SOAP. – Cirrhosis of the Liver – SỔ TAY LÂM SÀNG

Cirrhosis of the Liver

Kathy R. Reese and Cheryl A. Glass

Definition

A.Cirrhosis is the final stage of a pathological process within the liver that leads to fibrosis and replacement of normal hepatic tissue with structurally abnormal nodules known as regenerative nodules. It is considered irreversible but in mild cases has been shown to be reversible with treatment of the underlying condition. The scarring is most often caused by long-term exposure to toxins including alcohol and viral infections.

B.The natural history of liver cirrhosis (LC) is an asymptomatic compensated phase followed by a decompensated phase, marked by the development of overt clinical signs; the most frequent are ascites (5%–10%), bleeding, encephalopathy, and jaundice. Following the first appearance of any of these, the disease usually progresses more rapidly toward death or need for liver transplantation. The development of hyponatremia (serum sodium concentration <130 mmol/L in patients with cirrhosis) carries an ominous prognosis, as it is associated with increased morbidity and mortality.

C.Once decompensation has occurred; cirrhosis becomes a systemic disease, with multi-organ/system dysfunction. Cirrhosis also leads to an increased risk of developing hepatocellular carcinoma (HCC).

D.The concept of diagnosis of cirrhosis is changing from the documentation of histological F4 fibrosis to the identification of patients truly at risk of developing complications.

1.Prevention of cirrhosis can be accomplished by the primary care provider by screening for alcohol abuse, viral hepatitis, and risk factors for development of nonalcoholic steatohepatitis (NASH).

2.Management of cirrhosis involves identifying preexisting hepatic disease, avoiding further injury to the liver, and managing the complications.

Incidence

A.In the United States, chronic liver disease (CLD) and cirrhosis are the 12th leading cause of death, about 1.5% of deaths per year with a higher incidence in males. The transition from compensated asymptomatic cirrhosis to decompensated cirrhosis occurs at a rate of about 5% to 7% per year. The three most common causes of cirrhosis are chronic alcoholism, chronic hepatitis C virus (HCV), and nonalcoholic fatty liver disease (NAFLD).

B.Alcoholic liver disease (ALD) is one of the main causes of CLD worldwide and accounts for up to 48% of cirrhosis associated deaths in the United States.

1.Patients with ALD are at increased risk of developing HCC, with a lifetime risk of 3% to 10% and an annual risk of about 1%. Alcohol is also a frequent cofactor in patients with other type of liver disease where it accelerates hepatic fibrosis. Long-term heavy alcohol users remain at risk for advanced liver disease with alcoholic steatohepatitis (ASH), cirrhosis, and HCC.

2.Diagnosis of ALD requires documentation of chronic heavy alcohol use and exclusion of other causes of liver disease. Approximately 1 in 12 adults have alcohol use disorder (AUD) defined as consumption of more than three drinks per day in men and more than two drinks in women, or binge drinking defined by the National Institution of Alcoholism and Alcohol Abuse as more than five drinks in males and more than four drinks in female consumed over a 2-hour period.

3.Obesity and cigarette smoking are risk factors for HCC in patients with ALD.

4.Most patients with ALD present for medical care after they have developed jaundice or complications of cirrhosis.

C.NAFLD is a condition of excessive fat storage; there are two types, simple fatty liver and NASH:

1.Simple fatty liver (nonalcoholic fatty liver [NAFL]) has the presence of fat but little or no inflammation or liver cell damage. Simple fatty liver typically does not progress to cause liver damage or complications.

2.NASH causes inflammation and liver cell damage in addition to fatty liver. NASH may lead to cirrhosis or HCC.

D.Cirrhosis is complicated by bleeding from portal hypertension and also by portal vein thrombosis (PVT). PVT occurs in approximately 20% to 50% of patients with cirrhosis, particularly advance cirrhosis. PVT is a hallmark of poor outcome. PVT vascular complications include increase of portal hypertension and bleeding risk, and higher complications in the early post–liver transplantation period. At this time, clinical and laboratory variables to adequately assess the thrombotic risk in LC are limited. A meta-analysis shows than anticoagulants are efficacious and safe for treatment of PVT in patients with cirrhosis, but suggest the need of planning interventional clinical trials.

Pathogenesis

A.CLD resulting from various underlying etiologies causes death of hepatocytes, triggering an increase in hepatic enzymes. This process results in chronic inflammation, which over time leads to fibrosis of the liver. Fibrosis is a precursor to cirrhosis, or the replacement of normal liver parenchyma with regenerative nodules. Activation of hepatic stellate cells (HSCs) is a pivotal event in fibrosis. Defenestration and capillarization of liver sinusoidal endothelial cells are major contributing factors to hepatic dysfunction in LC. Activated Kupffer cells destroy hepatocytes and stimulate the activation of HSCs. Repeated cycles of apoptosis and regeneration of hepatocytes contribute to pathogenesis of cirrhosis.

B.The liver’s ability to metabolize bilirubin is compromised, leading to elevated bilirubin levels. The liver’s ability to synthesize clotting factors is reduced, creating elevated bleeding times. As the liver becomes increasingly fibrotic, the pressure in the portal system increases the risk of esophageal varices and gastrointestinal (GI) bleeding.

Predisposing Factors

A.Toxicity:

1.Alcohol abuse.

2.Medications:

a.Methotrexate use.

b.Acetaminophen.

B.Inflammation:

1.Hepatitis C.

2.Hepatitis B.

3.Autoimmune hepatitis.

4.Sarcoidosis.

5.Schistosomiasis, syphilis, brucellosis.

C.Genetic:

1.NASH.

2.Hemochromatosis.

3.Primary biliary cirrhosis.

4.Primary sclerosing cholangitis (PSC).

5.Alpha-1 antitrypsin deficiency.

6.Wilson disease.

7.Hereditary hemorrhagic telangiectasia.

8.Polycystic liver disease.

9.Celiac disease. (Liver disease and Crohn’s disease (CD) share widespread risk factors. Liver disorders such as autoimmune hepatitis, elevation of liver enzyme levels, primary biliary cirrhosis, nonspecific hepatitis, PSC, and NAFLD have been reported in patients with CD.)

D.Congestive heart failure (CHF)—(right sided).

E.Budd–Chiari syndrome—a rare condition through which the venous outflow from the liver is blocked through either narrowing of the vessels or by thrombotic occlusion.

F.Idiopathic portal fibrosis.

Common Complaints

Patients can present with symptoms of cirrhosis or complications from cirrhosis.

A.Symptoms of cirrhosis include the following:

1.Abdominal distention.

2.Jaundice.

3.GI bleeding.

B.Complications include the following:

1.Hepatocellular carcinoma.

2.Hepatic encephalopathy (HE)—caused by the inability of the liver to metabolize toxic products; can vary in severity from mild barely perceptible symptoms (Grade 1) to coma (Grade 4).

3.Ascites.

4.Acute GI bleeding.

5.Bacterial peritonitis.

6.Hepatorenal syndrome.

7.Hepatopulmonary syndrome.

8.Hepatic hydrothorax.

9.Portopulmonary hypertension.

Other Signs and Symptoms

A.Nonspecific: Anorexia, weight loss, weakness, and fatigue.

B.Pruritus.

C.Digital clubbing.

D.Dark-colored urine.

E.Sleep disturbances—indicative of encephalopathy.

F.Due to alteration in hormones, women develop anovulation and amenorrhea whereas men develop hypogonadism and gynecomastia.

G.Decreased blood pressure (BP)—sometimes noted when a previously hypertensive patient.

Subjective Data

A.Inquire regarding duration of symptoms, associated factors, progression of symptoms, location of pain, severity of symptoms, and any exacerbating factors noted by the patient or family.

B.Review the patient’s past medical history with attention to immunization status, prior infections, and hepatic disease.

C.Has the patient had a liver biopsy? If yes, when and what were the results?

D.Has the patient been treated for hepatitis B or hepatitis C?

TABLE 14.2 Herbal and Nutritional Supplements Used in Liver Disease

Sho-saiko-go (Xiao-Chai-Hu-Tang)	Bupleurum (Bupleurum chinense, Bupleurum kaoi)
Salvianolic acid B	Oxymatrine
Milk Thistle (Silybum marianum)	MitoQ (Coenzyme Q10)
Licorice root (Glycyrrhiza glabra)	Long pepper (Fructus Piperis Longi)
Dandelion (Taraxacum officinale)	Japanese knotweed (Polygonum cuspidatum)
Asian ginseng (Panax ginseng)	Cordyceps (Cordyces sinensis)
Chinese privet (Ligustum lucidem)	Angelica (Angelica Archangelica)
Reishi mushroom (Ganoderma lucidum)	Centella (Centella asiatica)
Kudzu (Pueraria lobate)	Fringe tree (Chionanthus virginicus)
SAMe (nutritional supplement)	Holy basil (Ocimum sanctum L.)
Phosphatidychole (nutritional supplement)	Liver Dr.

1.How long ago was the patient treatment?

2.Did the patient complete therapy? If not, why?

3.What was the patient’s response to therapy (i.e., non-responder, relapser, etc.)?

E.Review the patient’s medication list including prescription and over-the-counter (OTC) medications. Note any hepatotoxic drugs, particularly methotrexate. See Table 14.2 for a nonexhaustive list of herbal and nutritional supplemental products that the patient may be using for cirrhosis.

F.Review the patient’s surgical history.

G.Does the patient have a history of varices? If yes, has any procedure been done including banding or a transjugular intrahepatic portosystemic shunt (TIPS)?

H.Review the patient’s social history including alcohol use, sexual preference and behavior, drug use (particularly history of intravenous [IV] drug use), international travel, and dietary history.

I.Review the patient’s family history, particularly for inheritable disease

J.Review for presence of HE:

1.Moderate encephalopathy signs and symptoms include difficulty thinking, personality changes, poor concentration, confusion, forgetfulness, poor judgement, problems with handwriting or other small hand movements, and fetor hepaticus breath odor.

2.Severe encephalopathy signs and symptoms include lethargy, altered mental status, confused speech, seizures, severe personality changes, and extrapyramidal signs (Parkinson’s-like state).

K.Perform a thorough review of systems because decompensated cirrhosis affects many other organ systems.

Physical Examination

A.Check BP, pulse, respirations, height, and weight to calculate body mass index (BMI). Observe for decrease in weight or reduction in BP.

B.Screening tests:

1.Substance abuse screening.

a.CAGE questionnaire for detecting alcoholism is available at www.hepatitisc.uw.edu/page/substance-use/cage.

b.Alcohol Use Disorders Inventory Test (AUDIT) at every visit. The AUDIT tool is available at www.hepatitisc.uw.edu/page/substance-use/audit-c.

2.Screen for depression at each visit. The Patient Health Questionnaire-9 (PHQ-9) calculator is located at www.mdcalc.com/phq-9-patient-health-questionnaire-9.

3.Screen for generalized anxiety disorder (GAD) for patients with ALD. The GAD questionnaire is available at adaa.org/screening-generalized-anxiety-disorder-gad.

4.Cognitive testing for mental status/signs of encephalopathy includes the following:

a.The clock-draw test (CDT); refer to Section II: Procedures.

b.Clinical Hepatic Encephalopathy Staging Scale (CHESS): Nine items ranging from normal (0) to deep coma (9). A copy of the CHESS is available at www.liver.ca/wp-content/uploads/2018/02/HE-Staging-Scale-CHESS-ENG.pdf.

c.The Stroop Color and Word Test (SCWT). In the most common version patients are required to read three different tables as fast as possible. Patients read names of colors (color-words) printed in black (W) and name different color patches (C). Conversely the name color-word (CW) are printed in inconsistent color ink (i.e., red is printed in green ink). In this incongruent condition, the patient is required to name the color of the ink instead of reading the word. The Encephalapp Stroop Test is available for download for Apple iOS from www.encephalapp.com and is available for Android systems through Google Play.

5.Inspect:

a.Observe overall appearance including gate and coordination including evaluation for fetor hepaticus breath odor noted with HE, described as a distinctive strong, musty smell like a combination of rotten eggs and garlic.

b.Observe skin for jaundice and telangectasia.

c.Inspect eyes for scleral icterus.

d.Check palms for presence of palmar erythema.

e.Inspect distal extremities for peripheral edema and clubbing.

f.Assess for gross asymmetries across the abdomen. Note any abdominal distention or protrusion.

g.Assess chest wall for presence of gynecomastia.

h.Inspect abdominal wall for presence of dilated vessels.

i.Inspect for gynecomastia and small testes.

6.Auscultate:

a.Evaluate presence of bowel sounds in all quadrants.

b.Listen over the area of the liver for and bruits or venous hums.

7.Palpate:

a.Palpation of the abdomen can be significant for a firm nodular liver, hepatomegaly may or may not be present.

b.Palpate for splenomegaly.

c.Assess the abdominal distention for ascites, which can occur with a fluid wave. A positive test is noted when a shock wave of fluid moves against the fingertips pressed along the flank of the abdomen as the fluid is pushed from one side of the abdomen to the other by the force of a tap along the opposite flank:

i.Grade 1, mild ascites, is only detectable by ultrasound.

ii.Grade 2, moderate ascites, manifests by moderate symmetrical distension of the abdomen.

iii.Grade 3, large or gross ascites, is manifested by marked abdominal distension.

d.Palpate the scrotum to evaluate size of the testes.

8.Percuss: Percuss the costal margins for dullness. Begin percussion over the lungs and move from the area of resonate lung sounds to the areas of dullness. Mark the area of change. Start in the right lower quadrant (RLQ), repeating the same process. Measure the vertical distance from the top to the bottom. You can also use palpation to determine the lower border.

9.Neurologic:

a.Cranial nerve examination (refer to Section II: Procedures) for testing of sensations, temperature, and vibratory sensation.

b.Test for asterixis: Asterixis is the involuntary flapping of the wrist in a symmetric or asymmetric pattern with wrist extension. This test can also be elicited by the examiner pressing the patient’s wrists into hyperextension and then removing the pressure.

Diagnostic Tests

A.Liver biopsy is still considered the gold standard to identify the typical features of cirrhosis. However, alternative diagnostic methods have been validated in comparison to liver biopsy and have a good diagnostic accuracy for the diagnosis of cirrhosis:

1.Currently, the most important and frequent scenario that requires a mandatory liver biopsy is the differentiation between severe alcoholic hepatitis and decompensated alcoholic cirrhosis, because at the present time, there are no specific clinical signs or noninvasive methods to differentiate between the two conditions.

2.Liver biopsy remains key in the case of suspected NASH-related liver disease and in cholestatic and autoimmune CLD.

3.Noninvasive testing:

a.Ultrasound-based techniques.

i.Transient elastography (Fibroscan).

ii.Point shear-wave elastography.

iii.Two-dimensional (2D) shear wave elastography.

iv.Ultrasound and Doppler.

b.Clinical calculators:

i.Fibrosis-4 (FIB-4) calculator: (www.hepatitisc.uw.edu/page/clinical-calculators/fib-4).

ii.Echosense FibroMeter.

iii.Aspartate aminotransferase (AST)/platelet ratio index (APRI): www.hepatitisc.uw.edu/page/clinical-calculators/apri.

B.Platelet count, although never used alone, is used to look for portal hypertension.

C.AST/alanine transaminase (ALT) index—elevated but may be normal in cases of advanced liver disease.

D.AST/platelet ratio index.

E.Serum prothrombin time (PT)/international normalized ratio (INR)—elevation indicates a decline in the liver’s ability to produce clotting factors.

F.Complete blood count (CBC)—anemia, leukopenia, thrombocytopenia.

G.Total bilirubin—elevation.

H.Alkaline phosphatase (ALP)—elevated two to three times upper limit of normal.

I.Gamma-glutamyl transpeptidase (GGT)—elevated.

J.Albumin—hypoalbuminemia.

K.Sodium—hyponatremia.

L.Creatinine—elevated.

M.Alpha-fetoprotein—marker for HCC. Used for monitoring CLD and development of HCC.

N.Urine drug screen (if indicated).

O.Imaging:

1.Ultrasound—noted earlier.

2.Abdominal contrast-enhanced CT scan. (Not routinely used for diagnosis of cirrhosis as similar information is obtained with ultrasound without exposure to excessive radiation.)

3.MRI:

a.Abdominal contrast-enhanced MRI.

b.Magnetic resonance elastography.

c.Magnetic resonance angiography (MRA).

P.Endoscopy to visualize presence of varices. Noninvasive methods especially transient elastography are also being done to stratify the risk of varies.

Q.A diagnostic paracentesis is warranted to rule out spontaneous bacterial peritonitis.

R.Child–Pugh score for cirrhosis mortality estimates cirrhosis severity using total bilirubin, albumin, INR, presence/absence of ascites, and presence/absence of encephalopathy. An online calculator is available at www.hepatitisc.uw.edu/page/clinical-calculators/ctp.

S.Model of End-stage Liver Disease (MELD) score is used to estimate the severity and likely survival of patients awaiting liver transplantation. Factors include creatinine, bilirubin, INR, sodium, and recent dialysis. A score of 10 or greater indicates need for referral to hepatology. MELD exceptions (meaning these conditions are automatically given a score of 22 or greater) include HCC, hepatopulmonary syndrome, portopulmonary hypertension, and hepatic artery thrombosis. An online calculator is available at www.hepatitisc.uw.edu/page/clinical-calculators/meld.

Differential Diagnoses

A.Cirrhosis.

B.Hepatocellular carcinoma.

C.Budd–Chiari syndrome.

D.PVT.

E.Splenic vein thrombosis.

F.Inferior vena cava obstruction.

G.Sarcoidosis.

H.Schistosomiasis.

Plan

A.Immunizations: Patients should be up to date on all immunizations including hepatitis A and hepatitis B, if they are not already immune. Pneumococcal pneumonia and influenza is also recommended by the Centers for Disease Control and Prevention (CDC).

B.Patient teaching: Avoidance of hepatotoxins:

1.Alcohol: Long-term mortality is related to severity of underlying liver disease and is dependent on abstinence from alcohol. Prolonged abstinence is the most effective strategy to prevent disease progression and treatment of the underlying alcohol use disorder (AUD). Active alcoholism and previous alcohol use with less than 6 months of abstinence may be a contraindication to liver transplantation center’s policy.

2.Patients with obesity or chronic HCV should avoid consumption of alcohol.

3.Counsel patients to stop smoking.

4.Counsel patients that OTC medications, including Tylenol or medications containing Tylenol, should not be taken

5.Nonsteroidal anti-inflammatory drugs (NSAIDs) should not be used in patients with ascites.

6.Supplements: Many supplements are hepatotoxic.

7.Patients with hypovolemic hyponatremia have a fluid restriction (1,000 mL/d is recommended).

C.Pharmaceutical therapy: Because cirrhosis is the result of an underlying process, pharmaceuticals are directed at the causative agent (if applicable) or are used for supportive care of the complication:

1.The patient’s medications should be dose adjusted for hepatic impairment.

2.The use of diuretics, antibiotics, beta-blockers, and anticoagulants are indicated in the treatment of ascites, bacterial peritonitis, portal vein hypertension and PVT, respectively. Lactulose and rifaximin therapy are used in the management on HE.

3.The use of proton pump inhibitors (PPIs) is generally avoided if possible due to their association with increased rates of bacterial peritonitis.

4.Angiotensin-converting-enzyme (ACE) inhibitors, angiotensin II antagonists, or alpha-1 adrenergic receptor blockers should not generally be used in patients with ascites because of increased risk of renal impairment.

5.Aminoglycosides are discouraged in the presence of ascites; they are associated with an increased risk of acute kidney injury (AKI).

D.Diet: Refer to a dietician:

1.A moderate restriction of sodium intake (4.6–6.9 g of salt) is recommended in patients with moderate, uncomplicated ascites. This is generally equivalent to a no added salt diet with avoidance of preprepared meals.

2.Diets with a very low sodium content should be avoided because that is associated with diuretic-induced complications and can endanger a patient’s nutritional status.

3.Four to seven small frequent meals per day due to anorexia and nausea.

4.Adequate protein in diet. Historically, patients with cirrhosis have been told to avoid excessive protein in the diet; however, there is emerging evidence that eating more protein is helpful if the protein source is from vegetables, legumes, and eggs instead of meat.

Emergent Issues/Instructions

A.Patients presenting with acute GI bleeding should be hospitalized and undergo an urgent endoscopy.

B.Patients with moderate or severe alcohol withdrawal should be hospitalized. Severe forms of alcohol withdrawal include delirium tremens, generalized seizures, coma, cardiac arrest, and death.

Follow-Up

A.Follow-up visit frequency is dependent on the severity of cirrhosis as determined by the MELD score:

1.Less than 10: Every 6 to 12 months.

2.11 to 18: Every 3 months.

3.19 to 24: Every month.

4.25 or greater: Every week.

B.Monitor:

1.Lab—monitor liver enzymes, renal function, electrolytes, blood count, and alpha fetoprotein:

a.Development of HCC with ultrasonography every 6 months.

2.Encephalopathy—indicated by personality change, change in consciousness, and sleep disturbance.

3.Ascites—a therapeutic paracentesis is needed for symptom relief of tense ascites.

4.Esophageal varices and acute GI bleeding through frequent endoscopy—frequency is determined by severity of varices.

5.Bacterial peritonitis.

Consultation/Referral

A.Hepatology consultation:

1.Indicated for all patients whose diagnosis remains unclear after history, physical, serologic tests and imaging.

2.Indicated for patients with cirrhosis in which the causative agent requires treatment, such as hepatitis C.

3.Patients in need of secondary prophylaxis of esophageal variceal hemorrhage and treatment of refractory ascites, or those for whom paracentesis is ineffective, should be evaluated for a TIPS insertion.

4.Indicated for patients who would benefit from liver biopsy. Liver biopsy is avoided if the biopsy will not change the management of condition, such as a late-stage diagnosis.

5.MELD score should be calculated at the time of the diagnosis and recalculated frequently during management. Referral to a transplant center is indicated for a MELD score 10 or greater.

B.Patients with cirrhosis are best managed by an interdisciplinary team including drug and alcohol addiction specialists.

C.Dietary consultation.