Cirrhosis

Essentials of Diagnosis

• Result of injury that leads to both fibrosis and regenerating nodules

• May be reversible if cause is removed

• The clinical features result from hepatic cell dysfunction, portosystemic shunting, and portal hypertension

General Considerations

• The most common histologic classification of cirrhosis is micronodular, macronodular, and mixed forms

• Each form may be seen at different stages of the disease

• Risk factors

  • Chronic viral hepatitis

  • Alcohol

  • Drug toxicity

  • Autoimmune and metabolic liver diseases, including nonalcoholic fatty liver disease

  • Miscellaneous disorders

• Gluten enteropathy appears to be associated with an increased risk of cirrhosis

• Many patients have more than one risk factor (eg, chronic hepatitis and alcohol use) and likely a genetic predisposition

• Three clinical stages

  • Compensated

  • Compensated with varices

  • Decompensated (ascites, variceal bleeding, encephalopathy, or jaundice)

• Acute-on-chronic liver failure

  • Should be diagnosed in a patient with chronic cirrhosis and acute decompensation, which is defined as

    • New or worsening ascites

    • Gastrointestinal hemorrhage, including variceal hemorrhage

    • Overt hepatic encephalopathy

    • Worsening nonobstructive jaundice

    • Bacterial infection associated with another organ failure

  • Precipitating factors include

    • Infections

    • Hemodynamic instability

    • Heavy alcohol use

    • Drug hepatotoxicity

Micronodular cirrhosis

• Regenerating nodules are < 1 mm

• Typical of alcoholic liver disease (Laennec cirrhosis)

Macronodular cirrhosis

• Characterized by larger nodules, up to several centimeters in diameter, which may contain central veins

• Corresponds to postnecrotic (posthepatitic) cirrhosis; but may not always follow identifiable episodes of massive necrosis and stromal collapse

Demographics

• Eleventh leading cause of death globally

• Eighth leading cause of death in the United States with a prevalence rate of 0.27%

• Mexican Americans and African Americans have a higher frequency of cirrhosis than whites because of a higher rate of risk factors

Symptoms and Signs

• Can be asymptomatic for long periods

• Symptoms may be insidious or, less often, abrupt

• Fatigue, disturbed sleep, muscle cramps, anorexia, and weight loss are common

• Nausea and occasional vomiting

• Reduced muscle strength and exercise capacity

• Jaundice—usually not an initial sign—is mild at first, increasing in severity

• Abdominal pain from hepatic enlargement and stretching of Glisson capsule or from ascites

• Hematemesis is the presenting symptom in 15–25%

• Fever

  • Present in up to 35%

  • Usually reflects associated alcoholic hepatitis, spontaneous bacterial peritonitis, or intercurrent infection

• Amenorrhea in women

• Erectile dysfunction, loss of libido, sterility, and gynecomastia in men

• In 70% of cases, the liver is enlarged and firm with a palpable sharp or nodular edge; the left lobe may predominate

• Splenomegaly occurs in 35–50%

• Ascites, pleural effusions, peripheral edema, and ecchymoses are late findings

• Relative adrenal insufficiency appears common in advanced cirrhosis, even in absence of sepsis

Encephalopathy

• Characterized by

  • Day–night reversal

  • Asterixis

  • Tremor

  • Dysarthria

  • Delirium

  • Drowsiness

  • Coma

• Occurs late except when precipitated by an acute hepatocellular insult or an episode of gastrointestinal bleeding or infection

Skin

• Spider telangiectasias on the upper half of the body

• Palmar erythema, Dupuytren contractures

• Glossitis and cheilosis from vitamin deficiencies are common

• Dilated superficial veins of the abdomen and thorax that fill from below when compressed

Differential Diagnosis

• Chronic viral hepatitis

• Alcoholism

• Nonalcoholic fatty liver disease

• Cryptogenic cirrhosis

• Hemochromatosis

• Alpha-1-antiprotease deficiency

• Wilson disease

• Gluten enteropathy

• Primary biliary cholangitis

• Secondary biliary cirrhosis

  • Chronic obstruction due to stone, stricture, neoplasm

• Heart failure or constrictive pericarditis

• Hereditary hemorrhagic telangiectasia

Laboratory Tests

• Laboratory abnormalities are either absent or minimal in early or compensated cirrhosis

• Anemia

  • Usually macrocytic, from suppression of erythropoiesis by alcohol, and folate deficiency; normocytic, from hemolysis, acute blood loss from the GI tract; and microcytic, from hypersplenism, chronic blood loss from the GI tract

• White blood cell count

  • May be low, reflecting hypersplenism

  • May be high, suggesting infection

• Thrombocytopenia is secondary to

  • Alcoholic marrow suppression

  • Sepsis

  • Folate deficiency

  • Splenic sequestration

• Prolongation of the prothrombin time from reduced levels of clotting factors

• Modest elevations of serum aspartate aminotransferase (AST) and alkaline phosphatase and progressive elevation of serum bilirubin

• Serum albumin is low

• Gamma-globulin levels are increased and may be as high as in autoimmune hepatitis

• Vitamin D deficiency has been reported in 91% of patients with cirrhosis

• Patients with alcoholic cirrhosis may have elevated serum cardiac troponin I and B-type natriuretic peptide levels

• Combinations of tests (eg, AST and platelet count) are under study for predicting cirrhosis in patients with chronic liver diseases such as chronic hepatitis C

• See Ascites; or Peritonitis, Spontaneous Bacterial

Imaging Studies

• Ultrasonography

  • Can assess liver size and detect ascites or hepatic nodules, including small hepatocellular carcinomas

  • Together with Doppler studies, may establish patency of the splenic, portal, and hepatic veins

• Hepatic nodules can be characterized by contrast-enhanced CT or MRI

• Nodules suspicious for malignancy may be biopsied under ultrasound or CT guidance

Diagnostic Procedures

• Esophagogastroduodenoscopy confirms the presence of varices and detects specific causes of bleeding

• Liver biopsy may be performed by

  • Laparoscopy

  • Transjugular or endoscopic ultrasonographic approach in patients with coagulopathy and ascites

• Wedged hepatic vein pressure measurement may establish the presence and cause of portal hypertension

Medications

Ascites and edema

• Restrict sodium intake to 400–800 mg/day

• Restrict fluid intake (800–1000 mL/day) for hyponatremia (sodium < 125 mEq/L)

• Ascites may rapidly decrease on bed rest and dietary sodium restriction alone

• Use spironolactone (usually with furosemide) if there is no response to salt restriction

  • The initial dose of spironolactone is 100 mg daily orally

  • Dose may be increased by 100 mg every 3–5 days (up to a maximal conventional daily dose of 400 mg/day, though higher doses have been used) until diuresis is achieved, typically preceded by a rise in the urinary sodium concentration

  • Monitor for hyperkalemia

• Substitute amiloride, 5–10 mg daily orally, if painful gynecomastia develops from spironolactone

• Diuresis can be augmented with the addition of furosemide, 40–160 mg daily orally.

  • Monitor blood pressure, urinary output, mental status, and serum electrolytes, especially potassium

Anemia

• Iron deficiency anemia: ferrous sulfate, 0.3 g enteric-coated tablets, three times daily orally after meals

• Macrocytic anemia associated with alcoholism: folic acid, 1 mg once daily orally

• Packed red blood cell transfusions may be necessary to replace blood loss from variceal, other GI hemorrhage

Hemorrhagic tendency

• Treat severe hypoprothrombinemia with vitamin K (eg, phytonadione, 5 mg once daily orally or subcutaneously)

• If this treatment is ineffective, use large volumes of fresh frozen plasma. Because the effect is transient, plasma infusions are indicated only for active bleeding or before an invasive procedure

• Use of recombinant factor VII may be an alternative

Surgery

• Liver transplantation is indicated in selected cases of irreversible, progressive liver disease

• Absolute contraindications include

  • Malignancy (except small hepatocellular carcinomas in a cirrhotic liver)

  • Sepsis

  • Advanced cardiopulmonary disease (except hepatopulmonary syndrome)

Therapeutic Procedures

• Abstinence from alcohol is most important

• Diet

  • Should have adequate calories (20–40 kcal/kg /day body weight per day depending on the patient's body mass index and the presence or absence of malnutrition)

  • Should include protein 1.2–1.5 g/kg/day depending on the presence or absence of malnutrition) and, if there is fluid retention, sodium restriction

  • For hepatic encephalopathy, protein intake should be reduced to 60–80 g/day

• Vitamin supplementation is desirable

• L-carnitine, 300 mg orally four times a day, may help muscle cramps

• Patients should receive following vaccines

  • HAV, HBV

  • Pneumococcal

  • Influenza (yearly)

• The goal of weight loss with ascites without associated peripheral edema should not exceed 0.5–0.7 kg/day

• Large-volume paracentesis (> 5 L) is effective in patients with

  • Massive ascites and respiratory compromise

  • Ascites refractory to diuretics

  • Intolerable diuretic side effects

• Transjugular intrahepatic portosystemic shunt (TIPS)

  • In refractory ascites, reduces ascites recurrence and the risk of hepatorenal syndrome

  • Preferred to peritoneovenous shunts because of the high rate of its associated complications

  • Increases the risk of hepatic encephalopathy compared with repeated large-volume paracentesis

Complications

• Upper GI tract bleeding may occur from

  • Varices

  • Portal hypertensive gastropathy

  • Gastroduodenal ulcer

• Portal vein thrombosis, which also causes varices

• Liver failure may be precipitated by alcoholism, surgery, and infection

• The risk of carcinoma of the liver is increased greatly in patients with cirrhosis

• Hepatic Kupffer cell (reticuloendothelial) dysfunction and decreased opsonic activity lead to an increased risk of systemic infection

• Osteoporosis

Prognosis

• Prognostic scoring systems for cirrhosis include the Child-Pugh score (Table 16–8) and the Model for End-Stage Liver Disease (MELD) score

• MELD is used to determine priorities for liver transplantation

• In patients with a low MELD score (< 21), a low serum sodium concentration (< 130 mEq/L), an elevated hepatic venous pressure gradient, and persistent ascites predict a high mortality rate

• Only 50% of patients with severe hepatic dysfunction (serum albumin < 3 g/dL, bilirubin > 3 mg/dL, ascites, encephalopathy, cachexia, and upper GI bleeding) survive 6 months

• Long-term intravenous administration of albumin has been reported to improve 18-month survival in patients with cirrhotic ascites

• The risk of death is associated with

  • Muscle wasting

  • Age ≥ 65 years

  • Mean arterial pressure ≤ 82 mm Hg

  • Renal failure

  • Cognitive dysfunction

  • Ventilatory insufficiency

  • Prothrombin time ≥ 16 seconds

  • Delayed and suboptimal treatment of sepsis

  • Secondary infections

• Liver transplantation has markedly improved survival, particularly for patients referred for evaluation early

When to Refer

• For liver biopsy

• When the MELD score is ≥ 14

• For upper endoscopy to screen for gastroesophageal varices

When to Admit

• Gastrointestinal bleeding

• Stage 3–4 hepatic encephalopathy

• Worsening kidney function

• Severe hyponatremia

• Serious infection

• Profound hypoxia