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Even before examining Mrs. V, you can see that she has significant bilateral leg edema, a pivotal point in her presentation. Although there are some local diseases that can present with bilateral leg edema, the first step in such patients is always to look for systemic causes. While the history and physical are often not sensitive or specific enough to make a diagnosis, they are a good starting point for organizing the differential. So the first question to ask is, “Does Mrs. V have any signs, symptoms, or risk factors pointing to a cardiac, hepatic, or renal cause of her edema?” The results of this exploration will help rank the differential. Mrs. V’s history of a blood transfusion puts her at risk for chronic hepatitis and cirrhosis, and her vague abdominal complaints raise the possibility of ascites, more commonly seen with cirrhosis than HF or kidney disease. She is certainly at risk for both heart and kidney disease because of her history of hypertension and diabetes. While most patients with HF complain of shortness of breath, some describe only fatigue. Medication should be considered as a cause, since pioglitazone frequently causes edema; hypothyroidism does not cause pitting edema, and so is not likely. Finally, although it is uncommon for obstruction to cause bilateral edema, you should think about ovarian cancer causing malignant ascites and venous obstruction if another cause is not found. Table 17-1 lists the differential diagnosis.
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Always look for systemic causes of edema in patients with bilateral leg edema.
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In general, Mrs. V appears fatigued. Her BP is 100/60 mm Hg, pulse is 92 bpm, and RR is 16 breaths per minute. Sclera are anicteric, jugular venous pressure is normal, and lungs are clear. On cardiac exam, she has a normal S1 and S2, a soft S4, and no S3 or murmurs. Her abdomen is slightly distended, but soft and nontender; there is a fluid wave. Her liver is not enlarged, but the spleen is palpable. Rectal exam shows hemorrhoids and guaiac-negative stool. She has 2+ edema bilaterally.
Is the clinical information sufficient to make a diagnosis? If not, what other information do you need?
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Leading Hypothesis: Cirrhosis
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Textbook Presentation
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Patients with cirrhosis can be asymptomatic or have mild symptoms, such as fatigue. Some patients have the classic manifestations of portal hypertension: ascites, edema, variceal bleeding, encephalopathy, or hypersplenism.
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Etiology
More common causes
Alcohol
Chronic hepatitis B or C
Nonalcoholic fatty liver disease (NAFLD)
Hemochromatosis
Less common causes
Drugs and toxins (isoniazid, methotrexate, amiodarone)
Autoimmune hepatitis
Genetic metabolic diseases (Wilson disease, alpha-1-antitrypsin deficiency, glycogen storage diseases, porphyria)
Infections (schistosomiasis, echinococcosis, brucellosis)
Cardiac
Primary or secondary biliary cirrhosis
The 2 most common causes of cirrhosis in the United States are alcoholic liver disease and chronic hepatitis C.
Pathophysiology
Advanced fibrosis, or cirrhosis, causes architectural distortion of the hepatic vasculature, leading to shunting of the blood coming into the liver via the portal vein directly to the hepatic vein outflow system, which causes
Impaired hepatocyte function due to loss of normal sinusoids
Increased intrahepatic resistance, or portal hypertension
Increased risk of hepatocellular carcinoma related to regenerative activity and DNA damage
Consequences of cirrhosis and portal hypertension include
Formation of portosystemic collaterals (ie, varices)
Splanchnic vasodilation
Renal vasoconstriction and hypoperfusion of the kidneys, causing salt and water retention
Increased cardiac output
Decreased production of albumin and clotting factors
Increased capillary hydrostatic pressure
Edema due to a combination of salt and water retention (increasing hydrostatic pressures) and hypoalbuminemia (decreasing intravascular oncotic pressure)
Prognosis
Median survival from time of diagnosis of compensated cirrhosis is 10–12 years.
Up to 60% of patients progress to decompensated cirrhosis, defined as worsening portal hypertension and decreased hepatic reserve, at 10 years after diagnosis.
Rates of progression are quite variable and are related to the etiology of the cirrhosis, presence of other liver disease, available treatment (such as for chronic hepatitis B and C), and avoidance of hepatic toxins (such as alcohol).
5-year mortality approaches 85% after decompensation if transplantation is not performed.
In patients with cirrhosis but no varices and no ascites, the 1-year mortality rate is 1%.
In those with varices but no ascites, the 1-year mortality rate is 3.4%.
In those with varices and ascites, the 1-year mortality rate is 20%; in those with variceal bleeding and ascites, the 1-year mortality is 57%.
The Childs-Pugh-Turcotte classification of cirrhosis severity predicts prognosis (see Chapter 19, GI Bleeding).
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Evidence-Based Diagnosis
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Cirrhosis is a pathologic diagnosis definitively made only by examining the entire liver at autopsy or after liver transplantation.
The traditional gold standard is percutaneous liver biopsy, although due to sampling error, the sensitivity has been reported to be as low as 70–80%.
The clinical presentation is variable, making clinical diagnosis difficult.
Patients may have physical findings suggestive of chronic liver disease (see below), constitutional symptoms, asymptomatic liver enzyme or radiologic abnormalities, manifestations of portal hypertension (see below), or no symptoms at all. Cirrhosis is sometimes diagnosed at autopsy in patients in whom the disease never manifested.
Physical findings may increase the likelihood that a patient with liver disease has cirrhosis, but rarely rule out cirrhosis (Table 17-2).
Patients who show manifestations of portal hypertension (see below) are assumed to have cirrhosis.
Laboratory tests
A low platelet count in a patient with liver disease increases the probability of cirrhosis.
Platelet count < 110 × 103/mcL: LR+ = 9.8
Platelet count < 160 × 103/mcL: LR+ = 6.3; LR– = 0.29
Albumin < 3.5 g/dL (LR+ = 4.4) and a prolonged international normalized ratio (INR) (LR+ = 5.0) also increase the likelihood of cirrhosis.
The Bonacini cirrhosis discriminant score combines the alanine aminotransferase:aspartate aminotransferase (ALT:AST) ratio, the platelet count, and the INR into a score from 0–11; scores > 7 increase the likelihood of cirrhosis (LR+ = 9.4).
Several noninvasive models and techniques (FibroSURE, FibroScan) have been developed to predict cirrhosis in patients with chronic hepatitis C, although they are not currently used in place of biopsy.
FibroSURE includes the biomarkers alpha-2 macroglobulin, haptoglobin, gamma-glutamyl transpeptidase, apolipoprotein A1, ALT, and total bilirubin.
Correlates well with liver biopsy
Useful for distinguishing mild fibrosis from cirrhosis, but less accurate in identifying moderate fibrosis.
FibroScan is an imaging method that measures liver stiffness, which correlates with cirrhosis.
For predicting cirrhosis, the sensitivity is 86% and specificity 93% (LR+, 12.2; LR–, 0.15).
Less accurate in identifying moderate fibrosis (sensitivity 64%, specificity 87%; LR+, 4.9; LR–, 0.41)
Test characteristics of ultrasound to diagnose cirrhosis are variable (LR+, 2.5–11.6; LR−, 0.13–0.73).
MRI has sensitivity and specificity as high as 93% and 82%, respectively.
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Once it has been determined that the patient probably or definitively has cirrhosis, it is important to determine the specific cause of the cirrhosis (see Chapter 26, Jaundice & Abnormal Liver Enzymes) and to determine whether the patient has manifestations of portal hypertension: variceal bleeding, ascites, hepatic encephalopathy, and hypersplenism. The treatment of cirrhosis depends on the underlying cause. Treatments for selected causes of cirrhosis are discussed in Chapter 26, Jaundice & Abnormal Liver Enzymes.
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Manifestations of Portal Hypertension
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See Chapter 19, GI Bleeding.
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Textbook Presentation
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The patient complains of an inability to fasten her pants due to increasing abdominal girth, sometimes accompanied by dyspnea and edema.
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Epidemiology
Over 10 years, ascites develops in 50% of patients with cirrhosis.
1-year survival rates drop significantly once ascites develops.
Pathophysiology: Portal hypertension → arterial vasodilation of the splanchnic circulation → reduction in systemic vascular resistance → underfilling of arterial circulation → sodium and free water retention by the kidneys; also reduced glomerular filtration rate (GFR) → increased capillary permeability and lymph formation in the splanchnic organs.
Complications of ascites
Respiratory compromise due to compression of lung volumes
Hepatorenal syndrome (HRS): a syndrome of acute kidney injury associated with cirrhosis and a poor prognosis. The acute kidney injury may be acute (type 1) or subacute (type 2).
Diagnostic criteria
(1) Cirrhosis with ascites
(2) Serum creatinine > 1.5 mg/dL
(3) Serum creatinine stays above 1.5 mg/dL after at least 2 days of diuretic withdrawal and volume expansion with albumin.
(4) Absence of shock
(5) No current or recent treatment with nephrotoxic drugs
(6) Absence of parenchymal kidney disease (< 500 mg/dayof proteinuria, < 50 RBC/hpf, abnormalities on renal ultrasound)
Clinical phases (Table 17-3)
Incidence in patients with cirrhosis and ascites is 18% at 1 year and 39% at 5 years.
The prognosis is poor: 6-month mortality is about 50% for patients with type 2 HRS and 100% for those with type 1.
Precipitants of type 1 HRS include bacterial infections (especially spontaneous bacterial peritonitis), GI bleeding, acute hepatitis, over-diuresis, and large volume paracentesis.
Treatment of HRS
(1) Liver transplantation is the definitive treatment for both types of HRS.
(2) There are limited data regarding the use of transvenous intrahepatic portosystemic shunts (TIPS) and vasopressin derivatives to treat type 1 HRS.
Spontaneous bacterial peritonitis (SBP)
Prevalence of 10–30% in hospitalized cirrhotic patients, with 1-year recurrence rate of 70% and mortality rate of about 20%; 96% of patients with SBP have a Childs-Pugh-Turcotte grade of B or C
Overgrowth of intestinal bacterial and increased intestinal permeability lead to movement of bacteria into mesenteric lymph nodes; the bacteria can then enter the systemic circulation and colonize the ascitic fluid.
The 3 most common isolates are Escherichia coli, Klebsiella pneumoniae, and pneumococci.
Symptoms include fever (50–75% of patients), abdominal pain (27–72%), chills (16–29%), nausea/vomiting (8–21%), mental status changes (up to 50%), and decreased renal function (33%); about 13% of patients are asymptomatic.
Risk factors for SBP include ascitic fluid total protein level ≤ 1 g/dL, upper GI bleeding, a prior episode of SBP.
Diagnosis of SBP
(1) Criteria for performing a diagnostic paracentesis in patients with cirrhosis and ascites:
(a) Admission to the hospital for any reason
(b) Change in clinical status (fever, abdominal pain, mental status changes, ileus, septic shock)
(c) Development of leukocytosis, acidosis, or acute kidney injury
(d) Active GI bleeding
(2) Always inoculate blood culture tubes with ascitic fluid at the bedside to maximize yield of fluid cultures.
(3) Interpretation of ascitic fluid cell counts and cultures (Table 17-4)
Consider secondary peritonitis if more than 1 organism is cultured from the ascitic fluid.
(4) Other ascitic fluid findings that increase the likelihood of SBP include WBC count > 1000 cells/mcL (LR+ = 9.1), pH < 7.35 (LR+ = 9.0), and blood-ascitic fluid pH gradient ≥ 0.1 (LR+ = 11).
Treatment of SBP
(1) Empiric treatment should be started prior to return of culture results.
(2) IV cefotaxime is the best-studied antibiotic for SBP; oral ofloxacin can be used in outpatients without signs of sepsis or hepatic encephalopathy.
(3) IV albumin has been shown to reduce mortality and development of renal impairment, particularly in patients with a total bilirubin > 4 mg/dL, BUN > 30 mg/dL, or creatinine > 1 mg/dL.
(4) All patients who recover from SBP should receive secondary prophylaxis with oral norfloxacin, and all patients with acute GI bleeding should receive prophylaxis; other primary prophylaxis is controversial.
(5) Since 2-year survival after SBP is only about 30%, liver transplantation should be considered in patients who recover from SBP.
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Evidence-Based Diagnosis
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Physical exam: See Chapter 26, Jaundice & Abnormal Liver Enzymes
Peritoneal fluid analysis should be done in all patients with new ascites.
Initial tests should include cell count, albumin, total protein, and culture.
Serum-ascites albumin gradient is used to distinguish ascites due to portal hypertension from ascites due to other causes.
In portal hypertension, ascites occurs due to transudation, without changes in permeability that would allow albumin to leak into the ascitic fluid.
Therefore, the albumin content of ascitic fluid is low relative to serum.
This is in contrast to exudative types of ascites, such as ascites from infection or malignancy, in which albumin can leak into the ascitic fluid.
A serum ascites-albumin gradient (serum albumin-ascitic fluid albumin) of ≥ 1.1 mg/dL has a LR+ of 4.6 for the diagnosis of ascites due to portal hypertension; a serum ascites-albumin gradient of < 1.1 mg/dL has a LR− of 0.06 for the diagnosis of portal hypertension.
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Sodium restriction (sodium intake < 2 g/day) is commonly recommended, but there are no clinical trials showing that it leads to improved outcomes; fluid restriction of 1000–1500 mL/day is recommended if the serum sodium is < 130 mEq/L.
Spironolactone is the diuretic of choice to treat the aldosterone driven salt and water retention seen in cirrhosis.
75% of patients respond
Furosemide or other loop diuretics can be added in patients who do not respond to spironolactone alone; 90% of patients respond to sodium-restricted diets, spironolactone, and loop diuretics.
Hydrochlorothiazide and metolazone are not recommended.
In order to avoid hypovolemia and renal impairment, the rate of weight loss should not exceed 0.5 kg/day in the absence of peripheral edema or 1 kg/day in the presence of edema.
Aspirin and NSAIDs blunt the natriuretic effect of diuretics and should not be used in patients with ascites.
Large volume paracentesis with volume expansion (dextran or albumin) is done in patients unresponsive to diuretics.
TIPS
Creates a shunt between the high-pressure portal vein and the low-pressure hepatic vein, leading to improved hemodynamics and a decrease in ascites.
Complications include bleeding, shunt stenosis or thrombosis, right-sided HF, and encephalopathy in 30% of patients.
Used as a bridge to transplant
Liver transplantation
When should ascites be treated with measures beyond sodium restriction?
Not in grade 1 ascites (detectable only by ultrasound)
Grade 2 (moderate) and grade 3 (severe) ascites are generally treated due to patient discomfort and respiratory compromise.
Grade 2 should be treated with diuretics.
Grade 3 should be treated with paracentesis followed by diuretics.
Refractory ascites (ascites not responsive to maximal tolerated medical therapy) should be treated with repeated paracentesis or TIPS, or both.
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3. Hepatic Encephalopathy
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Textbook Presentation
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The classic presentation of hepatic encephalopathy is a patient with known cirrhosis who has mental status changes or is in a coma.
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A spectrum of reversible neuropsychiatric abnormalities seen in patients with cirrhosis
Must exclude other neurologic or metabolic causes prior to diagnosing hepatic encephalopathy
Overt hepatic encephalopathy (Table 17-5, grades 1–4) is found in 30–45% of patients with cirrhosis.
Minimal hepatic encephalopathy (deficits manifested only on neuropsychological testing) is found in 60% of patients with cirrhosis.
Patients with severe hepatic encephalopathy requiring hospitalization have a 1-year survival rate of < 50%.
Can be precipitated by a wide variety of insults including
Increased ammonia production due to
Excess dietary protein
Constipation
GI bleeding
Infection
Azotemia
Hypokalemia
Systemic alkalosis
Reduced metabolism of toxins because of hepatic hypoxia due to
Dehydration
Arterial hypotension
Anemia
Increased central nervous depressant effect with use of benzodiazepines or other psychoactive drugs
Reduced metabolism of toxins because diversion of portal blood, due to surgical or intrahepatic shunts
Always look for the underlying cause of worsening hepatic encephalopathy.
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Evidence-Based Diagnosis
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There is some correlation between the degree of elevation of ammonia (either arterial or venous) and the severity of the encephalopathy, but the ammonia level cannot be used to determine the presence or absence of hepatic encephalopathy.
Diagnosis is based on history and exclusion of other causes of encephalopathy in a patient with significant liver dysfunction.
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Identify and treat precipitating causes
Patients with an episode of overt hepatic encephalopathy should be treated indefinitely; the approach to minimal hepatic encephalopathy is evolving.
Treatment focuses on reduction of intestinal accumulation of ammonia.
Lactulose removes both dietary and endogenous sources of ammonia through its cathartic action; it also lowers pH, which reduces the population of urease-producing bacteria, and traps ammonia as ammonium ions in the gut lumen.
Frequently used in clinical practice, although most studies showing an improvement in encephalopathy are of poor quality.
Daily dose should be titrated to result in 2–4 soft stools/day.
Complications include hypovolemia and hypernatremia.
Antibiotics reduce the population of urease-producing bacteria.
Rifaximin may be superior to lactulose for overt hepatic encephalopathy and has been shown to improve cognitive status in patients with minimal hepatic encephalopathy.
Neomycin is equivalent to lactulose but has the potential to cause ototoxicity and nephrotoxicity with long-term use.
Consideration of liver transplantation is indicated in patients with hepatic encephalopathy.
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Textbook Presentation
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Cytopenias are found on routine blood testing in a patient with cirrhosis.
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Splenomegaly is found in 36–92% of patients with cirrhosis; 11–55% have the clinical syndrome of hypersplenism, defined as the presence of leukopenia or thrombocytopenia (or both) with splenomegaly.
There is a rough correlation between spleen size and degree of decrease in blood cells.
Blood cell abnormalities in liver disease
Thrombocytopenia is due to platelet sequestration in the spleen, impaired bone marrow production, and decreased platelet survival.
Leukopenia is due to sequestration in the spleen and is rare compared with thrombocytopenia (1 series found 64% of cirrhotic patients had thrombocytopenia, but only 5% had leukopenia).
Although not part of the syndrome of hypersplenism, anemia often occurs in patients with cirrhosis and is due to increased destruction in the spleen as well as iron or folate deficiency; there is also reduced erythropoietin production.
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Evidence-Based Diagnosis
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Hypersplenism is a clinical syndrome without a specific set of diagnostic criteria.
Hypersplenism is manifested by splenomegaly and a significant reduction in 1 or more cellular elements of the blood, in the presence of normal or hypercellular bone marrow.
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Treatment is usually not necessary.
Splenectomy or partial splenic embolization is sometimes done for severe thrombocytopenia with bleeding complications.
Granulocyte-macrophage colony-stimulating factor and erythropoietin are rarely used.
TIPS does not correct thrombocytopenia.