
fever
leukocytosis
up to 1/3 may be asymptomatic
PPI use associated with increased risk of SBP in cirrhotic patients, only use for clear indications
Portal vein thrombosis
may cause portal hypertension with GI bleeding and small bowel ischemia
prevalence among cirrhotics is 4.4-15%
responsible for ~5-10% of overall cases of portal hypertension
Sarcopenia
negative predictor of outcomes in patient's with cirrhosis
Hepatopulmonary syndrome
occurs in 5-10% of patients awaiting liver transplant
those with HPS have higher mortality than those without
results from pulmonary vasodilation that leads to gas exchanged abnormalities and hypoxemia
presentation varies form mild dyspnea to severe hypoxemia
clubbing, cyanosis, and vascular spiders can be seen on exam
Diagnosis
exclude other causes
PaO2 <80 mmHg or Aa gradient >15 mmHg on ABG
intrapulmonary vasodilation by contrast echocardiography and/or perfusion lung scanning
late bubbles on contrast echocardiography
left sided bubbles after the 4th or 5th beat indicative of an intrapulmonary shunt
versus: bubbles at the second beat reflect presence of intracardiac shunt
Portopulmonary Hypertension (POPH)
detected in 4-8% of liver transplant candidates
results from pulmonary vasoconstrictors that are released from the splanchnic circulation
diagnosis made through right heart catheterization
pulmonary arterial pressure > 25 mmHg
mild POPH with mean pulmonary arterial pressure (MPAP) <35 mmHg is not of major concern
moderate (MPAP ≥ 35 mmHg) and severe POPH (MPAP ≥ 45 mmHg) are predictors of increased mortality following liver transplant
mortality is 100% with MPAP > 50 mmHg
if MPAP can be reduced with vasodilator therapy to < 35 mmHg and pulmonary vascular resistance less than 400 dynes.s.cm-5, transplant is possible
pulmonary capillary wedge pressure < 15 mmHg
pulmonary vascular resistance > 240 dyenes/s/cm-5
Thrombocytopenia
moderate = plt < 100 x10^9/L
severe = plt <50 x 10^9/L
Ascites
Serum-ascites albumin gradient (SAAG)
SAAG >1.1 and ascites total protein <2.5
ascites related to cirrhosis
SAAG >1.1 and ascites total protein >2.5
ascites related to post-sinusoidal hypertension
cardiac ascites
Budd-Chiari
veno-occlusive disease
SAAG <1.1 and ascites total protein <2.5
Nephrotic syndrome
SAAG <1.1 and ascites total protein >2.5
tuberculous peritonitis
malignant causes
vaccinate against HAV and HBV
Non-selective beta-blockers are used for primary or secondary prophylaxis of variceal bleed
titrate to goal of 50-60 bpm
propranolol
nadolol
carvedilol
maximum dose of 12.5 mg daily
higher doses are associated with increased side effects and hypotension due to alpha 1 antagonism and excessive first past metabolism
more robust effect on reduction of portal pressure than nadolol or propranolol
reduce portal pressure, splanchnic blood flow, and gastroesophageal collateral blood flow
decrease in hepatic venous pressure gradient >20% is associated with lower rate of first variceal hemorrhage, ascites, and death
reduction in cardiac output via β1 thus reducing portal venous inflow
reduction in splanchnic vasoconstriction via β2 (the most important effect)
has also been shown to reduce gut bacterial translocation
avoid in relative hypotension and asthma
Primary prophylaxis for variceal bleed for patients who have never bled
non-selective beta blocker (NSBB)
serial variceal band ligation
combination of NSBB and band ligation is not recommended given association with more side effects without additional benefit beyond treatment with either therapy alone
Secondary prophylaxis
NSBB + variceal ligation
patients who have already bled are at high risk for rebleeding and death
median rate of rebleed if untreated is ~60% within the first 1-2 yr
Early TIPS evaluation can be considered if
there is continued bleeding despite band ligation
or at first presentation with Child's C severity (score 10-13) or Child's Class B with active hemorrhage at endoscopy
TIPS within 72 hr of EGD following initial vasoactive/endoscopic therapy is associated with improved outcomes
Contraindications
advanced age
HCC
heart failure
significant hepatic encephalopathy
Variceal bleeding
treat with antibiotics for prophylaxis
bacterial infections cirrhotics with upper GI bleed can occur in up to 45% of cases
EGD within 12 hr of presentation
transfuse for goal hb ~7-8 g/dL
overtransfusion or volume overexpansion can precipitate variceal rebleeding
restrictive transfusion strategy, holding until Hb is <7 g/dL, leads to improved survival
transfuse platelets prior to EGD if plt < 50 x 10^9/L to reduce risk of bleeding during and after procedure
octreotide IV
Gastric varices
tissue adhesive recommended over band ligation because of higher efficacy
failure to control bleeding or if there is recurrent bleed from GOV1, TIPS is recommended
Ascites
dietary sodium restriction
fluid restriction not required unless there is severe hyponatremia with Na <120-125 mEq/L
Spironolactone is more effective than loop diuretics
start at dose 50-100 mg daily
may cause painful gynecomastia
Furosemide
start at 20-40 mg daily
maintain ratio of 2:5 of furosemide:spironolactone
Side effects of diuretics
encephalopathy
electrolyte abnormalities
large volume paracentesis (LVP)
when patient's fail diuretics and dietary salt restriction
after LVP there is a significant alteration of systemic circulation
acute increase of cardiac output
reduction in systemic vascular resistance and arterial blood pressure
this can be prevented with albumin volume expansion
give 8g albumin per L removed
TIPS indicated for diuretics intolerance or refractory ascites requiring frequent LVP (> 2x per month)
Peritoneal catheter - mainly used in the palliative setting
Peritoneovenous shunt
a subcutaneously placed silicone tube that transfers ascites from the peritoneal cavity to the systemic circulation
can be performed in patients not candidates for TIPS or transplant
carries risk of occlusion, infection, and bleeding
definitive treatment for refractory cases is liver transplant
Portal vein thrombosis
extent of clot should be assessed with MRI
when thrombus involves the main portal vein or is progressing into the mesenteric vein, intestinal ischemia/infarction may occur and anticoagulation should be initiated
lovenox and coumadin preferred
not enough evidence to support use of DOACs
Hepatic hydrothorax
should NOT be treated with chest tube
can lead to hemodynamic, renal, and electrolyte abnormalities
oral diuretics and repeated thoracentesis may only be transiently effective with refractory hydrothorax
TIPS should be considered in refractory cases
definitive treatment for refractory cases is liver transplant
Spontaneous bacterial peritonitis (SBP)
all patients with cirrhosis and ascites who are hospitalized should undergo diagnostic paracentesis
Diagnosis with ascites neutrophil count (not total WBC count) >250/mm^3
bacteria are isolated from ascitic fluid in only 40-50% of cases
SBP is mostly a monobacterial infection
patients with SBP are at high risk for developing AKI, which is associated with poor survival
treat with IV antibiotics and albumin
give albumin 1.5g/kg of body weight on day one and 1 g/kg on day 3
reduces incidence of AKI and improves survival in patients with SBP
give IV ceftriaxone or cefotaxime
probability of SBP recurrence is ~70% at 1 yr
Short term antibiotic prophylaxis limited to 7 d in the case of GI bleed
Long term antibiotic prophylaxis if...
recovered from a prior episode of SBP
prophylaxis until ascites resolved
ascites total protein <1.5 g/dL and at least one of the following...
Child-Pugh ≥9 with serum bilirubin ≥ 3 mg/dL
Cr ≥ 1.2 mg/dL
BUN ≥ 25 mg/dL
Na ≤ 130 mg/dL
Risk of C diff colitis with long term antibiotic prophylaxis
PPI use associated with increased risk of SBP in cirrhotic patients, only use for clear indications
Hepatic encephalopathy (HE)
usually precipitant-induced in >80% of cases by...
dehydration
over diuresis
infection
GI bleed
constipation
use of narcotics and sedatives
may also be caused by PVT, HCC
identify and treat precipitant
blood ammonia level will not help in the diagnosis or management
lactulose
titrate to goal 2-3 soft, formed bowel movements per day
add rifaximin for recurrent or persistent hepatic encephalopathy
zinc can be used if there is documented deficiency (not first line for recurrent HE)
L-ornithine L-acetate decreases ammonia levels and improves psychometric testing (not first line for recurrent HE)
Acute kidney injury (AKI)
discontinue diuretics and lactulose
obtain cultures and diagnostic paracentesis for SBP
May be caused by...
pre-renal (albumin responsive) azotemia
ATN
hepatorenal syndrome (HRS)
volume expansion with albumin
initiate midodrine and octreotide for HRS if does not improve with trial of albumin and other etiologies are ruled out
Hepatopulmonary syndrome
treatment options are limited
MELD exception points granted in advanced cases with PaO2 < 60 mmHg
oxygen management after transplant may be challenging but oxygen requirements typically improve slowly after OLT
HCC
determine if falls within Milan criteria
presence of portal hypertension (may be suggested by thrombocytopenia in a well compensated cirrhotic) may argue against surgical resection
in this case proceed with ablative therapy as a bridge to transplant and to prevent progression of tumor
single tumors (<2.5 cm) that are favorably located may be equally well treated by either resection or ablation
screen for HCC
AFP and abdominal ultrasound every 6 mo
if a mass is noted proceed with triple phase CT or MRI to confirm diagnosis
enhances on arterial phase and washes out on delayed images with rim visible
routine biopsy is not recommended given risk of
bleeding
tumor seeding
possible false negative due to sampling error
screen for varices
EGD at diagnosis of cirrhosis
repeat EGD every 2-3 years if there is no evidence of decompensation
repeat EGD at first episode of decompensation
MELD exception points are given for...
HCC
hepatopulmonary syndrome
qualifies for exception points when paO2 is < 60 mmHg with normal CXR and spirometry
portopulmonary hypertension
certain inherited and metabolic liver diseases such as
hereditary hypercholesterolemia
hyperoxaluria
familial amyloid polyneuropathy
polycystic liver disease
Portopulmonary hypertension
mild POPH with mean pulmonary arterial pressure (MPAP) <35 mmHg is not of major concern
moderate (MPAP ≥ 35 mmHg) and severe POPH (MPAP ≥ 45 mmHg) are predictors of increased mortality following liver transplant
mortality is 100% with MPAP > 50 mmHg
if MPAP can be reduced with vasodilator therapy to < 35 mmHg and pulmonary vascular resistance less than 400 dynes.s.cm-5, transplant is possible
advanced HCC with vascular invasion
AIDS (not HIV infection) is a contraindication for transplant
most common early post-transplant complications
acute cellular rejection
hepatic artery thrombosis
biliary stricture
Recurrent HCV
universal for those transplanted with a detectable viral load prior to transplant
clinical course is variable but progression of liver damage and fibrosis appears accelerated
treatment post transplant can be curative in up to 96-98% of patients on immunosuppression
differentiate recurrent HCV from acute cellular rejection with liver biopsy
central endotheliitis is more consistent with acute cellular rejection
lobular hepatitis is more consistent with recurrent HCV
Post-transplant malignancy
cumulative incidence of de novo cancer increases form 3-5% at 1-3 yrs to 11-20% at 10 yr post-transplant
squamous cell carcinoma and basal cell carcinoma of the skin are the most common form in solid organ transplants
cigarette smokers are at increased risk of long cancer and oropharyngeal cancer
colon cancer is increased in those undergoing transplant for PSC if they have concomitant IBD
risk of prostate cancer does NOT increase after liver transplant
Pregnancy post-transplant
liver transplantation restores sexual function and fertility as early as a few months after transplant
pregnancy outcomes for mother an infant post-transplant are generally good, but risk is increased for
preterm delivery
hypertension/preeclampsia
fetal growth restriction
gestational diabetes
risk of congenital anomalies and live birth rate are comparable to the general population
PCP
Bactrim
CMV
valganciclovir
HSV
fluconazole
Tacrolimus
2 mo post-transplant: goal level ~10 ng/mL
8 mo post-transplant: goal level 5-7 ng/mL
Mycophenolate mofetil
liver dysfunction due to insufficient functional liver mass
post-operative coagulopathy
severe elevations in AST/ALT
rising INR
acidosis
altered mental status
hypotension
unstable
Abdominal Ultrasound with doppler
hepatic artery without flow visualized
list for re-transplant as Status 1A (highest priority)
avoid anticoagulation
IV heparin dangerous in the setting of immediate post-transplant status and acutely failing allograft
diagnosed on liver biopsy alone
occurs in 20-30% of transplant recipients
under-immunosuppression
low tacrolimus level
Major histologic features
predominantly lymphocytic
mixed inflammatory infiltrate in the portal triad
ductilitis
destructive or nondestructive nonsuppurative cholangitis involving interlobular bile duct epithelium
endotheliits
high dose corticosteroids (first line)
>90% of patients respond to this
fever
leukopenia
anemia
secretory diarrhea
maculopapular rash
leukopenia
anemia
normla LFTs
Versus: acute cellular rejection where LFTs are elevated
can result from recurrent episodes of acute cellular rejection or chronic under-immunosuppression
Liver biopsy
ductopenia
cholestasis
HSV
CMV
multinucleated hepatocytes
intranuclear inclusions
Bilirubin : alkaline phosphatase ration > 2 = suggestive of fulminant Wilson's disease
copper level takes too long to result
ceruloplasmin is low in half of all patients with acute liver failure regardless of etiology
High transaminases, low bilirubin = suggestive of acetaminophen toxicity or ischemic injury
Autoantibodies should be routinely assessed
serum ammonia < 75 uM = rarely develops intracranial hypertension (ICH)
arterial ammonia >100 uM on admission = independent risk factor for the development of high-grade hepatic encephalopathy
arterial ammonia >200 uM predicts ICH
Intracranial Hypertension
decrease risk of ICH by giving hypertonic saline to raise serum sodium to 145-155 mEq/L
In cases refractory to osmotic agents (e.g., mannitol and hypertonic saline), therapeutic hypothermia (cooling to a core temperature of 32C-34C) may be used to bridge patients to transplantation