Cirrhosis and Portal Hypertension

Key Points

1
The major causes of cirrhosis include chronic hepatitis B, chronic hepatitis C, alcoholic liver disease, nonalcoholic steatohepatitis (NASH), and hemochromatosis.
2
Etiologic classification of cirrhosis is more clinically relevant than morphologic classification (micronodular, macronodular, mixed), because morphologic appearance is relatively nonspecific with regard to etiology, and important management and treatment decisions are best addressed once the cause of cirrhosis has been determined.
3
Important and potentially life-threatening complications of cirrhosis include ascites, spontaneous bacterial peritonitis, variceal hemorrhage, hepatic encephalopathy, hepatorenal syndrome, hepatopulmonary syndrome, and hepatocellular carcinoma (HCC).
4
The Child-Pugh classification is useful in assessing prognosis and estimating the potential risk of variceal bleeding and operative mortality.
5
The Model for End-stage Liver Disease (MELD) combines international normalized ratio (INR), serum creatinine level, serum bilirubin level, and serum sodium levels to create a score that is used to predict prognosis and prioritize timing of liver transplantation.

Cirrhosis

Definition

1.
The word cirrhosis is derived from the Greek word kirrhos, meaning “orange or tawny,” and osis, meaning “condition.”
2.
The World Health Organization (WHO) definition of cirrhosis is a diffuse process characterized by fibrosis and the conversion of normal liver architecture into structurally abnormal nodules that lack normal lobular organization.
3.
Structural changes in the liver and resulting impairment of hepatic function may manifest as the development of
- ▪
  Jaundice
- ▪
  Portal hypertension
- ▪
  Varices
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  Ascites
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  Spontaneous bacterial peritonitis
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  Hepatorenal syndrome
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  Hepatic encephalopathy
- ▪
  Progressive hepatic failure
4.
The WHO definition distinguishes cirrhosis from other types of liver disease that have either nodule formation or fibrosis, but not both. These other hepatic disorders may be characterized by prehepatic or posthepatic portal hypertension, which occurs in the absence of cirrhosis. Nodular regenerative hyperplasia, for example, is characterized by diffuse nodularity without fibrosis, whereas chronic schistosomiasis is characterized by Symmers pipestem fibrosis with no nodularity.

Classification

1.
Morphologic classification was historically used to describe cirrhosis as the following:
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  Micronodular cirrhosis, with uniform nodules <3 mm in diameter: Causes include alcohol, hemochromatosis, biliary obstruction, hepatic venous outflow obstruction, jejunoileal bypass, and Indian childhood cirrhosis.
- ▪
  Macronodular cirrhosis, with nodular variation ≥3 mm in diameter: Causes include chronic hepatitis C, chronic hepatitis B, alpha-1 antitrypsin deficiency, and primary biliary cholangitis.
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  Mixed cirrhosis, a combination of micronodular and macronodular cirrhosis: Micronodular cirrhosis frequently evolves into macronodular cirrhosis.

Given limitations in morphologic grouping, including considerable overlap between categories, change in morphology with disease progression, need for invasive testing, and generally low specificity, this classification system has limited clinical utility.

Etiologic classification of cirrhosis is the most clinically useful and preferred approach for categorization.

▪
This method of classification aims to ascertain the etiology of liver disease by combining clinical, biochemical, genetic, histologic, and epidemiologic data.

▪

The two most common causes of cirrhosis in developed countries are excessive alcohol use and viral hepatitis. As the incidence of obesity and diabetes mellitus continues to rise, a parallel increase in NASH has been observed; by the year 2030, NASH is projected to be one of the leading causes of cirrhosis. Table 11.1 lists the etiologic classification and tests used to determine the cause.

TABLE 11.1

Etiology and Diagnostic Evaluation of the Common Causes of Cirrhosis

Etiology	Diagnostic Evaluation
Infection
Hepatitis B	HBsAg, anti-HBs, anti-HBc, HBV DNA
Hepatitis C	Anti-HCV, HCV RNA
Hepatitis D	Anti-HDV
Toxins
Alcohol	History, AST/ALT ratio, IgA level, liver biopsy
Cholestasis
Primary biliary cholangitis	AMA, IgM level, liver biopsy
Secondary biliary cirrhosis	MRCP, ERCP, liver biopsy
Primary sclerosing cholangitis	MRCP, ERCP, liver biopsy
Autoimmune
Autoimmune hepatitis	ANA, IgG level, smooth muscle antibodies, liver-kidney microsomal antibodies, liver biopsy
Vascular
Cardiac cirrhosis	Echocardiogram, liver biopsy
Budd-Chiari syndrome	CT, US, MRI/MRA
Sinusoidal obstruction syndrome	History of offending drug use, liver biopsy
Metabolic
Hemochromatosis	Iron studies, HFE gene mutation, liver biopsy
Wilson disease	Serum and urinary copper, ceruloplasmin, slit-lamp eye examination, liver biopsy
Alpha-1 antitrypsin deficiency	Alpha-1 antitrypsin level, protease inhibitor type, liver biopsy
NASH	History, risk factors (obesity, diabetes mellitus, hyperlipidemia), liver biopsy
Cryptogenic	Exclude NASH, celiac disease, drugs

AMA, Antimitochodrial antibodies; anti-HBc, antibody to hepatitis B core antigen; anti-HBs, antibody to hepatitis B surface antigen; anti-HCV, antibody to hepatitis C virus; anti-HDV, antibody to hepatitis D virus; AST, aspartate aminotransferase; ALT, alanine aminotransferase; CT, computed tomography; ERCP, endoscopic retrograde cholangiopancreatography; HBsAg, hepatitis B surface antigen; IgA, immunoglobulin A; IgM, immunoglobulin M; MRCP, magnetic resonance cholangiopancreatography; MRA, magnetic resonance angiography; MRI, magnetic resonance imaging; NASH, nonalcoholic steatohepatitis; US, ultrasonography.

▪
Most cases of cryptogenic cirrhosis are felt to be “burned out” NASH.

Pathology

Liver biopsy is indicated in selected patients with chronic liver disease when the clinical, biochemical, and imaging data are not definitive for cirrhosis or its etiology.

1.
Gross examination: The liver surface is irregular, with multiple yellowish nodules; depending on the severity of the cirrhosis, the liver may be enlarged because of multiple regenerating nodules or, in the final stages, small and shrunken.
2.
Pathologic criteria for the diagnosis of cirrhosis
- ▪
  Nodularity (regenerative nodules)
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  Fibrosis (deposition of connective tissue creates pseudolobules)
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  Fragmentation of the sample
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  Abnormal hepatic architecture
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  Hepatocellular abnormalities
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  Pleomorphism
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  Dysplasia
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  Regenerative hyperplasia
3.
Information obtained from histologic examination
- ▪
  Establishment of the presence of cirrhosis
- ▪
  Assessment of grade of histologic activity
- ▪
  Determination of the cause of cirrhosis in some cases
4.
Histologic methods for determining the specific cause of cirrhosis
- ▪
  Immunohistochemistry (e.g., hepatitis B virus)
- ▪
  Polymerase chain reaction (PCR) techniques (e.g., hepatitis C virus)
- ▪
  Quantitative copper measurement (Wilson disease)
- ▪
  Periodic acid-Schiff (PAS)–positive, diastase-resistant globules (alpha-1 antitrypsin deficiency)
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  Quantitative iron measurement (hemochromatosis)

Clinical Features

The manifestations of cirrhosis are protean. Patients with cirrhosis may come to clinical attention in numerous ways:

1.
Stigmata of chronic liver disease on physical examination (e.g., palmar erythema, spider telangiectasias)
2.
Abnormal serum chemistry test results and hematologic indices (e.g., serum aminotransferases, bilirubin, alkaline phosphatase, albumin, prothrombin time, platelet count)
3.
Imaging abnormalities (e.g., small, shrunken, nodular liver or evidence of portal hypertension on cross-sectional imaging)
4.
Complications of decompensated liver disease (e.g., ascites, variceal hemorrhage, encephalopathy)
5.
Cirrhotic appearance of the liver at the time of laparotomy or laparoscopy
6.
Autopsy

A patient with cirrhosis may present with none, some, or all of the following findings:

1.
General
- ▪
  Fatigue
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  Anorexia
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  Malaise
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  Sleep-wake reversal
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  Weight loss
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  Muscle wasting
2.
Gastrointestinal
- a.
  Parotid gland enlargement
- b.
  Diarrhea
- c.
  Cholelithiasis
- d.
  Gastrointestinal bleeding
  - ▪
    Esophageal, gastric, duodenal, rectal, and/or stomal varices
  - ▪
    Portal hypertensive gastropathy, enteropathy, and/or colopathy
3.
Hematologic
- a.
  Anemia
  - ▪
    Folate deficiency
  - ▪
    Spur cell anemia (hemolytic anemia in the setting of severe alcoholic liver disease)
  - ▪
    Splenomegaly with resulting pancytopenia
- b.
  Thrombocytopenia
- c.
  Leukopenia
- d.
  Impaired coagulation
- e.
  Disseminated intravascular coagulation
- f.
  Hemosiderosis
- g.
  Portal vein thrombosis
4.
Pulmonary
- a.
  Decreased oxygen saturation
- b.
  Altered ventilation-perfusion relationships
- c.
  Portopulmonary hypertension
- d.
  Hyperventilation
- e.
  Reduced pulmonary diffusion capacity
- f.
  Hepatic hydrothorax
  - ▪
    Accumulation of fluid within the pleural space in association with cirrhosis and in the absence of primary pulmonary or cardiac disease
  - ▪
    Usually right sided (70%)
  - ▪
    Typically associated with clinically apparent ascites, but can be found in patients without obvious ascites
- g.
  Hepatopulmonary syndrome
  - ▪
    Triad of liver disease, an increased alveolar-arterial gradient while breathing room air, and evidence of intrapulmonary vascular dilatations
  - ▪
    Wide range of reported prevalence rates in cirrhotic patients from approximately 5% to 50%
  - ▪
    Characterized by dyspnea, platypnea, orthodeoxia, digital clubbing, and severe hypoxemia (PO ₂ <80 mm Hg, often <60 mm Hg)
  - ▪
    Intrapulmonary shunting demonstrated by contrast-enhanced (“bubble”) echocardiography or technetium-99m macroaggregated albumin scanning; pulmonary arteriography rarely required
  - ▪
    Associated with significantly increased risk of mortality without liver transplantation; risk increases with severity of hypoxemia (see Chapter 33 )
  - ▪
    MELD score exception points may be given to patients with significant hypoxemia (PO ₂ <60 mm Hg).
  - ▪
    Complete resolution is typical after liver transplantation; the time course of improvement is variable and often delayed up to 1 year.
5.
Cardiac: Hyperdynamic circulation, diastolic dysfunction
6.
Renal
- - ▪
    Secondary hyperaldosteronism leading to sodium and water retention
  - ▪
    Renal tubular acidosis (more frequent in alcoholic cirrhosis, Wilson disease, and primary biliary cholangitis)
  - ▪
    Hepatorenal syndrome
7.
Endocrinologic
- a.
  Hypogonadism
  - ▪
    Male patients: Loss of libido, testicular atrophy, impotence, decreased amounts of testosterone
  - ▪
    Female patients: Infertility, dysmenorrhea, loss of secondary sexual characteristics
- b.
  Feminization (acquisition of estrogen-induced characteristics)
  - ▪
    Spider telangiectasias
  - ▪
    Palmar erythema
  - ▪
    Gynecomastia
  - ▪
    Changes in body hair patterns
- c.
  Diabetes mellitus
8.
Neurologic
- a.
  Hepatic encephalopathy
  - ▪
    Variants include spastic paraplegia and acquired non-Wilsonian hepatocerebral degeneration.
- b.
  Peripheral neuropathy
- c.
  Asterixis
9.
Musculoskeletal
- - ▪
    Reduction in lean muscle mass
  - ▪
    Hypertrophic osteoarthropathy: Synovitis, clubbing, and periostitis
  - ▪
    Hepatic osteodystrophy
  - ▪
    Muscle cramping
  - ▪
    Umbilical herniation
10.
Dermatologic
- a.
  Spider telangiectasias
- b.
  Palmar erythema
- c.
  Nail changes
  - ▪
    Azure lunules (Wilson disease)
  - ▪
    Muercke nails: Paired horizontal white bands separated by normal color
  - ▪
    Terry nails: White appearance of the proximal 2/3 of the nail plate
- d.
  Jaundice
- e.
  Pruritus
- f.
  Dupuytren contractures
- g.
  Clubbing
- h.
  Paper money skin
- i.
  Caput medusae
- j.
  Easy bruising
11.
Infectious

Infectious complications cause significant morbidity and mortality in patients with cirrhosis.
- a.
  Spontaneous bacterial peritonitis
- b.
  Urinary tract infection
- c.
  Respiratory tract infection
- d.
  Bacteremia
- e.
  Cellulitis

Certain infectious agents are more virulent and more common in patients with liver disease. These include Vibrio vulnificus, Campylobacter jejuni, Yersinia enterocolitica, Plesiomonas shigelloides, Enterococcus faecalis, Capnocytophaga canimorsus, and Listeria monocytogenes, in addition to organisms transmitted from other species. In patients with hemochromatosis, L. monocytogenes, Y. enterocolitica, and V. vulnificus may have enhanced virulence in the presence of excess iron.

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