Case 1: Fever and abdominal pain with cirrhosis
A 45-year-old man is admitted to the hospital for a 2-day history of fever and abdominal pain. His medical history is notable for cirrhosis due to chronic hepatitis C, esophageal varices, ascites, and minimal hepatic encephalopathy. His medications are furosemide, spironolactone, nadolol, lactulose, zinc, vitamin A, and vitamin D.
On physical examination, temperature is 36.5°C (97.7°F), blood pressure is 100/50 mm Hg, pulse rate is 84/min, and respiration rate is 20/min. BMI is 28. Abdominal examination discloses distention consistent with ascites. The abdomen is nontender to palpation.
Laboratory studies show hemoglobin 10 g/dL (100 g/L), leukocyte count 3,500/µL (3.5 × 109/L), platelet count 70,000/µL (70 × 109/L), INR 1.5 (normal range, 0.8-1.2), albumin 2.5 g/dL (25 g/L), alkaline phosphatase 220 units/L, alanine aminotransferase 30 units/L, aspartate aminotransferase 40 units/L, total bilirubin 4 mg/dL (68.4 µmol/L), creatinine 1.8 mg/dL (159 µmol/L). Urinalysis is normal.
Abdominal ultrasound discloses cirrhosis, splenomegaly, and ascites. The portal and hepatic veins are patent, and there is no hydronephrosis. Diagnostic paracentesis discloses a cell count of 2,000/µL with 20% neutrophils, a total protein level of 1 g/dL (10 g/L), and an albumin level of 0.7 g/dL (7 g/L), consistent with spontaneous bacterial peritonitis.
Which of the following is the most appropriate treatment?
B. Cefotaxime and albumin
C. Furosemide and spironolactone
D. Large-volume paracentesis
Case 2: Bacterial peritonitis and creatinine increase
A 60-year-old woman who was hospitalized for spontaneous bacterial peritonitis 4 days ago is now evaluated for an increase in serum creatinine level. Her medical history is notable for cirrhosis due to primary biliary cirrhosis. She also has esophageal varices, ascites, and minimal hepatic encephalopathy. Her medications are furosemide, spironolactone, nadolol, ceftriaxone, and ursodeoxycholic acid. Furosemide, spironolactone, and nadolol were stopped on admission.
On physical examination, temperature is 36.5°C (97.7°F), blood pressure is 100/50 mm Hg, pulse rate is 96/min, and respiration rate is 28/min. BMI is 32. Pulmonary examination discloses crackles at the right lung base. Abdominal examination discloses distention consistent with ascites. The abdomen is nontender to palpation.
Laboratory studies show INR 1.8 (normal range, 0.8-1.2), albumin 2.5 g/dL (25 g/L), alkaline phosphatase 205 units/L, alanine aminotransferase 50 units/L, aspartate aminotransferase 60 units/L, total bilirubin 7 mg/dL (119.7 µmol/L), creatinine 3.0 mg/dL (265 µmol/L)—increased from an initial admission value of 0.9 mg/dL (79.6 µmol/L).
Urinalysis shows 1-3 erythrocytes, no leukocytes, no renal epithelial cells, no hyaline casts and urine sodium <10 mEq/L (10 mmol/L).
Abdominal ultrasound discloses cirrhosis, splenomegaly, and ascites. The portal and hepatic veins are patent. There is no hydronephrosis. Urine output has decreased over the 4 days of her hospitalization.
Which of the following is the most appropriate treatment?
Case 3: Cirrhosis patient with increasing girth
A 75-year-old man is evaluated for a 3-week history of increasing abdominal girth. He has alcoholic liver disease with cirrhosis. He is not a candidate for liver transplantation at this time because of recent alcohol use and medical nonadherence. His only medication is propranolol.
On physical examination, the patient is alert and oriented. Temperature is 36.2°C (97.2°F), blood pressure is 106/58 mm Hg, pulse rate is 58/min, and respiration rate is 16/min. BMI is 20. There are no focal neurologic deficits. There is no asterixis. Abdominal examination reveals shifting abdominal dullness. There is 1+ lower extremity edema.
Laboratory studies show albumin 2.0 g/dL (20 g/L), blood urea nitrogen 8 mg/dL (2.9 mmol/L), serum creatinine 1.6 mg/dL (141 µmol/L), sodium 119 mEq/L (119 mmol/L), potassium 3.6 mEq/L (3.6 mmol/L), chloride 87 mEq/L (87 mmol/L), bicarbonate 21 mEq/L (21 mmol/L), glucose 95 mg/dL (5.3 mmol/L), osmolality 250 mosm/kg H2O.
Urine studies show osmolality 156 mosm/kg H2O (normal range, 300-900 mosm/kg H2O), potassium 5 mEq/L (5 mmol/L) (normal range for men, 11-99 mEq/L [11-99 mmol/L]) and sodium <5 mEq/L (5 mmol/L) (normal range for men, 18-301 mEq/L [18-301 mmol/L]).
A diagnostic paracentesis reveals findings consistent with transudative ascites; the ascitic fluid absolute neutrophil count is 50/µL.
Which of the following is the most appropriate management for this patient's hyponatremia?
A. 3% saline
D. Fluid restriction
Case 4: Variceal bleeding and alkalosis
A 42-year-old man hospitalized for recurrent variceal bleeding is evaluated 48 hours after admission for severe metabolic alkalosis. He has a 4-year history of alcoholic cirrhosis. He received endoscopic therapy for the varices. In the first 24 hours following admission, he required six units of packed red blood cells and four units of fresh frozen platelets to maintain hemodynamic stability. Today he feels confused but otherwise reports no symptoms. Medications are nadolol, octreotide, and intravenous ciprofloxacin.
On physical examination, temperature is normal, blood pressure is 100/70 mm Hg, and pulse rate is 96/min. BMI is 20. Cardiopulmonary examination is normal. Ascites is noted. There is 2+ presacral edema and 2+ leg edema.
Laboratory studies, on hospital admission and on day 2:
- Serum creatinine: 1.2 mg/dL (106 µmol/L) [admission]
- Sodium: 138 mEq/L (138 mmol/L) [admission] 136 mEq/L (136 mmol/L) [day 2]
- Potassium: 3.8 mEq/L (3.8 mmol/L) [admission] 5.0 mEq/L (5.0 mmol/L) [day 2]
- Chloride: 105 mEq/L (105 mmol/L) [admission] 85 mEq/L (85 mmol/L) [day 2]
- Bicarbonate: 21 mEq/L (21 mmol/L) [admission] 38 mEq/L (38 mmol/L) [day 2]
- Urine chloride: <5 mEq/L (5 mmol/L) [day 2]
Arterial blood gas studies on ambient air on day 2 show pH 7.52 and PCO2 48 mm Hg (6.4 kPa).
Which of the following is the most appropriate management?
A. Add acetazolamide
B. Add furosemide
C. Add isotonic saline
D. Discontinue octreotide
Case 5: ED patient with abdominal pain, ascites, hepatomegaly
A 35-year-old woman is evaluated in the emergency department for a 2-week history of abdominal pain, increased abdominal girth, and peripheral edema. Medical history is noncontributory.
On physical examination, temperature is normal, blood pressure is 120/65 mm Hg, pulse rate is 55/min, and respiration rate is 22. Marked scleral and mucosal icterus is present. Cardiopulmonary examination discloses normal heart sounds without murmur and symmetric breath sounds. She has 3+ pitting edema of the lower extremities to the midthigh. Hepatomegaly and ascites are noted on abdominal examination.
Laboratory studies show hematocrit 37%, hemoglobin 12.5 g/dL (125 g/L), leukocyte count 10,000/µL (10 × 109/L), mean corpuscular volume 72 fL, platelet count 1,095,000/µL (1,095 × 109/L), albumin 1.5 g/dL (15 g/L), total bilirubin 6.0 mg/dL (102.6 µmol/L), alkaline phosphatase 300 units/L, alanine aminotransferase 550 units/L, aspartate aminotransferase 600 units/L. Urinalysis is normal.
Doppler ultrasound of the abdomen shows occlusion of the hepatic veins.
Which of the following is the most appropriate next step in the evaluation of this patient?
A. Antiphospholipid antibody assay
B. Antithrombin activity assay
C. Flow cytometry for paroxysmal nocturnal hemoglobinuria
D. JAK2 V617F mutational analysis
E. Protein C activity assay
Answers and commentary
Correct answer: B. Cefotaxime and albumin.
The most appropriate treatment is cefotaxime and albumin. The diagnosis of spontaneous bacterial peritonitis (SBP) is made in the setting of a positive ascitic fluid bacterial culture and/or an elevated ascitic fluid absolute polymorphonuclear (PMN) cell count (250/microliter) without evidence of secondary causes of peritonitis. Patients with negative cultures have the same clinical presentation and outcomes compared with those with positive cultures.
Intravenous cefotaxime or a similar third-generation cephalosporin is the treatment of choice for SBP. Three of the most common isolates are Escherichia coli, Klebsiella pneumoniae, and pneumococci. Oral fluoroquinolone treatment may be indicated in ambulatory patients with stable hepatic and kidney function and ascitic fluid absolute PMN cell count of 250/microliter or greater. While a significant number of hospitalized patients with SBP recover, it has been shown that kidney failure associated with SBP increases the risk for mortality. The use of cefotaxime plus intravenous albumin at 1.5 g/kg on admission and 1 g/kg on day 3 has been shown to decrease in-hospital mortality by 20% in patients with serum creatinine values of 1.5 mg/dL (133 micromoles/L) or greater, as in this patient. Patients with advanced liver disease, including those with a serum total bilirubin of 4 mg/dL (68.4 micromoles/L) or greater, as seen in this patient, also benefit from intravenous albumin to prevent kidney failure associated with SBP.
The use of cefotaxime alone in this patient is not appropriate, because the risk for progressive kidney dysfunction could still exist in the absence of intravenous albumin.
Oral diuretics such as furosemide and spironolactone should be withheld in patients with ascites and SBP to minimize the risk of worsening kidney function.
There is no evidence that large-volume paracentesis improves outcomes in patients with SBP; in fact, it may worsen kidney function owing to excessive fluid shifts.
- In patients with spontaneous bacterial peritonitis, the concomitant use of intravenous albumin with antibiotic therapy is associated with a survival benefit compared with antibiotic therapy alone.
Correct answer: A. Albumin.
The most appropriate treatment is intravenous albumin. Hepatorenal syndrome (HRS) occurs primarily in the setting of spontaneous bacterial peritonitis. Type 1 HRS is typically defined by at least a doubling of the initial serum creatinine to greater than 2.5 mg/dL (221 micromoles/L) in less than 2 weeks. Type 2 HRS is not as rapidly progressive but is a common cause of death in patients with refractory ascites. The major criteria for the diagnosis of HRS include cirrhosis with ascites; serum creatinine greater than 1.5 mg/dL (133 micromoles/L); no improvement of serum creatinine (improvement is defined by a decrease to <1.5 mg/dL [133 micromoles/L]) after at least 2 days of diuretic withdrawal and volume expansion with 1.5 L or more of albumin; absence of shock or hypotension; no current or recent treatment with nephrotoxic drugs; and the absence of parenchymal kidney disease (no significant proteinuria [<500 mg/d], hematuria, findings of acute tubular necrosis [pigmented granular casts on urinalysis], or evidence of obstruction on ultrasound). Systemic vasoconstrictor agents are recommended for the initial treatment of type 1 HRS. The most promising agent that reverses type 1 HRS is terlipressin; however, it is not currently available in the United States. The next most promising treatment is intravenous albumin, which has been shown in randomized trials to be associated with improvement in serum creatinine level and urine output in patients with type 1 HRS. Although reports exist supporting the use of octreotide with midodrine and intravenous albumin for type 1 HRS, the uncertain status of midodrine availability potentially eliminates this regimen as a realistic option. Furthermore, there is no evidence demonstrating clinical benefit with octreotide monotherapy.
Studies investigating dopamine or low-dose vasopressin in combination with albumin for the treatment of type 1 HRS have not demonstrated significant clinical benefit.
- In patients with suspected hepatorenal syndrome, volume expansion should be performed with intravenous albumin.
Correct answer: D. Fluid restriction.
At this time, the most appropriate management for this patient's hyponatremia is fluid restriction. The absence of neurologic findings suggests that this patient's hyponatremia is chronic, and rapid correction is therefore not indicated. Asymptomatic hyponatremia in patients with cirrhosis is a poor prognostic marker, and the benefits of correcting hyponatremia in asymptomatic patients who are not candidates for imminent liver transplantation are not clear. Thus, ongoing observation of the serum sodium concentration and mental status while implementing fluid restriction is indicated. Some experts recommend implementing fluid restriction only when the serum sodium level is less than 120 mEq/L (120 mmol/L) or as a component of therapy in patients with neurologic symptoms attributed to hyponatremia.
Hypertonic (3%) saline is only indicated in the presence of neurologic symptoms or for correction of hyponatremia when the serum sodium level is less than 130 mEq/L (130 mmol/L) immediately preceding liver transplantation; however, care should be taken to avoid increasing the serum sodium level above 8 to 10 mEq/L (8-10 mmol/L) per day given the increased risk for osmotic demyelination syndrome.
Conivaptan blocks both the V2 and V1a receptors, the latter of which can decrease blood pressure and increase the risk of variceal bleeding in patients with cirrhosis and is therefore relatively contraindicated in this group.
Demeclocycline can be used to manage asymptomatic hyponatremia due to the syndrome of inappropriate antidiuretic hormone secretion (SIADH). This patient does not have SIADH, as indicated by the presence of edema, ascites, and low urine sodium concentration. Furthermore, demeclocycline exhibits increased nephrotoxicity in those with underlying liver disease and is contraindicated in these patients.
- Fluid restriction is indicated for the management of asymptomatic hyponatremia in patients with cirrhosis when the serum sodium level is less than 120 mEq/L (120 mmol/L) or as a component of therapy in patients with neurologic symptoms attributed to hyponatremia.
Correct answer: A. Add acetazolamide.
The addition of acetazolamide is indicated for this patient with significant metabolic alkalosis and hypervolemia. Metabolism of citrate contained in the blood products administered to this patient resulted in production of excess bicarbonate and metabolic alkalosis. Patients with normal kidney function and renal perfusion ordinarily can excrete excess bicarbonate, and the serum bicarbonate typically only increases by 1 to 2 mEq/L (1-2 mmol/L), even with a very high filtered load of bicarbonate. Decreased renal blood flow in patients with cirrhosis, conversely, impairs kidney bicarbonate excretion because of increased proximal tubular reabsorption of filtered bicarbonate, leading to retention of the increased bicarbonate load and metabolic alkalosis. Acetazolamide promotes bicarbonate excretion and is the best therapeutic option for this patient with hypervolemia because it ameliorates both the metabolic alkalosis and sodium overload.
Furosemide facilitates sodium chloride but not bicarbonate excretion. Although this would result in increased sodium excretion, it might exacerbate the metabolic alkalosis if the patient becomes hypovolemic and develops further compromise of renal perfusion. This would lead to increased tubular bicarbonate reabsorption as well as enhanced bicarbonate generation in the cortical collecting duct.
Isotonic saline is unlikely to correct renal hypoperfusion in patients with cirrhosis and ascites who have underlying renal vasoconstriction and renal sodium avidity and therefore would not promote excretion of the increased bicarbonate load. Most of the infused sodium chloride would be retained because of increased tubular sodium chloride reabsorption, thereby aggravating the ascites and fluid overload.
In patients with active variceal bleeding, splanchnic vasoconstrictors such as octreotide are commonly used as an adjunctive treatment to endoscopic therapy. Infusions are typically continued for 3 to 5 days. Despite widespread use, octreotide is not associated with decreased mortality. This agent is not associated with metabolic alkalosis, and discontinuation of octreotide will not correct this patient's metabolic alkalosis.
- Acetazolamide promotes bicarbonate excretion and can be used to ameliorate metabolic alkalosis in patients with hypervolemia and sodium overload.
Correct answer: D. JAK2 V617F mutational analysis.
JAK2 V617F mutational analysis is the most appropriate next step in the evaluation of this patient. She has Budd-Chiari syndrome, which is characterized by thrombosis of the hepatic veins, upper-quadrant pain, and hepatomegaly, with rapid development of jaundice and ascites. Liver chemistry tests are abnormal, and serum aminotransferases can range from 100 to 200 units/L to more than 600 units/L. An estimated 60% of patients with this syndrome have or eventually will be diagnosed with a myeloproliferative disorder, particularly polycythemia vera (PV) and essential thrombocytosis. The JAK2 V617F gene mutation is present in 97% of patients with PV and in 50% of those with essential thrombocythemia and should be measured in all patients with Budd-Chiari syndrome. Positive findings indicate a myeloproliferative disorder and suggest the need for cytoreductive therapy.
The antiphospholipid syndrome is associated with an increased risk for venous and arterial thromboembolism. Common sites of thrombosis include the calf but may also include the renal and hepatic veins. There is also a strong correlation between this syndrome and pregnancy loss. The antiphospholipid syndrome is not associated with thrombocytosis.
Flow cytometric analysis for GPI-anchored proteins on the surface of erythrocytes or leukocytes is the best choice for diagnosis of paroxysmal nocturnal hemoglobinuria (PNH), which is also associated with Budd-Chiari syndrome but not thrombocytosis. PNH is associated with complement-mediated hemolytic anemia or with the development of aplastic anemia.
Antithrombin deficiency is an autosomal dominant disorder, and protein C deficiency is inherited as an autosomal recessive trait. Deficiencies of protein C and antithrombin lead to an increased risk for venous thromboembolism, usually of the calf, and are not associated with thrombocytosis.
- Fifty percent to 60% of patients with Budd-Chiari syndrome have or eventually will be diagnosed with a myeloproliferative disorder, particularly polycythemia vera and essential thrombocytosis.