A 47-Year-Old Women With Alcoholic Cirrhosis and SOB
A 47-year-old woman is admitted to the hospital secondary to increasing
shortness of breath. The patient has a history of alcoholic cirrhosis (diagnosed
by liver biopsy 3 months ago) with ascites. She states that her abdomen
has increased in size and that her breathing has become increasingly difficult.
She has had mild abdominal discomfort for the last week but denies fever,
nausea, vomiting, hematemesis, melena, or mental status changes. She denies
excess fluid or salt intake and has been compliant with her medications,
which include Lasix and Aldactone. Her social history is significant for
heavy alcohol intake for 15 years. She denies current drug or tobacco use.
Question 1
You are the resident on the floor admitting the patient. The
patient carries a diagnosis of cirrhosis; however, you realize it is important
to review the relationship between alcohol and liver function before examining
the patient.
How does ethanol damage the liver?
Question 2
On physical examination her vital signs reveal a low-grade temperature
and a respiratory rate of 28 breaths/minute. Her sclerae are icteric, and
she has several spider nevi on the chest. She has bibasilar crackles and
bilateral E-A changes. Her abdominal examination reveals tense distension
and shifting dullness. Liver size is difficult to evaluate due to the ascites.
There is mild right upper quadrant tenderness but no peritoneal signs.
There is no peripheral edema, and rectal examination reveals brown stool,
heme negative.
What are the causes and clinical features of cirrhosis?
Question 3
The laboratory data for your patient reveal a mild transaminase
elevation, prothrombin time 16.2 sec, INR 1.9, albumin 1.8 g/dl, total
protein 4.9 g/dl, WBC 13.3 K, plts 78 K, Hgb 10.8 g/dl, electrolytes are
normal, viral hepatitis profile is negative, ammonia 32, total bilirubin
2.2 g/dl, and alkaline phosphatase 167. Arterial blood gas is consistent
with respiratory alkalosis and a PaO2 of 58. Chest x-ray shows small bilateral
pleural effusions with compressive atelectasis but no infiltrates. Abdominal
ultrasound shows a large amount of ascites, irregular liver surface, and
splenomegaly. Upon receiving the above information, you place the patient
on 2 L O2 by nasal cannula and perform a therapeutic abdominal paracentesis.
While waiting for the infusion you try to remember the complications of
cirrhosis.
How much do you know about the complications of cirrhosis? Test your
knowledge.
Question 4
The initial physical examination revealed a protuberant abdomen
with a fluid wave, shifting dullness, and prominent flanks.
With what entity are these physical findings consistent and what
are the associated complications?
Question 5
The next day the medical student on the case comes to you concerned
about the patient. She states that the patient thought that she was in
Mexico and living on a tobacco farm and that the student was actually a
mule used to haul the tobacco.
What is the likely diagnosis leading to such a mental status change?
What is another complication that may lead to renal failure?
Question 6
The large-volume paracentesis was completed without complications,
and the patient tolerated the procedure well. You were able to remove 5
L of fluid that you sent for analysis. The cell count was normal, and the
gram stain was negative. The patient is feeling and breathing much better
and remains very stable for the next 24 hours. You are preparing to discharge
the patient when the medical students ask you about liver transplantation
for this patient.
What are the indications and eligibility criteria for liver transplantation?
Case Follow-Up
The patient was discharged 2 days after paracentesis with resolution
of dyspnea. The patient was referred to a regional transplant center for
evaluation and is currently on the waiting list for orthotopic liver transplantation.
Answers
Question 1 - Alcohol Damage of the Liver
How does ethanol damage the liver?
Alcohol abuse is the most common cause of liver disease in the Western
world. Alcohol exerts its damaging effects by several different cellular
pathways. Ethanol has a direct effect on membrane fluidity, leading to
loss of membrane regulatory control and cell swelling. Another pathway
involves the production of excess acetaldehyde from the metabolism of alcohol.
Acetaldehyde exerts toxic effects on the hepatocyte and is responsible
for a more severe lesion. During alcohol metabolism NADPH is formed, leading
to an elevated redox potential favoring accumulation of hepatic triglycerides.
There are three patterns of alcoholic liver disease. Steatosis (fatty
liver) involves the accumulation of triglycerides in hepatocytes. This
process begins within the first few days of alcohol intake and progresses
with continued intake. This condition is completely reversible if alcohol
intake is discontinued. Clinically it presents as moderate to massive hepatomegaly,
right upper quadrant pain, and mild transaminase elevation. Diagnosis is
confirmed by liver biopsy showing large droplet fat occupying most of the
hepatocyte that resolves upon cessation of drinking.
Alcoholic hepatitis is a more serious pattern and implies acute liver
cell necrosis with an inflammatory reaction. The histologic triad characteristic
of this pattern includes (1) alcoholic hyaline (eosinophilic aggregates)
also known as Mallory bodies, (2) infiltration by inflammatory cells, and
(3) development of a network of intralobular connective tissue. The clinical
presentation of this disease is highly variable, spanning the spectrum
from asymptomatic to hepatic failure. Symptoms may include fever, jaundice,
anorexia, nausea, vomiting, and weight loss. Physical examination reveals
stigmata of liver disease. Laboratory evaluation reveals only mild elevation
of transaminases SGOT:SGPT >2, leucocytosis, prolonged prothrombin time,
and hypoalbuminemia. Diagnosis is confirmed by liver biopsy. The outcome
is unpredictable but return to normal is possible with discontinuation
of alcohol intake. Most commonly, alcoholic hepatitis leads to cirrhosis
and may precipitate hepatic failure and death.
Question 2 - Cirrhosis
What are the causes and clinical features of
cirrhosis?
Cirrhosis is an alteration of the liver architecture and is characterized
by the following: (1) interconnecting fibrous scars, (2) fibrous bands,
(3) parenchymal nodules, and (4) formation of abnormal arteriovenous interconnections.
Cirrhosis has been divided to micronodular and macronodular, but these
are purely descriptive terms. The causes of cirrhosis in descending order
of frequency follow.
Alcoholic cirrhosis (Laennec's cirrhosis) may be a sequela of alcoholic
hepatitis. This type of cirrhosis is micronodular and accounts for close
to 50% to 70% of cirrhosis in the Western world.Chronic hepatitis progresses
to macronodular cirrhosis. The causes of chronic active hepatitis are multiple
and include HBV, HCV, autoimmune injury, toxin exposure, and drug reactions
(isoniazid, amiodarone). Biliary cirrhosis may be either primary or secondary.
Secondary biliary cirrhosis develops after prolonged extrahepatic biliary
tract obstruction that leads to bile retention, inflammation, fibrosis,
and eventual cirrhosis. Inherited metabolic disorders can also lead to
cirrhosis. These include Wilson's disease, alpha-1-antitrypsin deficiency
and hereditary hemochromatosis.
Alpha-1-antitrypsin deficiency (A1AT) is characterized by low levels
of this protease inhibitor resulting in an imbalance favoring activity
of destructive enzymes causing liver and lung injury. Hepatic congestion
secondary to heart failure can cause cirrhosis known as cardiac cirrhosis.
It is an uncommon complication of right heart failure and is mostly associated
with constrictive pericarditis or rheumatic heart disease. Cryptogenic
cirrhosis accounts for 10% of cases. In this circumstance, cirrhosis is
found incidentally or presents as a complication of end-stage liver disease.
The diagnosis is one of exclusion.
The clinical presentation of early cirrhosis is variable. Initially
symptoms include anorexia, weight loss, weakness, and debilitation. Physical
examination reveals a firm, large liver, jaundice, spider angiomas, gynecomastia,
leukonychia, muscle wasting, and testicular atrophy. In the later stages
of cirrhosis complications develop with additional clinical findings, which
will be discussed later. Other physical abnormalities such as Dupuytren's
contracture, xanthomas, Kayser-Fleischer rings, and a bronze discoloration
of the skin are appreciated in specific forms of cirrhosis.
Laboratory evaluation of cirrhosis may reveal elevated bilirubin, mild
transaminase elevation, hypoalbuminemia, and prolonged prothrombin time.
Diagnosis is confirmed by percutaneous liver biopsy, which usually reveals
distortion of hepatic architecture and the presence of nodules and scar
tissue.
Question 3 - Complications of Cirrhosis
How much do you know about the complications
of cirrhosis? Test your knowledge.
The manifestations of cirrhosis are divided into those related to hepatocellular
injury (previously described) and to mechanical factors. The main complication
of cirrhosis is portal hypertension. In the normal liver the resistance
to portal venous flow is very low. However, when the liver architecture
is altered (cirrhosis), resistance increases. This increase in resistance,
along with the increase in portal venous inflow, is the mechanism for the
development of portal hypertension. Cirrhosis is the main cause of this
elevated resistance, but other causes include portal vein occlusion, hepatic
vein occlusion (Budd-Chiari syndrome), veno-occlusive disease (seen after
bone marrow transplant, or chemotherapeutic agents), schistosomiasis, alcoholic
hepatitis, sarcoidosis, and other disorders that alter normal venous architecture.
Varices form because venous blood flows to vasculature of lower resistance.
These include the system connecting the portal vein to the azygos vein,
gastric veins, and hemorrhoidal veins. The increase in flow to this system
leads to varices in the submucosa of the lower esophagus and gastric fundus.
These varices may bleed when the portal pressure is 12 mm Hg above the
inferior vena cava pressure.
Variceal bleeding is the most lethal complication of portal hypertension.
Clinically the varices are silent until rupture, which most commonly presents
with hematemesis but can also present with melena or hematochezia. The
bleeding may be massive with 40% fatality for each episode and 90% chance
of recurrence within 1 year. Diagnosis is made by upper endoscopy. Endoscopy
should focus on the lower esophagus, as well as the fundus of the stomach,
since 10% of patients bleed from gastric varices. Diagnosis depends on
high clinical suspicion in the right patient, presence of hematemesis or
lower GI bleeding, and nasogastric tube recovery of heme-positive material.
Management of variceal bleeding emphasizes restoration of circulating blood
volume and control of the hemorrhage.
Pharmacologic agents used to control the bleeding include vasopressin
and somatostatin. Vasopressin is a hormone derived from the posterior pituitary
that causes vasoconstriction of the splanchnic circulation. NTG should
be administered concurrently to counteract its systemic vasoconstriction
with end-organ ischemia. Other measures used to control bleeding include
balloon tamponade (Sengstaken -Blakemore tube) and endoscopic-injection
sclerotherapy. It is important to remember that balloon tamponade is only
used as a temporary treatment. Emergency shunt surgery is reserved for
variceal bleeding that is refractory to the above measures and is associated
with 25% to 50% mortality.
Management of persistent or recurrent variceal bleeding may involve
use of the transjugular intrahepatic portosystemic stent (TIPS), an experimental
procedure. This stent, placed with the help of fluoroscopic guidance, shunts
venous blood flow from the high resistance portal system to the right hepatic
vein. This intervention reduces the portal venous pressure gradient (usually
to less than 12 mm Hg), reducing intravariceal pressure and preventing
rupture and further bleeding. The main complication of this procedure is
encephalopathy because blood perfuses the central nervous system without
having passed through the liver first. The incidence of encephalopathy
depends on the shunt diameter (smaller shunts, 8 mm, result in decreased
incidence of encephalopathy).
Variceal bleeding is associated with high morbidity and mortality; therefore
prophylactic measures are essential. Prophylactic portosystemic shunts
have been used and decrease the rate of rebleeding, but have not been shown
to alter survival. Propranolol, a beta-adrenergic blocker, reduces mortality
associated with bleeding. This drug has been shown to prevent the first
episode of bleeding and to effect a decreased rate of rebleeding. Propranolol
dosing needs to be sufficient to reduce the resting heart rate by 25%,
which results in decreased variceal wall tension. Patient compliance is
a major concern, since abrupt discontinuation can lead to rebound hypertension
with acute rebleeding.
Question 4 - Ascites
The initial physical examination revealed a
protuberant abdomen with a fluid wave, shifting dullness, and prominent
flanks. With what entity are these physical findings consistent and what
are the associated complications?
Ascites refers to the accumulation of fluid in the peritoneal cavity.
Ascites is appreciated on physical examination by detecting shifting dullness,
bulging flanks, or a fluid wave. Cirrhosis is a common cause of ascites,
but other causes include pancreatitis, a ruptured intraabdominal viscus,
right heart failure, nephrotic syndrome, trauma, and Meigs' syndrome. In
cirrhosis multiple factors lead to ascites, and these include: low albumin
with loss of oncotic force within the vascular and interstitial spaces,
renal retention of sodium and water, and portal hypertension with increased
hepatic lymph production and transudation. Ascites resulting from cirrhosis
is most commonly a transudate with protein content less than 1.1 g/dl.
The diagnosis of ascites needs to be confirmed by ultrasound unless its
presence is unquestionable by physical examination. Other imaging studies
include CT scan and plain view of the abdomen (characteristic ground-glass
appearance).
Management of uncomplicated ascites involves the following steps: (1)
restriction of sodium and water (2 g Na/day and 2000 ml/day water) and
(2) use of diuretics, specifically spironolactone. This is an aldosterone
antagonist that has been proven to be more effective than loop diuretics
because of its independence on blood flow for presentation to the nephron
in patients with cirrhosis/ascites. Aldactone (spironolactone) is started
at a dose of 50 to 100 mg bid and increased to 400 mg daily. If diuresis
is not adequate with the 200 mg/day dose, then furosemide can be added
(usual starting dose 40 mg/day). It is important to remember that spironolactone
prevents the renal excretion of potassium and therefore should not be used
in patients with renal insufficiency.
Ascites that is difficult to control by standard management is divided
into two categories. In the first group, unresponsive ascites, diuretic
use does not result in adequate natriuresis. In this group of patients
the diuretic metolazone (Zaroxolyn) may be cautiously tried because it
acts on the proximal tubule by inhibiting sodium reabsorption. In the second
group, refractory ascites, natriuresis is achieved only in expense of a
reduction in GFR. In this group a 4- to 8-week waiting period is necessary
before labeling the patient refractory. During this waiting period reversible
insults (alcoholic hepatitis, acute tubular necrosis, bacterial peritonitis)
should be resolved before the diagnosis is accepted. Once ascites is confirmed
to be refractory, peritoneovenous shunting should be considered. The LeVeen
shunt is a subcutaneous stent that results in the transfer of fluid from
the peritoneal cavity to the internal jugular vein via a one-way valve.
Large-volume paracentesis can also be used in the management of ascites.
In many studies removal of large fluid volume, 4 to 6 L/day, resulted in
shorter hospital stays and fewer complications than traditional diuretic
therapy. In refractory ascites, large-volume paracentesis is equally as
effective as the LeVeen shunt. One of the potential complications of this
procedure is a decrease in the intravascular volume. It is, therefore,
recommended that during large-volume paracentesis patients receive an intravenous
infusion of albumin at the rate of 10 g/L of fluid removed. Finally, truly
refractory ascites may be an indication for liver transplantation.
Spontaneous bacterial peritonitis (SBP) is an infection of the abdominal
peritoneum and occurs in 10% to 25% of cirrhotic patients. The exact pathogenesis
is unknown. The most likely mechanism involves the hematogenous seeding
of the peritoneal cavity with enteric bacteria (translocation). These organisms
enter the portal venous system via collaterals, avoiding the reticuloendothelial
system of the liver. Another contributing factor is the low level of protein
found in ascitic fluid. This reflects low complement levels (low opsonic
activity), which in turn leads to decreased phagocytosis of bacteria. The
incidence of SBP is higher in patients with ascitic fluid protein levels
below 1.0 g/dl. The most common bacteria responsible are Escherichia coli,
Klebsiella pneumoniae, Streptococcus pneumoniae, alpha-hemolytic streptococci
and group D streptococci. Clinically, patients present with fever and/or
abdominal pain; however, it is important to remember that one third of
patients are completely asymptomatic. Laboratory data usually reveal a
peripheral leukocytosis. Diagnosis is made by obtaining ascitic fluid for
analysis. Direct inoculation of blood culture vials (broth) with 10 ml
of fluid increased culture yield. Patients with suggestive clinical picture
and fluid containing greater than 500 WBC/ml with 50% or higher granulocytes
should be started on antibiotics before culture results confirm the presence
of bacteria. Treatment of SBP involves intravenous administration of antibiotics
astreonam + vancomycin or cefotaxime, with activity versus gram-negative
bacilli. Follow-up examination of the fluid at 48 hours should be done
to verify improvement. Prophylactic therapy for SBP is controversial. One
antibiotic that has proven to decrease the incidence of recurrent SBP is
norfloxacin (400 mg/day). This fluoroquinolone acts by selectively eliminating
gram-negative bacilli from the intestinal flora, which is followed by a
reduction in the rate of SBP.
Question 5 - Hepatic Encephalopathy
What is the likely diagnosis leading to such
a mental status change? What is another complication that may lead to renal
failure?
One of the most difficult complications of cirrhosis is hepatic encephalopathy.
This results from the portosystemic shunting of nitrogenous amines that
can be neurotoxic. Precipitating factors include azotemia, use of sedatives/tranquilizers,
gastrointestinal bleeding, infection, hypokalemic alkalosis, or excess
protein intake. The symptoms and signs of this disease include (1) asterixis,
a flapping motion seen when the patient is asked to hold his arms horizontally
with the hands extended at the wrists, (2) fetor hepaticus, a feculent-fruity
odor of the breath, and (3) mental status changes that vary from mood alterations
to lethargy, confusion, stupor, and finally coma. Ammonia levels may be
elevated but do not correlate with the stage of disease. Hepatic encephalopathy
can be classified in four categories: (1) agitation, (2) lethargy with
asterixis, inappropriate behavior, and slurred speech, (3) stupor with
hyperactive reflexes and nystagmus, and (4) deep coma with dilated pupils
and opisthotonos.
Management of hepatic encephalopathy should emphasize correction of
the precipitating factors. Other therapeutic measures should include temporary
dietary protein restriction and use of lactulose or neomycin. Protein intake
should be limited to 1 g/kg. Lactulose works by reducing intestine intraluminal
pH and promoting diarrhea. The acidic environment created promotes protonation
of ammonia to NH4+, which is not well absorbed and is excreted in stool.
Neomycin is an aminoglycoside antibiotic that decreases urease-producing
bacteria and is as effective as lactulose. The use of neomycin is limited
by attendant side effects of ototoxicity and nephrotoxicity.
The hepatorenal syndrome is another complication of cirrhosis. This
is a potentially fatal complication and is defined by the presence of renal
failure in combination with cirrhosis. This renal failure is characterized
by decrease in GFR, azotemia, and oliguria. The exact pathogenesis is unknown,
but precipitating factors include vigorous diuretic use, large-volume paracentesis
without volume repletion and sepsis. These conditions all lead to decreased
renal blood flow and GFR, both of which might precede overt renal failure.
It is important to rule out prerenal azotemia before settling on the diagnosis
of the hepatorenal syndrome.
Other complications of cirrhosis include gallstones, which form secondary
to an increase in bilirubin from hemolytic anemia and hypersplenism. Peptic
ulcer disease occurs with greater incidence in patients with cirrhosis.
Hypoxia develops secondary to two possible mechanisms. Ascitic fluid may
interfere with diaphragmatic movement, leading to the sensation of dyspnea,
and retarding adequate ventilation. The second mechanism is known as the
hepatopulmonary syndrome. This is due to the formation of abnormal arteriovenous
circuits in the lung, wherein perfusion is position dependent. Changes
of position lead to alterations of ventilation and perfusion leading to
hypoxemeia. Primary liver cell cancer is often seen in cirrhotic livers
and is associated with hepatitis B and C and less commonly with cirrhosis
due to alcohol.
Another manifestation of portal hypertension is splenomegaly, which
results in thrombocytopenia and leukopenia. The decrease in platelets is
clinically significant because of the usual concomitant coagulopathy of
liver disease.
Question 6 - Liver Transplantation
What are the indications and eligibility criteria
for liver transplantation?
Orthotopic liver transplantation (OLT) has become routine therapy for
advanced liver disease. This procedure has improved life expectancy, and
most OLT recipients are able to return to work and have a relatively normal
life. This success is due to improvement in surgical technique, effective
immunosuppressive therapy, and better guidelines regarding indications
for transplantation. The most common indication for adult liver transplantation
is end-stage cirrhosis. In evaluating a cirrhotic patient for liver transplantation,
one should use the Child-Turcotte classification. This classification uses
albumin, bilirubin, control of ascites, degree of encephalopathy, and nutrition
status to determine the patient's clinical condition. Worsening of the
above parameters indicates clinical deterioration resulting in life-threatening
events. Detection of such deterioration by the Child score is important
in confirming candidacy for liver transplantation. Additional clinical
events that may signal the need for transplantation include recurrent SBP,
refractory variceal bleeding, hepatorenal syndrome, symptomatic coagulopathy,
and the nonspecific but debilitating symptoms of fatigue and weakness.
The above events are common to end-stage cirrhosis. Other more specific
events that also signal the need for transplantation are progressive, severe
bone disease, seen in primary biliary cirrhosis and primary sclerosing
cholangitis, and recurrent bacterial cholangitis, often seen in patients
with primary sclerosing cholangitis. The disease-specific indications for
liver transplantation are acute liver failure, cirrhosis from previous
alcohol abuse, cirrhosis from chronic hepatitis C, cryptogenic cirrhosis,
primary biliary cirrhosis, cirrhosis from other viral hepatitis (B and
D), primary sclerosing cholangitis, cirrhosis from autoimmune chronic active
hepatitis, cirrhosis due to alpha-1-antitrypsin deficiency, Budd-Chiari
syndrome, and hepatocellular carcinoma.
It is also important to consider other factors in determining candidacy
for liver transplantation. The most common disease pre-OLT is alcoholic
cirrhosis. Abstinence from alcohol is a requirement before consideration
for liver transplantation. After transplant, patients need to be compliant
with immunosuppressive medications. Patients must be emotionally capable
to handle such a life-long commitment. Family support and adequate resources
are also essential for successful liver transplantation.
Case Follow-Up
The patient was discharged 2 days after paracentesis with resolution
of dyspnea. The patient was referred to a regional transplant center for
evaluation and is currently on the waiting list for orthotopic liver transplantation.
