The following cases and commentary, which focus on the liver, are excerpted from ACP's Medical Knowledge Self-Assessment Program (MKSAP 18).
Case 1: New-onset ascites in patient with hepatitis C
A 55-year-old man is evaluated in the hospital for new-onset ascites. He has a history of cirrhosis due to hepatitis C viral infection. His only medication is propranolol.
On physical examination, pulse rate is 58/min; other vital signs are normal. The abdomen is soft and distended consistent with ascites.
Laboratory studies show a serum albumin level of 2.5 g/dL (25 g/L), serum total bilirubin level of 3.6 mg/dL (61.6 µmol/L), and serum creatinine level of 1.4 mg/dL (123.8 µmol/L).
Paracentesis with analysis of ascitic fluid shows a leukocyte count of 200/µL with 30% neutrophils, albumin level of 0.4 g/dL (4 g/L), and total protein level of 0.9 g/dL (9 g/L).
Which of the following is the most appropriate next step in management?
A. Increase propranolol therapy
B. Initiate albumin infusion
C. Initiate ciprofloxacin therapy
D. Initiate lisinopril therapy
Case 2: Confusion, coagulopathy, and jaundice
A 30-year-old man is evaluated in the emergency department for the recent onset of confusion and jaundice of 6 weeks' duration. His medical history is unremarkable.
On physical examination, the patient is confused. His temperature is 36.9 °C (98.4 °F), blood pressure is 102/60 mm Hg, pulse rate is 115/min, and respiration rate is 22/min. Jaundice and asterixis are noted. No organomegaly is noted.
Laboratory studies show hematocrit 38%, leukocyte count 11,000/μL (11 × 109/L), platelet count 350,000/μL (350 × 109/L), INR 2.6, alanine aminotransferase 200 U/L, aspartate aminotransferase 150 U/L, total bilirubin 18.6 mg/dL (318.1 µmol/L), and creatinine 3.0 mg/dL (265.2 µmol/L).
On abdominal ultrasound, the liver appears normal with intact vasculature. No splenomegaly or dilation of bile ducts is noted.
Which of the following is the most appropriate next step in management?
A. Administer fresh frozen plasma
B. Initiate hemodialysis
C. Perform endoscopic retrograde cholangiopancreatography
D. Refer for liver transplantation
Case 3: History of cirrhosis
A 56-year-old man is evaluated in the emergency department for altered mental status of 18 hours' duration. He has a history of cirrhosis due to hepatitis C viral infection and also has anxiety. He has not changed his diet recently, and he has no symptoms suggestive of gastrointestinal bleeding. His bowel movements have been regular and unchanged. His only medication is alprazolam started 2 weeks earlier, after a visit to an urgent care center.
On physical examination, vital signs are normal. Oxygen saturation is 96% breathing ambient air. Abdominal examination is unremarkable; there is no evidence of ascites. Psychomotor slowing and asterixis are noted. There are no focal neurologic findings. The remainder of the examination is unremarkable.
Complete blood count, serum electrolytes and creatinine, and blood glucose are normal.
In addition to starting lactulose, which of the following is the most appropriate next step in management?
A. CT of the head
B. Initiate a protein-restricted diet
C. Initiate rifaximin
D. Withdraw alprazolam
Case 4: Increased urine output
A 61-year-old woman is evaluated in the hospital for abdominal discomfort and worsening ascites. She reports a significant decrease in urine output over the preceding 3 days. She has a history of cirrhosis due to primary biliary cholangitis. Her medications are furosemide and spironolactone.
On physical examination, blood pressure is 90/58 mm Hg; other vital signs are normal. The abdomen is distended with a positive fluid wave.
Laboratory studies show a serum creatinine level of 2.8 mg/dL (247.5 µmol/L) (3 weeks ago, 1.2 mg/dL [106.1 µmol/L]) and a serum sodium level of 133 mEq/L (133 mmol/L).
Urine studies show a sodium level of less than 10 mEq/L (10 mmol/L) and no protein, leukocytes, erythrocytes, or casts.
Analysis of ascitic fluid shows a leukocyte count of 180/μL with 30% neutrophils. Cultures of ascitic fluid are negative.
A kidney ultrasound shows no evidence of obstruction or kidney parenchymal disease.
Which of the following is the most likely diagnosis?
A. Acute interstitial nephritis
B. Acute tubular necrosis
C. Hepatorenal syndrome
D. Membranous glomerulonephritis
Case 5: Recent treatment for ascites
A 55-year-old man is evaluated for ascites. He recently went to the emergency department, where paracentesis was performed. He was then discharged for outpatient follow-up. He has a history of cirrhosis due to nonalcoholic steatohepatitis and also has hypertension. Endoscopy 3 months earlier showed small varices without stigmata, making prophylaxis for esophageal variceal bleeding unnecessary. His only medication is lisinopril.
On physical examination, vital signs are normal; BMI is 28. Abdominal examination shows abdominal distention without tenderness.
Laboratory studies of the ascitic fluid show a leukocyte count of 80/µL with 20% neutrophils and protein level of 1.6 g/dL (16 g/L). Serum studies show a creatinine level of 1.3 mg/dL (114.9 µmol/L) and sodium level of 134 mEq/L (134 mmol/L).
An abdominal ultrasound from the emergency department shows changes consistent with cirrhosis. The portal vein and hepatic veins are patent with normal flow direction. A moderate amount of free-flowing ascites is seen.
In addition to initiating a sodium-restricted diet, which of the following is the most appropriate next step in management?
A. Discontinue lisinopril
B. Initiate free-water restriction
C. Initiate propranolol
D. Insert an indwelling drain into the peritoneal cavity
Answers and commentary
Correct answer: C. Initiate ciprofloxacin therapy.
Initiation of indefinite primary prophylaxis with ciprofloxacin is the most appropriate next step in the management of this patient with ascites. Patients with ascites are at risk for developing spontaneous bacterial peritonitis (SBP), a common infection in patients with cirrhosis. SBP has a mortality rate of 20%. Long-term primary antibiotic prophylaxis may reduce mortality in patients at high risk for SBP. Criteria for patients at high risk include an ascitic-fluid total protein level less than 1.5 g/dL (15 g/L) in conjunction with any of the following: serum sodium level less than or equal to 130 mEq/L (130 mmol/L), serum creatinine level greater than or equal to 1.2 mg/dL (106.1 µmol/L), blood urea nitrogen level greater than or equal to 25 mg/dL (8.9 mmol/L), serum bilirubin level greater than or equal to 3 mg/dL (51.3 µmol/L), or Child-Turcotte-Pugh class B or C cirrhosis. Patients who have had a bout of SBP should also receive lifelong antibiotic prophylaxis to reduce the risk for recurrence. In the setting of variceal hemorrhage, a limited 7-day course of antibiotics initiated at the time of bleeding is indicated to prevent infectious complications from intestinal bacterial translocation.
Increasing this patient's propranolol is not indicated because, although β-blocker therapy can reduce the risk for variceal bleeding, the patient already has a pulse rate of less than 60/min. Nonselective β-blockers such as propranolol may be associated with higher transplant-free survival in patients with cirrhosis overall but may decrease transplant-free survival in the first 6 months after SBP or in patients with refractory ascites, and discontinuation should be considered at that time.
Albumin infusion may decrease the frequency of hepatorenal syndrome and improves survival in patients with SBP, but its role in primary prevention of SBP is undefined and its use for primary prevention not recommended.
Systemic blood pressure decreases in patients with decompensated cirrhosis resulting in reductions in renal perfusion and glomerular filtration rate. This leads to elevated levels of vasopressin, angiotensin, and aldosterone. ACE inhibitors, such as lisinopril, and angiotensin receptor blockers impair these compensatory efforts to maintain blood pressure and can worsen kidney perfusion in the setting of ascites due to portal hypertension; therefore, initiating lisinopril is inappropriate in this patient.
- Primary prophylactic antibiotic therapy is indicated for patients at high risk for the development of spontaneous bacterial peritonitis, including patients with very low ascitic-fluid protein levels and those with advanced liver failure.
Correct answer: D. Refer for liver transplantation.
Referral for liver transplantation is the most appropriate choice for this patient with acute liver failure. Acute liver failure is defined by the manifestation of hepatic encephalopathy within 26 weeks of developing symptoms of liver disease. The development of jaundice was this patient's first symptom of liver disease. Within 6 weeks, he developed coagulopathy, with an INR of 2.6, as well as symptoms of hepatic encephalopathy (confusion and asterixis). Liver injury is distinct from acute liver failure and presents with elevated liver test results and/or jaundice in the absence of evidence of liver function failure. The most common causes of acute liver failure are medications, especially acetaminophen, and viral infections, although many cases are due to indeterminate causes. The prompt recognition of acute liver failure is essential due to high rates of mortality. Patients require frequent monitoring for hypoglycemia, hypophosphatemia, acute kidney injury, infections, and progressive hepatic encephalopathy, which can be accompanied by cerebral edema and intracranial hypertension. Liver transplantation improves the survival rate; therefore, referral to a liver transplantation center is essential upon recognition of acute liver failure.
The presence of an elevated INR reflects decreased synthesis of liver-derived clotting factors, and the administration of fresh frozen plasma is not indicated in the absence of demonstrable bleeding or the need for invasive procedures.
Kidney failure is common in the setting of acute liver failure, and many patients require renal replacement therapy, which should be performed in a liver transplant center. Most patients requiring hemodialysis in this setting tolerate continuous renal replacement therapy better than intermittent hemodialysis.
There are several appropriate indications for endoscopic retrograde cholangiopancreatography (ERCP), and one of the most common is the evaluation of biliary obstruction. In these cases, ERCP can both be diagnostic and therapeutic if the obstruction can be removed or bypassed. In this patient, ERCP is not indicated because the ultrasound shows no signs of biliary obstruction.
- Acute liver failure is an indication for immediate referral to a liver transplantation center.
Correct answer: D. Withdraw alprazolam.
Discontinuing alprazolam is the most appropriate next step in the management of this patient. Hepatic encephalopathy is a significant, potentially reversible, complication of cirrhosis, with cognitive impairment ranging from mild personality changes to overt coma. Hepatic encephalopathy is a clinical diagnosis and should be suspected in patients with cirrhosis who have changes in mental status, mood, or behavior. Hepatic encephalopathy can be seen in the setting of acute liver failure as well as cirrhosis. The initial management of hepatic encephalopathy centers on identifying and mitigating a precipitating factor. Up to 80% of patients have a precipitating factor, most commonly infection or gastrointestinal bleeding. Other precipitants include opioids, benzodiazepines, electrolyte abnormalities, hypoglycemia, hypoxia, transjugular intrahepatic portosystemic shunt placement, inappropriate lactulose dosing, and dehydration. In this patient who uses a benzodiazepine, alprazolam therapy should be discontinued and alternative means of managing anxiety must be sought. Tapering is likely unnecessary in this patient because the medication was initiated recently. All patients with overt episodic hepatic encephalopathy should undergo screening for infections, including diagnostic paracentesis when ascites is present.
CT of the head can be a useful study in patients with altered mental status of unknown cause, but in patients with hepatic encephalopathy without a history of head trauma or a focal neurological examination, head CT is unnecessary.
Early concerns regarding dietary protein consumption as a precipitant of hepatic encephalopathy have been largely debunked, and outside of rare circumstances, dietary protein restriction should not be undertaken, even in the setting of acute hepatic encephalopathy. Furthermore, due to the high risk for protein-calorie malnutrition in patients with cirrhosis, dietary protein restriction can result in worsened clinical outcomes.
Lactulose is first-line treatment and should be titrated to produce three stools per day. Rifaximin is added to lactulose for prevention of recurrent episodes after a second episode of hepatic encephalopathy. Due to its expense, it is not a first-line therapy for hepatic encephalopathy.
- Up to 80% of patients with hepatic encephalopathy have a precipitating factor, most commonly infection or gastrointestinal bleeding.
Correct answer: C. Hepatorenal syndrome.
Hepatorenal syndrome is the most likely diagnosis in this patient. In patients with end-stage liver disease and portal hypertension, hepatorenal syndrome is characterized by the development of oliguric kidney failure, bland urine sediment, and marked sodium retention (edema, ascites, low urinary sodium). Two types of hepatorenal syndrome have been recognized. Type 1 is characterized by acute kidney dysfunction and is usually triggered by a precipitating event such as spontaneous bacterial peritonitis, other infections, gastrointestinal hemorrhage, or a major surgical procedure. Type 2 is more common and is characterized by more slowly progressive kidney failure in patients with refractory ascites.
Type 1 hepatorenal syndrome is characterized by a rise in serum creatinine of at least 0.3 mg/dL (26 μmol/L) and/or ≥50% from baseline within 48 hours with a bland urinalysis and normal findings on renal ultrasonography. It is also supported by a lack of improvement in kidney function after withdrawal of diuretics and two days of volume expansion with intravenous albumin. Often patients with hepatorenal syndrome also have low urine sodium, low fractional excretion of sodium, and oliguria. In addition, patients should have no evidence of shock, no current or recent use of nephrotoxic drugs, and no evidence of renal parenchymal disease (proteinuria less than 0.5 g/day, no microhematuria, and normal renal ultrasound). The main treatment of hepatorenal syndrome is the removal of drugs that may reduce kidney perfusion and volume expansion. Ultimately, hepatorenal syndrome is a condition for which the only cure is liver transplantation.
Acute interstitial nephritis may be associated with drugs, infection, autoimmune diseases, and malignancy. It should be suspected in a patient who presents with an elevated serum creatinine level and urinalysis showing leukocytes, leukocyte casts, and possibly eosinophiluria; urinary sodium level is typically elevated.
Acute tubular necrosis is most commonly caused by ischemia or toxins (including drugs). Urinalysis typically shows pigmented granular (muddy brown) casts and tubular epithelial cells; urinary sodium is typically elevated.
Membranous glomerulonephritis is associated with the nephrotic syndrome (proteinuria, edema, hypertension, microhematuria) and erythrocytes or erythrocyte casts; urinary sodium can be low.
- In patients with end-stage liver disease and portal hypertension, hepatorenal syndrome is characterized by the development of oliguric kidney failure, bland urine sediment, and marked sodium retention (edema, ascites, low urinary sodium).
Correct answer: A. Discontinue lisinopril.
Discontinuing lisinopril is the most appropriate next step in the management of this patient with ascites. Blood pressure falls with worsening cirrhosis, resulting in reduced renal blood flow and glomerular filtration. A compensatory upregulation of the renin-angiotensin system results in increased levels of vasoconstrictors, including vasopressin, angiotensin, and aldosterone, which support systemic blood pressure and kidney function. ACE inhibitors and angiotensin receptor blockers impair the compensatory response to cirrhosis-related hypotension and thereby impair the ability to excrete excess sodium and water and may also affect survival. Medications that decrease kidney perfusion, including NSAIDs, ACE inhibitors such as lisinopril, and angiotensin receptor blockers, should be discontinued because their use often worsens ascites due to portal hypertension. The mainstay of therapy of ascites is to initiate dietary changes, restricting sodium intake to less than 2000 mg (87 mEq) daily. If sodium restriction does not result in significant improvement of ascites, the initiation of diuretic therapy with spironolactone with or without furosemide can be effective in increasing urinary sodium excretion.
Free-water restriction can be useful for the management of dilutional hyponatremia that is sometimes seen in patients with advanced liver dysfunction. This patient has a normal serum sodium concentration, so free-water restriction is not indicated.
Propranolol and other nonselective β-blockers are often used prophylactically for the prevention of variceal hemorrhage, but they do not have a role in the management of ascites. Furthermore, in some patients with ascites that is refractory to medical management, β-blockers may worsen clinical outcomes, including survival.
Indwelling drains for ascites have been used for patients with malignant ascites, but in the setting of portal hypertensive ascites, such as seen in this patient, indwelling drains are associated with a high risk for infection and their use is contraindicated.
- Medications that decrease kidney perfusion, including NSAIDs, ACE inhibitors, and angiotensin receptor blockers, should be discontinued in patients with ascites.