I. Problem/Condition.

Cirrhosis resulted in almost 50,000 deaths in 2010 making it the the eighth leading cause of death in 2010. Cirrhosis is derived from the Greek κιρρóς, meaning orange-yellow color of the injured liver, and is a consequence of chronic liver disease usually occurring over years of repeated liver injury.

At first, hepatic injury appears to be reversible and therapy is aimed at the underlying cause. In its advanced stage, hepatic injury is irreversible and characterized by diffuse fibrosis and regenerative nodules. The gold standard for diagnosis of cirrhosis is liver biopsy, however, it is most commonly diagnosed with the combination of laboratory, radiologic and clinical data.

Cirrhosis is most commonly caused by chronic alcoholism and chronic hepatitis C virus infection. Patients with cirrhosis may present with a variety of signs and symptoms due to irreversible loss of hepatocyte function. Many patients with liver disease present with fatigue, anorexia, abdominal distention from ascites, jaundice of the skin, and infections due to a somewhat immunocompromised state. Medical management is focused on the relief of these symptoms.

II. Diagnostic Approach.

A. What is the differential diagnosis for this problem?

Cirrhosis can present in various ways as there are various complications. The presence of one or more of these complications is not always indicative of cirrhosis and it is thus important to understand the differential diagnosis for some of these most common complications.

Ascites, for example, is most commonly due to cirrhosis but can also be caused by heart failure, kidney failure, malignancy, infection (fungal, parasitic and tuberculosis), vasculitis (systemic lupus erythematosus and Henoch-Schonlein purpura), and pancreatitis.

Peripheral symmetric edema of the lower extremities can be due to heart failure, kidney disease (nephrotic syndrome or sodium (Na) retention), pregnancy, malnutrition, and medications such as calcium channel blockers.

Jaundice in cirrhosis is usually due to impaired hepatic bilirubin uptake due to portosystemic shunts. Uptake can also be impaired in heart failure and Gilbert’s syndrome. There are various other causes of jaundice due to conjugated and/or unconjugated hyperbilirubinemia.

Patients with cirrhosis can also present with profound encephalopathy believed to be from ammonia build-up. The differential diagnosis for encephalopathy is vast and includes infection, metabolic abnormalities, toxicity from drugs or medications, epilepsy, intracranial lesions, endocrine abnormalities, and other causes of hyperammonemia such as inherited urea cycle disorders and ureterosigmoidostomy.

B. Describe a diagnostic approach/method to the patient with this problem.

The gold standard for diagnosis of cirrhosis is liver biopsy. The most common method is percutaneous with or without ultrasound guidance. Bleeding is a common complication from percutaneous liver biopsy and occurs in approximately 1 out of every 100 patients.

Other techniques include transjugular and laparoscopic. The transjugular approach is preferred when a patient has a high risk of bleeding or in the presence of ascites. Laparoscopic liver biopsy is preferred when biopsy of multiple areas of the liver is desired or to avoid the spread of cancer. Liver biopsy is limited by sampling error.

Liver biopsy is infrequently recommended. The clinical presentation can be highly suggestive of cirrhosis making an invasive procedure unnecessary and painful. It carries a fairly high risk of bleeding for the patient. Additionally, there is discomfort during the procedure and interpretation can be affected by sampling error. Cirrhosis is now more commonly diagnosed by clinical presentation as well as radiologic and laboratory data.

A recommended initial approach is to obtain serum labs, an ultrasound of the abdomen and perform a focused physical exam. Initial serum laboratory studies should include liver function tests (albumin (ALB), aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (AP), bilirubin, and gamma-glutamyl transpeptidases (GGT)), electrolyte panel, creatinine, coagulation studies (prothrombin time and partial thromboplastin time), and cell count.

Other laboratory tests that would help determine etiology include hepatitis panel, autoimmune antibodies, transferrin saturation, alpha 1 antitrypsin, copper and ceruloplasmin level.

Ultrasonography is the initial recommended radiographic evaluation of the liver. It is well tolerated and provides important information with respect to the echotexture and size of the liver as well as presence of some of the complications of liver disease such as portal hypertension with or without ascites and splenomegaly, hepatocellular carcinoma and Budd-Chiari syndrome.

In a cirrhotic patient, you would expect to find a small, irregular and nodular liver with increased echogenicity. A new type of sonographic device, the Fibroscan or EchoSens, measures “stiffness” of the liver. Ultrasound elastography produces an image of the liver as well as a stiffness reading in kilopascals. The test is much faster than a biopsy (approximately 5 minutes) and is painless.

1. Historical information important in the diagnosis of this problem.

Newly diagnosed cirrhotics

For a newly diagnosed cirrhotic, history should include questions pertaining to etiology of cirrhosis. Ask about alcohol consumption, especially quantity and duration (cirrhosis usually develops in patients that drink an average of 80 grams per day for about 10 to 15 years). History should include risk factors for hepatitis such as piercings and tattoos, sexual history, blood transfusions, and illicit drug use. It is also important to obtain information regarding family history of liver disease or other autoimmune diseases. Finally, ask about sick contacts and obtain a travel history.

Patients with known cirrhosis

For patients with known cirrhosis, ask questions pertaining to a history of complications or decompensated cirrhosis. If a patient has a history of spontaneous bacterial peritonitis (SBP), ask about compliance to daily oral antibiotic suppressive therapy. Non-compliance might indicate a need for a broader spectrum antibiotic if presenting with SBP.

For patients with a history of gastrointestinal (GI) bleed, ask specific questions with respect to new bleed (melena, hematemesis, hematochezia, etc.) in addition to most recent esophagogastroduodenoscopy (EGD) and colonoscopy.

For patients with a history of hepatic encephalopathy ask about compliance with primary suppressive therapy such as lactulose and ask about triggers (hypovolemia or poor per os (PO) intake, GI bleed, infection, etc.).

For patients with a history of ascites, ask about frequency of large volume paracentesis, dietary Na and fluid intake, as well as compliance to diuretics. Finally, find out if the patient is on a transplant list and if they see a specialist.

A complete review of systems for newly diagnosed or known cirrhotics should include questions specific to all of the complications. For example, skin findings such as bruising and itching or ascites symptoms such as anorexia, nausea, vomiting, and abdominal distention or symptoms suggestive of encephalopathy such as disturbance in sleep-wake cycle and confusion.

2. Physical Examination maneuvers that are likely to be useful in diagnosing the cause of this problem.

Physical findings consistent with portal hypertension
  • Ascites: Test for flank dullness. With the patient in the supine position, percussion is done over the abdomen starting at the umbilicus to the flanks. Note the transition from tympany to dullness. Ascites is present when there is dullness over the lateral abdomen and tympany over the umbilicus.

  • Splenomegaly: palpate spleen.

  • Caput medusae: prominent umbilical vein.

Findings secondary to alteration in sex hormone metabolism

  • Gynecomastia: proliferation of breast tissue.

  • Testicular atrophy.

  • Spider angiomata: Place a glass slide over the spider angiomata and you notice the central arteriole pulsating.

  • Palmar erythema: Most prominent in the thenar and hypothenar aspects of the palm.

Other physical exam findings in cirrhotic patients due to liver impairment include the following:

  • Jaundice: Yellow skin and mucus membranes, which occur once bilirubin reaches levels greater than 2 mg/dL (milligram/deciliter).

  • Clubbing of fingers.

  • Encephalopathy: Test for asterixis. Asynchronous and bilateral flapping motions of outstretched and dorsiflexed hands. Also test for hyperactive deep tendon reflexes. Observe for presence of Fetor hepaticus, a distinctive breath odor associated with hepatic encephalopathy caused by increased concentrations of dimethyl sulfide due to severe portal-systemic shunting.

  • Nail changes: Muehrcke’s nails are horizontal white bands. Terry’s nails are when the proximal two thirds of the nail plate appears white and the distal third is red. Both Muehrcke’s and Terry’s nails are thought to be from hypoalbuminemia.

  • Dupuytren’s contracture: Test by asking the patient to extend fingers. The fingers (most commonly the fourth and fifth digits) cannot be fully extended. Palpate the patient’s palm and you will feel areas of fibrosing or nodules.

3. Laboratory, radiographic and other tests that are likely to be useful in diagnosing the cause of this problem.

Laboratory studies to consider are those that would assist you in not only the diagnosis of cirrhosis but also in determining the etiology and severity of liver disease. The following are suggested initial laboratory tests as well as abnormalities you may see in a patient with cirrhosis:

  • Aminotransferases: Aspartate transaminase (AST) and alanine transaminase (ALT) are usually elevated. Most forms of chronic hepatitis have an AST:ALT ratio of less than 1. An AST:ALT ratio greater than 2 but both less than 300 is suggestive of alcohol-related cirrhosis. If both AST and ALT are greater than 500, the differential diagnosis is limited to acute viral hepatitis, common bile duct stone, drug or toxic liver, Budd-Chiari syndrome, ischemic hepatitis, acute fatty liver of pregnancy, Wilson’s disease, chronic active hepatitis, veno-occlusive disease, and HELLP (hemolysis, elevated liver enzymes, low platelet count) syndrome. Also remember, that you can see a normal AST and ALT in cirrhosis.

  • Alkaline phosphatase is usually elevated but less than three times the upper limit of normal. Elevations beyond this may be seen in primary sclerosing cholangitis or primary biliary cirrhosis.

  • Bilirubin is elevated in decompensated cirrhosis. It can be used to calculate prognosis and eligibility for transplant along with the creatinine and international normalized ratio (INR).

  • Albumin is made exclusively in the liver. Levels fall as liver disease progresses. Low levels are also seen in heart failure, malnutrition, nephrotic syndrome, extensive burns, protein-losing enteropathy, inflammatory bowel disease, hemodilution (e.g. pregnancy), and acute or chronic inflammation.

  • Prothrombin time (PT): Eleven clotting factors are synthesized in the liver. As the liver loses synthetic function, PT will rise. This is a very sensitive test given that factor VII has a very short half-life of 3-5 hours and is thus quick to decline when there is liver impairment. High levels are also seen in various other conditions including vitamin K deficiency, factor VII inhibitor or deficiency, treatment with warfarin or heparin, disseminated intravascular coagulopathy (DIC), and other rare factor deficiencies.

  • Glucose: Hypoglycemia may be seen in a decompensated cirrhotic with malnutrition. The liver stores glycogen, which is usually enough glucose for about 18 hours.

  • Platelets: Thrombocytopenia seen in cirrhosis is multifactorial. It is seen in those with portal hypertension with congestive splenomegaly because there can be temporary sequestration of up to 90% of circulating platelet mass. Also, it can be due to decreased thrombopoietin levels, which is primarily produced in the liver. Low levels may also be seen in patients with cirrhosis due to coagulopathy or viral myelosuppression in those with hepatitis C virus infection.

  • Hemoglobin: Anemia is usually multifactorial as well and due to acute or chronic GI bleeding, folate deficiency, direct toxicity from alcoholism, hypersplenism, bone marrow suppression, anemia of chronic disease, and hemolysis.

  • White blood count: Leukopenia and neutropenia are due to hypersplenism and splenic margination.

  • Creatinine: A normal creatinine in this patient population is closer to the lower limit of normal because of their low muscle mass. If elevated, the patient may need to be evaluated for hepatorenal syndrome.

  • Electrolytes: Na can often be low and indicate a cirrhotic patient’s hypervolemic state.

  • Alpha-fetoprotein (AFP) is used to screen for hepatocellular carcinoma (HCC). A level greater than 500 mcg/L (microgram/liter) in a patient at risk for HCC is highly suggestive of HCC.

Other laboratory values that can be considered to further assess etiology of cirrhosis include a hepatitis panel (hepatitis B surface antigen and surface antibody, hepatitis C antibody), fasting iron studies (ferritin and transferrin), copper and ceruloplasmin, serum alpha-1 antitrypsin, and anti-smooth muscle, anti-mitochondrial, anti-nuclear, anti-actin, anti-liver cytosol-1, anti-liver-kidney microsome-1, and anti-neutrophil cytoplasmic antibodies.

Initial radiographic evaluation of the liver should be done with ultrasonography as it is easily available, inexpensive and will provide a lot of information regarding liver disease severity and possible concurrent complications of liver disease. In a cirrhotic patient, you would expect to find a small, irregular and nodular liver with increased echogenicity.

C. Criteria for Diagnosing Each Diagnosis in the Method Above.


D. Over-utilized or “wasted” diagnostic tests associated with the evaluation of this problem.

It is unnecessary to obtain ammonia levels for the diagnosis of encephalopathy when it can instead be diagnosed by clinical assessment. There is also no utility in checking daily ammonia levels as improvement or deterioration can also be assessed clinically.

III. Management while the Diagnostic Process is Proceeding.

A. Management of cirrhosis.

The most important initial management for patients with cirrhosis is to prevent further damage to the liver. Patients will need to be counseled extensively regarding potential liver toxins so that they are aware of what they must avoid. Abstinence of alcohol is highly recommended and a substance abuse consult may be necessary to achieve this goal.

Acetaminophen may be used, however, no more than 2 grams per day. There are many other medications that will need to be stopped or dosed appropriately for a patient with cirrhosis. Finally, prevent further liver damage by vaccinating patients for hepatitis A and B, if appropriate. Patients with autoimmune liver disease or other treatable forms of liver disease will need to undergo further evaluation for therapy by specialists.

Treatment of the underlying cause can help diminish fibrotic changes even in advanced fibrosis. Patients with chronic hepatitis B or C and cirrhosis should be evaluated for treatment with antiviral agents. Studies have shown significant regression of liver stiffness in patients who achieve sustained virological response following treatment of hepatitis C.

Patients with cirrhosis should be monitored for some of the most common complications and measures should be taken to prevent them. Surveillance for hepatocellular carcinoma involves ultrasonography of the liver every 6 months. Surveillance of esophageal varices to prevent a bleed should be done on a scheduled basis determined by a gastroenterologist based on initial EGD findings.

Follow-up EGD is usually performed 2 years later if initial EGD shows no evidence of esophageal varices. Patients with esophageal varices that are at increased risk of bleeding may benefit from a nonselective beta-blocker or endoscopic variceal ligation depending on initial findings.

Many patients with cirrhosis present with various symptoms and they will need to be managed with supportive care. For example, many patients with ascites have nausea from the fluid compressing their GI tract. Patients will need medical management of the ascites as well as supportive care with perhaps nutritional supplements or anti-emetics to treat the nausea and resultant anorexia.

Consider placing a nutrition consult to educate regarding a low Na diet (if recommended based on serum Na and volume status) and fluid restriction.

Finally, determine if it is appropriate to refer to a liver transplant center by calculating their model for end-stage liver disease (MELD) score. The transplantation evaluation is typically started once a patient has a MELD score > 10.

Treat life threatening complications of cirrhosis:

1. Ascites

2. Spontaneous bacterial peritonitis

3. Hepatorenal syndrome

4. Hepatic encephalopathy

5. Varices and variceal bleed

6. Hepatocellular carcinoma

7. Portal vein thrombosis

8. Hepatopulmonary syndrome

9. Portal gastropathy

B. Common Pitfalls and Side-Effects of Management of this Clinical Problem.

If using benzodiazepines for alcohol withdrawal, consider using lorazepam or oxazepam which have a shorter half-life.

Overhydration of patients with cirrhosis should be avoided because you can worsen portal hypertension and place them at risk for GI bleed.

For all patients with cirrhosis, consider your patient’s risk of bleeding (e.g. coagulopathy and varices) when choosing an agent for prevention of venous thromboembolism. Keep in mind however, that these patients are also at risk of developing clots because they have decreased levels of antithrombin, protein C and S and plasminogen.

If ascites is present, always consider obtaining a diagnostic paracentesis to rule out the presence of spontaneous bacterial peritonitis.

Beta blockers should be tapered and discontinued in patients with late stage cirrhosis with refactory ascites as well as in cirrhotic patients with sepsis or hepatorenal syndrome as decrease in cardiac output results in decrease renal perfusion and increased mortality.