CIRRHOSIS OF THE LIVER (etiology, diagnosis, classification, differential diagnosis, complications, treatment)

Cirrhosis is the sequela of a wide variety of chronic, progressive liver diseases. Cirrhosis is present when these processes have so scarred the liver that its normal architecture is disrupted and regenerating nodules of parenchyma appear. The pattern of scarring seldom permits determination of the specific etiology, but associated histologic features may point to the cause. A specific diagnosis generally requires a combination of history, physical findings, laboratory tests, and identification of characteristic histologic features. In the United States, excessive alcohol intake and chronic hepatitis C are the most common causes of cirrhosis. In other parts of the world, particularly in Asian countries, chronic hepatitis B and hepatitis C are the dominant causes of cirrhosis.

Cirrhosis is - Diffuse disorganization of normal hepatic structure by regenerative nodules that are surrounded by fibrotic tissue.














Post mortem specimen of cirrhotic liver and enlarged spleen




Post mortem specimen of banded oesophageal varix




*    Viral

*    Alcoholic

*    Toxic

*    Autoimmune

*    Metabolic

*    ongestive

*    Biliary

*    Cryptogenic Hepatitis



I.                  ACTIVE:

-         Quickly progressive

-         Slowly progressive

-         Latent


Child - Turcotte and Pugh




Class A


(5-6 points)

Class B

Subcompensation (7-9 points)

Class C

Decompensation (10 and >points)





Bilirubin, mcmol/l




Albumine, g/l




Prothrombin time










1-2 st.

3-4 st.













Approach to the Patient with Suspected Cirrhosis

presenting symptoms

Fatigue and malaise are common in all forms of cirrhosis, but these nonspecific symptoms are found in almost all acute and chronic liver diseases. Characteristic but nondiagnostic physical findings of cirrhosis include palmar erythema and spider nevi. Other typical findings include gynecomastia, testicular atrophy, and evidence of portal hypertension (splenomegaly, ascites, and prominence of the veins of the abdominal wall). Other physical abnormalities, such as Dupuytren contracture, xanthelasma, xanthomas, Kayser-Fleischer rings, a bronze discoloration of the skin, and hyperpigmentation, are found in specific forms of cirrhosis. The cirrhotic liver is usually large, and the left lobe is often palpable below the xiphoid process. Only a patient in the advanced inactive stage of disease exhibits a small and shrunken liver.

Gynaecomastia in liver cirrhosis

Vein dilatation and tortuosity in the abdominal wall of a cirrhotic patient suffering from ascites and jaundice


Dupuytrens contracture in liver cirrhosis

diagnostic evaluation

Percutaneous liver biopsy can unequivocally establish the presence of cirrhosis. However, cirrhosis can be inferred by the presence of splenomegaly, ascites, spider angiomas on physical examination, or findings of cirrhosis and portal hypertension on imaging studies in patients with underlying chronic liver disease. Liver biopsy can be performed safely when there is no history of unusual bleeding after surgery or dental work and when tests for coagulation yield normal or only mildly abnormal results. Reasonable guidelines include an international normalized ratio (INR) for prothrombin time no greater than 1.5, a partial thromboplastin time of no more than 10 seconds beyond the control value, and a platelet count of at least 50,000/mm3. Other relative contraindications to biopsy include lack of patient cooperation or the presence of ascites or right lower lobe pneumonia. If coagulation abnormalities cannot be corrected or if moderate to severe ascites is present, an adequate amount of tissue for biopsy can be safely obtained using the transjugular, or transvenous, approach. Marked distortion of hepatic architecture, with regenerative nodules surrounded by scar tissue, provides definitive evidence of cirrhosis. Liver biopsy also helps identify the cause of cirrhosis. In particular, bile duct invasion and destruction with associated granulomas suggest the presence of primary biliary cirrhosis; excess iron in bile duct cells and liver cells points to hereditary hemochromatosis; and Mallory hyalin associated with polymorphonuclear cell reaction usually indicates alcoholic liver disease. A decreased serum albumin level and a prolonged prothrombin time are characteristic of cirrhosis. Other serum chemistries, such as elevated aminotransferase and alkaline phosphatase levels, are often abnormal. Computed tomography, magnetic resonance imaging, or hepatic ultrasonography with Doppler flow studies may reveal findings consistent with cirrhosis. These findings may include splenomegaly, ascites, an irregular liver surface, increased echogenicity and reversal of portal blood flow, and intra-abdominal varices. In addition, upper endoscopy often establishes the presence of esophagogastric varices.



Liver cirrhosis with ascites (longitudinal section): the left lobe of liver is rounded and plump; intrahepatic vessels are reduced. Irregular and inhomogeneous structure. Clear undulatory limitation (arrow) on the underside due to nodular transformation.
Wide hypoechoic fringe due to ascites



Specific Forms of Cirrhosis


Synonyms for alcoholic cirrhosis include portal, Laënnec, nutritional, and micronodular cirrhosis. Because alcohol produces a direct toxic effect on the liver in animals, alcoholic cirrhosis is the most appropriate term.


Alcoholic liver disease, including alcoholic cirrhosis, is directly attributable to chronic ingestion of large quantities of alcohol.



Liver disease related to alcohol consumption fits into 1 of 3 categories: fatty liver, alcoholic hepatitis, or cirrhosis (Table 1). Fatty liver, which occurs after acute alcohol ingestion, is generally reversible with abstinence and is not believed to predispose to any chronic form of liver disease if abstinence or moderation is maintained. Alcoholic hepatitis is an acute form of alcohol-induced liver injury that occurs with the consumption of a large quantity of alcohol over a prolonged period of time; it encompasses a spectrum of severity ranging from asymptomatic derangement of biochemistries to fulminant liver failure and death. Cirrhosis involves replacement of the normal hepatic parenchyma with extensive thick bands of fibrous tissue and regenerative nodules, which results in the clinical manifestations of portal hypertension and liver failure.


Table 1. Forms of Alcoholic Liver Disease


Fatty Liver

Alcoholic Hepatitis


Histologic specificity 
for alcoholic cause











Generally no



The prevalence of alcoholic liver disease is influenced by many factors, including genetic factors (eg, predilection to alcohol abuse, gender) and environmental factors (eg, availability of alcohol, social acceptability of alcohol use, concomitant hepatotoxic insults), and it is therefore difficult to define. In general, however, the risk of liver disease increases with the quantity and duration of alcohol intake. Although necessary, excessive alcohol use is not sufficient to promote alcoholic liver disease. Only 1 in 5 heavy drinkers develops alcoholic hepatitis, and 1 in 4 develops cirrhosis

. Different alcoholic beverages contain varying quantities of alcohol (Table 2 ). Although fatty liver is a universal finding among heavy drinkers up to 40% of those with modest alcohol intake (≤ 10 g/day) also exhibit fatty changes.1Based on an autopsy series of men, a threshold daily alcohol intake of 40 g is necessary to produce pathologic changes of alcoholic hepatitis. Consumption of more than 80 g per day is associated with an increase in the severity of alcoholic hepatitis, but not in the overall prevalence. There is a clear dose-dependent relation between alcohol intake and the incidence of alcoholic cirrhosis. A daily intake of more than 60 g of alcohol in men and 20 g in women significantly increases the risk of cirrhosis. In addition, steady daily drinking, as compared with binge drinking, appears to be more harmful.

Table 2. Alcohol Content of Some Common Beverages


Amount (oz)

Absolute Alcohol (g)










Liquor (80 proof)






The liver and, to a lesser extent, the gastrointestinal tract, are the main sites of alcohol metabolism. Within the liver there are 2 main pathways of alcohol metabolism: alcohol dehydrogenase and cytochrome P-450 (CYP) 2E1. Alcohol dehydrogenase is a hepatocyte cytosolic enzyme that converts alcohol to acetaldehyde. Acetaldehyde subsequently is metabolized to acetate via the mitochondrial enzyme acetaldehyde dehydrogenase. CYP 2E1 also converts alcohol to acetaldehyde.

Liver damage occurs through several interrelated pathways. Alcohol dehydrogenase and acetaldehyde dehydrogenase cause the reduction of nicotinamide adenine dinucleotide (NAD) to NADH (reduced form of NAD). The altered ratio of NAD/NADH promotes fatty liver through the inhibition of gluconeogenesis and fatty acid oxidation. CYP 2E1, which is upregulated in chronic alcohol use, generates free radicals through the oxidation of nicotinamide adenine dinucleotide phosphate (NADPH) to NADP. Chronic alcohol exposure also activates hepatic macrophages, which then produce tumor necrosis factor-alpha (TNF-alpha). TNF-alpha induces mitochondria to increase the production of reactive oxygen species. This oxidative stress promotes hepatocyte necrosis and apoptosis, which is exaggerated in the alcoholic who is deficient in antioxidants such as glutathione and vitamin E. Free radicals initiate lipid peroxidation, which causes inflammation and fibrosis. Inflammation is also incited by acetaldehyde that, when bound covalently to cellular proteins, forms adducts that are antigenic

Natural history

With abstinence, morphologic changes of the fatty liver usually revert to normal. Although the short-term prognosis in patients with alcoholic steatosis is excellent, with longer follow-up it has been found that cirrhosis develops more commonly in alcohol abusers with fatty liver changes than in those with normal liver histology. Morphologic features that predict progression to fibrosis, cirrhosis, or both include severe steatosis, giant mitochondria, and the presence of mixed macrovesicular-microvesicular steatosis.

Historically, the 30-day mortality rate in patients with alcoholic hepatitis ranges from 0% to 50%. Clinical and laboratory features are powerful prognostic indicators for short-term mortality. Hepatic encephalopathy, derangement in renal function, hyperbilirubinemia, and prolonged prothrombin time are seen more often in patients who succumb to the illness than in those who survive. Both the discriminant function and the model for end-stage liver disease (MELD) score can be used to predict short-term mortality in patients with alcoholic hepatitis.

The Lille model is another prognostic scoring system that incorporates 6 reproducible clinical variables, including change in bilirubin in the first week during steroid therapy for severe alcoholic hepatitis. It is more accurate than the Child, Maddrey, Glasgow, or MELD scores in predicting death at 6 months in patients with severe alcoholic hepatitis. Long-term survival in patients with alcoholic hepatitis who discontinue alcohol is significantly longer than in those who continue to drink. Three-year survival approaches 90% in abstainers, whereas it is less than 70% in active drinkers. Duration of survival in both groups remains considerably below that of an age-matched population.

Cirrhosis has historically been considered an irreversible outcome following severe and prolonged liver damage. However, studies involving patients with liver disease from many distinct causes have shown convincingly that fibrosis and cirrhosis might have a component of reversibility. For patients with decompensated alcoholic cirrhosis who undergo transplantation, survival is comparable to that of patients with other causes of liver disease; 5-year survival is approximately 70%.

Effects of alcohol abuse

Alcoholic cirrhosis may develop in women after less alcohol consumption than is necessary to cause cirrhosis in men. Daily alcohol consumption of approximately 50 g, or three or four drinks (one drink = 12 oz of beer, 5 oz of wine, or 1.5 oz of 80-proof liquor), for 10 to 15 years is associated with alcoholic liver disease in women, whereas 80 g, or five or six drinks a day, is associated with alcoholic cirrhosis in men. Its development does not require concomitant malnutrition, although this condition is almost invariably present. Malnutrition undoubtedly reflects a substitution of alcohol for normal dietary calories. All persons who drink heavily experience a bland fatty infiltration, which is reversible when alcohol ingestion ceases. Although the development of alcoholic cirrhosis usually requires more than 10 years of heavy drinking, the disease can develop more rapidly. Alcoholic cirrhosis typically progresses as a result of repeated bouts of clinical and subclinical alcoholic hepatitis. Alcoholic hepatitis, another manifestation of alcoholic liver disease and a frequent precursor to alcoholic cirrhosis, refers to the pathologic Mallory stain findings of alcoholic hyalin surrounded by polymorphonuclear cell inflammation [see Figure 1]. These necrotic lesions are accompanied by collagen formation and are typically found in a pericentral location.


Clinical features

Physical examination usually shows the liver to be enlargedsometimes to a marked degree. Hepatomegaly reflects inflammation, fatty infiltration, and extensive scar formation. The typical histologic picture consists of a weblike scar that separates liver cell cords and surrounds small nodules of liver cells [see Figure 2].

An acute clinical syndrome is manifested in only a minority of patients in whom alcoholic hepatitis can be histopathologically demonstrated. Patients with this syndrome, which warrants immediate hospitalization, have a temperature of 38 C (100.4 F) or higher, right upper quadrant pain and tenderness, an enlarged liver, leukocytosis, and jaundice. Not all features are necessarily evident. In patients with severe disease, mortality ranges from 10% to 40%. Some patients with alcoholic hepatitis demonstrated by biopsy do not have cirrhosis, and in half of these patients, the liver returns to normal after cessation of alcohol consumption; cirrhosis develops in the remainder.




Figure 1 (a) Liver biopsy specimen from a 34-year-old man with a 7- year history of heavy alcohol consumption demonstrates a zone of fibrosis, ballooning liver cells, and inflammation (arrows). (b) Higher magnification of the specimen reveals typical alcoholic hyalin (thick arrow) and a polymorphonuclear cell inflammatory reaction (thin arrows), which are features of alcoholic hepatitis.




Figure 1c Alcoholic cirrhosis. Fibrous septa act as a bridge between centrilobular regions and portal tracts with the development of cirrhosis


The overall clinical diagnosis of alcoholic liver disease, using a combination of physical findings, laboratory values, and clinical acumen, is relatively accurate (Table 3). However, liver biopsy can be justified in selected cases, especially when the diagnosis is in question. A clinical suspicion of alcoholic hepatitis may be inaccurate in up to 30% of patients. In addition to confirming the diagnosis, liver biopsy is also useful for ruling out other unsuspected causes of liver disease, better characterizing the extent of the damage, providing prognosis, and guiding therapeutic decision making.

Table 3. Physical Examination and Laboratory Findings In Alcoholic Liver Disease

Physical Examination








Spider angioma

Parotid and lacrimal gland enlargement

Palmer erythema


Decreased body hair





Dupuytrens contracture


Muscle wasting




Testicular atrophy




Hepatomegaly or small shrunken liver



Hepatic tenderness





Confusion, stupor



Laboratory Findings



Liver synthetic function

Hyperbilirubinemia (usually conjugated)

Prolonged prothrombin time




Liver enzyme levels

Aspartate aminotransferase and alanine 
aminotransferase levels elevated, 
usually < 300 U/L; AST/ALT ratio ~ 2:1





Leukocytosis or leukopenia


Increased serum globulin levels




Elevated blood ammonia level


Respiratory alkalosis







The only established therapy for patients with alcoholic liver disease is to stop drinking alcohol. Patients with alcoholic cirrhosis who continue to drink seem to have a poorer prognosis than those who stop. The 5-year survival rate for patients who drink is less than 40% but may reach 60% to 70% if abstinence is maintained. Although pessimism abounds, as many as 30% of patients with alcoholic liver disease may succeed in abstaining completely. Thus, the emphasis in treatment should be to support patients efforts to stop drinking. Various rehabilitation units, peer support groups, and psychotherapeutic techniques are available.

Nutritional support.

The marked nutritional deficiencies noted in many patients with alcoholic cirrhosis have led most physicians to recommend nutritional support during the acute illness. A large cooperative study evaluated the role of an enteral food supplement in decompensated alcoholic liver disease. The investigators demonstrated a direct relation between caloric intake and survival and found that vigorous nutritional support enhanced survival, particularly in severely malnourished patients.

Glucocorticoid treatment.

Although there have been several studies of glucocorticoid treatment in patients with decompensated alcoholic liver disease, no convincing and consistent proof of efficacy has emerged, except in the subgroup of patients with severe alcoholic hepatitis and hepatic encephalopathy. However, only a few such patients qualify for glucocorticoid treatment, because patients with active gastrointestinal bleeding, infection, or renal insufficiency should not be treated. The usual treatment regimen is either prednisone or prednisolone, 40 mg daily for 4 weeks, followed by tapering of therapy over 1 to 2 weeks. Although propylthiouracil and colchicine have both been used in patients with alcoholic liver disease, the evidence warranting their use is not conclusive. Therefore, therapy for alcoholic cirrhosis is generally supportive and is aimed at improving nutrition, encouraging abstinence, and treating complications.


Liver Transplantation

Treatment of the patient with alcoholic cirrhosis mirrors the care of patients with any other type of cirrhosis, and includes prevention and management of ascites, spontaneous bacterial peritonitis, variceal bleeding, encephalopathy, malnutrition, and hepatocellular carcinoma. Once advanced cirrhosis has occurred with evidence of decompensation (ascites, spontaneous bacterial peritonitis, hepatic encephalopathy, variceal bleeding), the patient should be referred to a transplantation center.

Acute alcoholic hepatitis is generally considered a contraindication to liver transplantation. For more than a decade, alcoholic cirrhosis has been the second leading indication for liver transplantation in the United States. Most transplantation centers currently require patients with a history of alcohol abuse to have documented abstinence of at least 6 months before undergoing transplantation. This requirement theoretically has a dual advantage of predicting long-term sobriety and allowing recovery of liver function from acute alcoholic hepatitis. This 6-month abstinence rule might not have much prognostic significance in predicting recidivism, however. Alcohol use of any quantity after transplantation for alcohol-related liver disease approaches 50% during the first 5 years, and abuse occurs in up to 15% of patients. (Table 4 ) summarizes investigated treatments for alcoholic liver disease.

Table 4. Treatments Investigated for Alcoholic Liver Disease


Routine Use Recommended?

Potential Benefit








Nutritional support


Survival, laboratory









Consider if DF ≥ 32

Survival, less renal failure




Consider (preliminary data)














Insulin, glucagon





Calcium channel blocker





Vitamin E










Silymarin (milk thistle)





Liver transplantation

Consider (for decompensated cirrhosis)

Survival ~ 70% at 5 yr



DF, discriminant function. SAMe, S-adenosyl-L-methionine



Primary biliary cirrhosis most often occurs in women between 30 and 50 years of age.7 The presence of serum autoantibodies, an association with other autoimmune diseases, and the resemblance of the bile duct lesions in primary biliary cirrhosis to those seen in chronic graft versus host disease suggest that immune mechanisms play an important role in the pathogenesis of this disorder. Studies have also shown that primary biliary cirrhosis is associated with the HLA-DR8 haplotype, suggesting a genetic predisposition to the disease.


Clinical features Presenting complaints in patients with primary biliary cirrhosis are fatigue and generalized pruritus. Jaundice may not develop until 5 to 10 years after the onset of pruritus and systemic symptoms. Some patients experience bone pain, multiple fractures, and vertebral collapse. The usual cause of primary biliary cirrhosis is osteoporosis, which occurs in 20% to 30% of patients. Less commonly, osteomalacia is also present. Factors that give rise to the bone abnormalities include malabsorption of calcium and phosphate, altered vitamin D metabolism, cholestyramine therapy, and poor nutrition. Physical examination often reveals xanthelasma, xanthomas, hepatosplenomegaly, hyperpigmentation, and excoriation of the skin [see Figure 3]. If the disease is advanced, scleral icterus, ascites, and edema will also be present.

Figure 2 Alcoholic cirrhosis in the liver of a 58-year-old man produces distortion with scar tissue (arrows) that spreads through the parenchyma and outlines small regenerating nodules.



Figure 3 This patient with advanced primary biliary cirrhosis demonstrates some characteristic signs of the disease: (a) xanthelasma, a common finding, and (b) xanthomas, which are prominent on the elbows.

Laboratory tests.

Typical laboratory findings of primary biliary cirrhosis include an elevated alkaline phosphatase level (usually > 300 IU/L and often > 700 IU/L), a serum cholesterol level above 300 mg/dl, an elevated IgM level, and antimitochondrial antibody detectable at high titer (in 90% to 95% of patients). A moderate number of patients with primary biliary cirrhosis have concomitant disease, such as renal tubular acidosis, cleroderma, CREST syndrome (calcinosis, Raynaud phenomenon, esophageal dysmotility, sclerodactyly, and telangiectasia), or Sjögren syndrome. Primary biliary cirrhosis may have clinical and laboratory features similar to those of cirrhosis secondary to chronic biliary tract disease. Indeed, carcinoma of the pancreas or biliary tree, common duct stones, postoperative bile duct stricture, and primary sclerosing cholangitis or pericholangitis secondary to inflammatory bowel disease may all mimic some of the laboratory and histologic features of primary biliary cirrhosis. There is seldom a need, however, to directly visualize the biliary tree in patients who display the typical clinical, laboratory, and histologic features of primary biliary cirrhosis.

Liver biopsy.

Liver biopsy may reveal bile duct destruction with lymphocytic-plasmacytic infiltration of portal areas, periportal granuloma formation, and portal scarring with linking of portal tracts [see Figure 4]. Ductular proliferation is common. When scarring is extensive, nodule formation, often with retention of the central veins, can be found. Bile stasis is usually periportal and indicates advanced disease.


The management of primary biliary cirrhosis includes ursodiol therapy and nonspecific treatment of pruritus, malabsorption, bone disease, and portal hypertension.

Specific treatment

Ursodiol, a hydrophilic bile acid, has been given to patients with primary biliary cirrhosis on the premise that altering the composition of the endogenous bile acid pool may prove beneficial by reducing the concentration of potentially toxic endogenous hydrophobic bile acids. In one large placebo-controlled trial, 2 years of treatment with ursodiol at a dosage of 13 to 15 mg/kg daily resulted in clinical, biochemical, and histologic improvement; decreased need for liver transplantation; and increased survival. These favorable results were confirmed by two additional large trialsa Canadian multicenter trial and a Mayo Clinic trial12which showed trends toward increased survival and decreased need for liver transplantation in the ursodiol treatment group. Most patients are given ursodiol because it appears to be effective, is safe, and may relieve pruritus. In a small pilot study, methotrexate appeared to be of benefit in patients with primary biliary cirrhosis, but therapy was associated with a number of side effects, including bone marrow suppression and pulmonary toxicity.13 In a 2-year study of the use of methotrexate in combination with ursodiol, no benefit was noted over the use of ursodiol alone, and methotrexate toxicity was substantial. General use of methotrexate is not warranted until its efficacy and safety profile is further studied. Corticosteroids, azathioprine, penicillamine, cyclosporine, and colchicines have been used to treat patients with primary biliary cirrhosis. Corticosteroids do not alter the course of the disease, and they accelerate the onset of osteoporosis. Azathioprine, cy closporine, and penicillamine are not used for therapy. Two randomized clinical trials evaluated the efficacy of colchicine therapy at a dosage of 0.6 mg twice daily. Colchicine improved the results of liver tests but without improvement in symptoms or histology. There was the suggestion that survival was enhanced. However, a long-term follow-up of one of the randomized colchicine trials did not confirm a survival benefit. Colchicine produced only minor side effects, which were easily controlled by dose reduction in these studies.






Figure 4 Dense portal inflammatory reaction (thin arrow) and portal granulomas (thick arrow) characterize primary biliary cirrhosis affecting the liver of a 29-year-old woman who underwent a cholecystectomy.

Nonspecific treatment.

Nonspecific therapy is directed at relieving symptoms during the slow but relentless course of the disease. The anion exchange resin cholestyramine may help alleviate pruritus. The usual dosage is 4 g given orally three times a day. Some patients find relief at a lower dosage, although others require up to 16 to 20 g/day. Cholestyramine is often poorly tolerated but may be more palatable when taken with meals or mixed in applesauce or juice. Rifampin (300 to 450 mg/day in divided doses) and ultraviolet light therapy may prove helpful in some patients with severe pruritus. Antihistamines seldom prove efficacious, but their sedative effects may allow a patient to sleep despite continuing pruritus. Malabsorption of fat-soluble vitamins in rough proportion to the degree of cholestasis occurs in patients with primary biliary cirrhosis. Fat-soluble vitamin supplements are thus recommended for patients with low serum levels. The usual treatment includes oral vitamin K (5 mg/day), a water-soluble form of vitamin A (10,000 to 25,000 U/day), vitamin D in the form of either 25-dihydroxyvitamin D3 [25-(OH)D3] (calcifediol) (50 ìg/day) or 1,25-dihydroxyvitamin D3 [1,25-(OH)2D3] (calcitriol) (0.5 to 1.0 ìg/day), supplemental calcium (1.5 g/day), and vitamin E (400 to 1,000 U/day). Serum calcium levels should be monitored during the first few months of vitamin D and calcium therapy.


The prognosis varies, but the clinical course is generally indolent. Major hepatic dysfunction usually does not occur until very late. The median survival time is about 10 years. Hemochromatosis Hepatic iron overload may be primary (most often caused by hereditary hemochromatosis) or secondary (related to transfusional iron loading, ineffective erythropoiesis, or end-stage liver diseaseparticularly alcoholic liver disease, chronic hepatitis C, and nonalcoholic steatohepatitis).19 Patients with these chronic liver diseases may have abnormal iron study results and elevated serum ferritin levels, but hepatic iron concentration measured from a liver biopsy specimen is most often normal or only slightly elevated. Hereditary hemochromatosis is characterized by the deposition of large amounts of iron in the liver parenchymal cells [see Figure 5]. The accumulation leads to periportal cell destruction and hepatic scarring, culminating in cirrhosis. The disease occurs 10 times more often in males than in females. Symptoms generally appear between 40 and 60 years of age in men or after menopause in women. Occasionally, the disease is manifested at a much earlier age.

Etiology and Genetics

Hereditary hemochromatosis is inherited as an autosomal recessive defect that affects approximately one in 300 persons. 19,20 The heterozygote carrier rate is estimated to be one in 10 to 12 of the white population. Heterozygotes may show some abnormalities of iron storage, but clinical disease does not develop under normal circumstances. In 1996, a candidate gene, termed HFE, was discovered; it encodes for a major histocompatibility complex class Ilike molecule and requires â2- microglobulin for normal presentation on the cell surface. Two missense mutations have been identified in the HFE gene: one results in a change of cysteine at position 282 to tyrosine (Cys282Tyr), and the second results in a change in histidine at position 63 to aspartate (His63Asp). Mutation in the homozygous form is present in 85% to 90% of patients with phenotypic hemochromatosis. Iron deposits in the pancreas and heart muscle lead to dysfunction of these organs. When the symptoms of hepatic dysfunction first appear, about half of patients have diabetes mellitus, 15% have congestive heart failure or arrhythmias, and a significant minority have stiffness and joint pain. Impotence, apparently related to pituitary dysfunction, is also common.


Clinical features In advanced disease, bronze discoloration of the skin secondary to deposition of both melanin and iron appears. The liver is moderately enlarged; splenomegaly is noted in about half of patients. When disease is less advanced, the skin may have normal color, and the liver may be barely palpable. Signs of portal hypertension eventually develop in most cases. Primary liver cell cancer occurs in about 15% to 20% of patients.

Laboratory tests.

Laboratory analysis reveals an increase in serum iron associated with an 80% to 90% saturation of serum transferrin (15% to 47% saturation is normal). Serum ferritin is usually elevated as well. An elevated mean linear attenuation coefficient (CT number) on CT scanning of the liver may signal the presence of increased hepatic iron stores.22 MRI may also demonstrate iron overload in hereditary hemochromatosis. Mild elevations of serum aminotransferase and alkaline phosphatase levels are not uncommon, but jaundice is unusual. The serum albumin level and the prothrombin time remain in the normal range until late in the course. Serum iron concentration and total iron-binding capacity can be used to screen populations for hemochromatosis. A fasting transferrin saturation of 62% or higher in men (and perhaps 50% in women) identifies a high proportion of patients who are homozygous for hemochromatosis. The serum ferritin concentration has not proved to be an effective screening tool, because too few homozygous individuals have elevated levels before clinical disease develops. Identifying a homozygous individual warrants investigating his or her siblings, because 25% of siblings are expected to be homozygous for the disease as well.



Figure 5 (a) A percutaneous liver biopsy specimen was taken from a 30-year-old woman with hepatosplenomegaly and amenorrhea of 6 months duration. Pigment both in hepatic parenchymal cells (thick arrow) and in bile duct cells (thin arrow) is apparent. (b) Higher-magnification iron stain of the specimen confirms that the pigment is iron both in parenchymal cells (thick arrow) and in bile duct cells (thin arrow). The woman, who also had hemochromatosis, required removal of 72 units of blood over 1.5 years to render her liver free of excess iron.

An elevated serum iron or serum ferritin level is not diagnostic, because these values can be raised in a wide variety of liver diseases marked by hepatic cell death. An elevated serum iron or ferritin level is not uncommon in decompensated alcoholic liver disease, acute viral hepatitis, or chronic active hepatitis. The widely accepted criteria for the diagnosis of iron overload caused by hereditary hemochromatosis include 4 g or more of iron removed by phlebotomy (16 units of blood) before the onset of iron-limited erythropoiesis or at least one of the following results derived from liver biopsy: grade 3 or 4 stainable iron in hepatocytes, hepatic iron concentration greater than 80 μmol (4,500 ìg) per gram of dry weight of liver tissue, and a hepatic iron index (hepatic iron concentration in ìmol divided by age in years) greater than 1.9. The identification of specific mutations in the HFE gene of patients with hemochromatosis has permitted the introduction of genetic testing in the clinical setting. Most patients of northern European descent with classic phenotypic hereditary hemochromatosis are homozygous for C282Y or, less commonly, are heterozygous for compound C282Y/H63D.

Liver biopsy

The characteristic finding on liver biopsy is a heavy deposit of hemosiderin granules in hepatocytes and bile duct cells. Fibrosis may range from minimal to well-established cirrhosis. At times, hereditary hemochromatosis is difficult to distinguish from cirrhosis with secondary iron overload. A preponderance of parenchymal iron relative to the amount of scar tissue and the presence of iron in the bile duct cells characterize hereditary hemochromatosis. Iron overload secondary to underlying cirrhosis is usually associated with advanced cirrhosis, relatively less stainable iron, and absence of iron in the bile ducts. When excess hepatic iron derives from an exogenous source, such as a series of massive transfusions for chronic hemolytic anemia, iron is prominent in the Kupffer cells. When the morphologic features of the liver biopsy do not clearly distinguish between hereditary hemochromatosis and secondary iron overload, quantitative analysis of the hepatic iron content may prove he lpful. Patients with hemochromatosis typically have quantitative hepatic iron values ranging from 200 to 800 μmol/g dry weight (normal, < 35 μmol/g), whereas patients with alcoholic siderosis have hepatic iron content ranging from 40 to 100 μmol/g. Another useful diagnostic test for hemochromatosis is calculation of the hepatic iron index; this value is usually greater than 2 in homozygotes and less than 2 in patients with alcoholic siderosis. Finally, tissue obtained from the heart, pancreas, or skin of patients with hemochromatosis shows heavy infiltration of stainable iron.


Early detection and treatment of patients with hereditary hemochromatosis is essential. The usual therapy is removal of the excess iron by weekly phlebotomy. Because each pint of blood contains 250 mg of iron, removal of 1 pint of blood a week will deplete the iron stores in most patients with hemochromatosis in 1 to 2 years. Therapy aims for persistently low serum iron and ferritin levels, which reflect absence of stainable iron on liver biopsy. Subsequent phlebotomies can be performed every 3 to 4 months to prevent reaccumulation of iron. If patients are identified before cirrhosis develops and total body iron depletion is successfully accomplished, life expectancy approaches normal. Treated patients who have cirrhosis do better than untreated patients but remain at risk for primary liver cell cancer years after successful iron depletion. Failure to deplete iron stores after 18 months of treatment is a poor prognostic sign. Signs of liver and cardiac disease abate in 70% of treated patients, but endocrine abnormalities and arthropathy are improved in only 20% of those treated. Repeated phlebotomies are obviously impractical in managing iron overload that results from the therapy for hemolytic anemia. In such patients, deferoxamine, administered subcutaneously at a dosage of 1 to 3 g over 12 hours, produces an average urinary iron loss of 50 mg each day. The addition of ascorbic acid, 500 mg/day orally, may double the rate of urinary iron excretion.


Wilson disease, or hepatolenticular degeneration, is an autosomal recessive disorder found in about one in 30,000 to 50,000 persons, with a gene frequency of 1:90 to 1:15


The disease is named after the American-born British neurologist, Dr. Samuel Alexander Kinnier Wilson who, in 1912, composed his doctoral thesis on the pathologic findings of "lenticular degeneration" in the brain associated with cirrhosis of the liver. Dr. Wilson's report was preceded almost 30 years earlier by Dr. Carl Westphal's clinical description of what he termed "pseudosclerosis" in patients suffering from tremors without anatomic findings on autopsy. Dr. Wilson's work built upon the experience in part from a series of patients collected by Sir William Gowers, who similarly identified the combination of neurologic and liver disease in 1888. Although the medicinal and toxic effects of copper have been known since antiquity, it was A.J. Glazebrook in 1945 and John Cumings in 1948 that linked copper accumulation with the basal ganglia and hepatic pathology. The genetic inheritance was originally proposed by H.C. Hall in 1921 as an autosomal recessive pattern, but subsequently confirmed by A.G. Bearnin 1953 by genetic ratio analysis calculation. Over 30 years later, its genetic locus was assigned to the long arm of chromosome 13. Ultimately, the genetic basis for Wilson disease (WD), the ATP7B mutation, was identified and cloned in 1993.

The diagnosis of WD first was dependent on recognition of the syndrome of neurologic findings with associated cirrhosis, but this was dramatically changed when Kayser-Fleischer (K-F) rings were identified as present in clinically affected patients. Diagnostic testing improved further decades later by the routine adoption of testing for liver dysfunction using serum and blood tests and liver biopsy to evaluate histology, quantify hepatic copper concentration, measure elevated urine copper excretion, and by the recognition that serum or plasma ceruloplasmin concentrations are reduced in most patients with WD. These findings form the basis for most of the phenotypic characterization of patients that we still use to date. Other adjunctive testing included the use of radiocopper testing for labeled ceruloplasmin that was useful for identifying the minority of patients with WD with normal levels of ceruloplasmin, but this test is rarely used today. The most recent advance in testing is molecular genetic testing that has followed the identification of the gene for WD and disease-specific mutations.

We have been able to effectively treat WD for less than a century. Historically, the disease was diagnosed after the development of neurologic symptoms and was invariably fatal. The first treatment developed was British anti-lewisite (BAL), a compound developed for countering the toxic effects of mustard gas that was found to be a chelator of copper. This parenterally administered medication resulted in increased copper excretion and reversed neurologic symptoms in many patients. The first oral treatment, d-penicillamine, was developed by John Walshe, who recognized the potential for this compound to chelate copper and induce cupriuria with high efficiency. He was also instrumental in the development of another chelating agent, trientine, and was the first to use tetrathiomolybdate in humans, a compound originally used by veterinarians for copper-poisoned sheep. Confirmation of the utility of tetrathiomolybdate has also been performed by Brewer et al. Schouwink was the first to propose using zinc to block copper absorption to treat WD, and this has been another useful oral therapy currently in use for many patients. A very important historic milestone with respect to treatment of WD was the recognition that preemptive treatment could prevent the development of disease progression, something that seems almost incontrovertible at this time, but which was not initially accepted. Liver transplantation is curative and represents a gross form of genetic therapy for WD.

Etiology and Genetics

Wilson disease results from mutations in the ATP7B gene inherited as an autosomal recessive trait on the long arm of chromosome 13. ATP7B encodes a transmembrane copper-dependent P-type ATPase located intracellularly. ATP7B protein transports copper both into the trans-Golgi network for incorporation into ceruloplasmin and also into the vesicles that merge with the bile canaliculus for biliary copper excretion. Reduction in ATP7B function results in decreased biliary copper excretion with increased copper accumulation in hepatic and extrahepatic tissues that leads to the clinical features of WD. This disorder has a global incidence of 1:30,000, and is present in all populations. Over 500 mutations have been identified with specific populations sharing distinct mutations. In Caucasian populations, up to 60% of patients have the point mutation H1069Q in exon 14. In one Central/Eastern European study, mutations in 3402delC, W779X, R778G, and 1340del4 represented more than 10% of those without H1069Q mutations. In other populations, separate mutations predominate, for example, Arg778Leu and Thr935Met mutations in Chinese populations; Q125R, A1003T, and I1102T in northwest Indian pedigrees; and Ser744Pro, Gly341Ser, and Glu1399Arg in a Saudi Arabian cohort. Further detail regarding the molecular genetics for WD are discussed in this issue by Bennett and Hahn.

Other genotypic elements such as modifier genes and gender-related factors may influence the phenotypic expression of hereditary liver disease including genetic hemochromatosis, α-1-antitrypsin deficiency and WD. For example, MURR1 (aka COMMD1), is thought to adversely interact with the WD gene protein product. In one study including 63 WD patients, 30% had detectable MURR1 gene changes that were associated with earlier onset of hepatic and neurologic disease. In a Polish cohort of fulminant WD patients, 92% (12 out of 13) were female, which highlights a gender-specific effect and possibly an associated hormonal influence on clinical phenotype.

In another example of the effect of modifier genes, tried to delineate why some patients have later-onset neurologic as well as hepatic symptoms by examining the potential influence of ApoE genotype in WD patients homozygous for the H1069Q mutation. Though the distribution of ApoE genotypes was similar to known distributions in healthy Europeans, the onset of symptoms was delayed by ~5 years in patients with the ApoE ε3/3 genotype to 25 years of age at presentation compared with patients with the ApoE ε3/4 genotype. Other phenotypic findings were not modified. Therefore, it is possible that the presence of ApoE ε3/3 attenuated the clinical manifestations in WD by mechanisms that might involve the antioxidant properties, membrane-stabilizing effects, and/or astrocyte axonal growth enhancement by the ApoE 3 protein. Few other homogeneous cohorts are available to validate this finding.

The genetic defect for Wilson disease is located on chromosome 13, where disease-specific mutations in a gene that codes for a copper-binding P-type adenosine triphosphatase protein have been identified. In this disorder, the excretion of copper into the bile appears to be defective, leading to an accumulation of excess copper in most body tissues. The incorporation of copper into ceruloplasmin is also impaired.


Clinical features By 15 years of age, affected persons have usually experienced symptoms caused by either neurologic or hepatic dysfunction. Although Wilson disease occasionally presents for the first time in persons as old as 30 years, this late an onset is the distinct exception. In about 40% of patients, the first manifestations of the disease are symptoms related to hepatic dysfunction. The hepatic disease is usually a chronic disorder manifested by fatigue, jaundice, spider nevi, ascites, edema, splenomegaly, and variceal hemorrhage. Associated hemolytic anemia is a clue to the diagnosis. Occasionally, the liver disease mimics severe acute hepatitis and progresses to death in a few days to weeks. Neurologic symptoms include tremors, rigidity, gait disturbances and clumsiness, slurring of speech, and personality changes. The pathognomonic sign is the Kayser-Fleischer ring, a thin, brown crescent of pigmentation at the periphery of the cornea. Although this feature is usually circumferential, it may be located only superiorly and inferiorly. Early in the disease, a slitlamp examination may be required to identify the telltale ring. It may be particularly difficult to detect on routine eye examination in brown-eyed patients.

Laboratory tests

On first examination, at least 50% of patients have hepatosplenomegaly and moderate liver function abnormality. Two distinguishing laboratory findings are depression or absence of serum ceruloplasmin and an increase of urinary copper levels from a normal value of less than 50 mg/day to as high as 1,000 mg/day. In a small percentage of patients with Wilson disease, serum ceruloplasmin or urinary copper levels may be normal, and Kayser-Fleischer rings may be absent. Hence, it is wise to evaluate all three of these factors because it is likely that at least one will be abnormal. In problematic cases, finding excess urinary copper after the administration of 1,000 mg of penicillamine may also help establish the diagnosis.29 If doubt persists, the ultimate standard is an increase in hepatic tissue copper concentration; however, this finding is conclusive only if the patient does not have long-standing cholestasis, which can also increase the hepatic copper concentration.


Treatment of Wilson disease requires the administration of either trientine or penicillamine, chelating agents that bind copper and promote the urinary excretion of 1,000 to 3,000 mg of copper a day. The usual dosage for either drug is 1 g/day. Clinical improvement generally parallels depletion of the tissue copper buildup. Trientine has become the preferred drug because penicillamine therapy is associated with significant side effects most commonly, nausea and abdominal discomfort immediately after taking the medication. More serious side effects of penicillamine include leukopenia and thrombocytopenia, which may, in a rare case, lead to aplastic anemia. A small percentage of patients experience the nephrotic syndrome. All patients with Wilson disease should be followed closely with routine urinalyses and blood counts, particularly during the first few months of therapy. Because penicillamine is a pyridoxine antagonist, 50 mg of pyridoxine should be given once a week. If trientine and penicillamine cannot be tolerated, oral zinc therapy should be considered. Elemental zinc may be administered in the form of zinc acetate in three divided doses on an empty stomach for a total daily dose of 150 mg. Zinc therapy increases fecal copper loss and induces a negative copper balance in patients with Wilson disease.30 The onset of action is delayed, however, and the longterm efficacy of zinc therapy is unknown.

α1-antitrypsin deficiency

Homozygous α 1-antitrypsin deficiency is associated with a rare syndrome of progressive cirrhosis.2 Although originally described in children with juvenile cirrhosis, the combination of α 1-antitrypsin deficiency and cirrhosis has been reported in adults. Adult patients usually have accompanying emphysema. The diagnosis of α 1-antitrypsin deficiency should always be considered in cases in which the cirrhosis does not have an obvious antecedent. On first presentation, most patients have moderate hepatomegaly and mild abnormality of liver function. Absence of α 1-antitrypsin globulin on protein electrophoresis makes the diagnosis very likely. Specific measurements of α 1-antitrypsin levels in the




Figure 6 (a) Nodules of liver tissue surrounded by scar tissuea feature of cirrhosisare seen in a surgical liver biopsy specimen from a 67-year-old man with emphysema and mild hepatomegaly. (b) In a higher-magnification view of the specimen, multiple, round, hepatic cell inclusion bodies (arrows) are distinctive for á1-antitrypsin globulin deficiency.


blood confirm the diagnosis. Genetic variants have been found, reflecting the existence of more than 75 different alleles for the gene that controls production of á1-antitrypsin. Protease inhibitor type ZZ (PiZZ) is the genotype generally associated with cirrhosis and emphysema. An amino acid substitution in the Z variant protein allows the α1-antitrypsin protein molecules to polymerize within the liver cell, thereby impairing excretion of the protein from the liver. Characteristic periodic acidSchiff positive (diastase- resistant) inclusion bodies containing abnormal α1-antitrypsin globulin can be seen in the hepatocytes [see Figure 6]. Individuals carrying a single PiZ allele may also be at risk for cirrhosis and liver failure.33 A significant proportion of patients homozygous for PiZZ who also have chronic liver disease show evidence of hepatitis B or hepatitis C infection. The most important treatment for α1-antitrypsin deficiency is avoidance of cigarette smoking, which markedly accelerates coexistent lung disease. There is no specific treatment for liver disease associated with α1-antitrypsin deficiency, and thus, therapy is supportive and includes avoidance of alcohol. Augmentation therapy to increase the circulating levels of α1-antitrypsin is used to treat emphysema but not liver disease in patients with antitrypsin deficiency. Patients with end-stage liver disease and liver failure caused by α1-antitrypsin deficiency are candidates for liver transplantation, and long-term survival is excellent.

Complications of Cirrhosis


Bleeding varices constitute one of the most serious complications of cirrhosis. Mortality during the acute episode may reach 60% to 70%. Many factors associated with decompensated cirrhosis augment this high risk, including general debility, coagulation defects, and hepatic encephalopathy; the size of the varix is also correlated with the risk of bleeding. Recurrent bleeding, common within the first 2 weeks of the initial episode, also contributes to the high mortality. If the patient survives longer than 6 weeks, the risk of recurrent bleeding drops sharply and approaches that of cirrhotic patients who have never bled. Bleeding esophageal varices are most reliably identified by upper gastrointestinal endoscopy [see Figure 7].

Treatment of Acute Variceal Bleeding

Endoscopic therapy.

Endoscopic therapy with variceal banding or sclerotherapy is the treatment of choice for the immediate control of esophageal variceal bleeding. Banding or sclerotherapy is also effective in the longterm control of recurrent esophageal variceal hemorrhage, but the effect on survival remains uncertain. Esophageal ligation is similar to the banding of hemorrhoids, but it is performed with a modified endoscope. In a meta-analysis of published trials, variceal ligation obliterated varices more rapidly than sclerotherapy and was as effective as sclerotherapy in controlling bleeding with less frequent side effects.43 Ligation is now considered the endoscopic treatment of choice for patients with esophageal variceal bleeding. In addition, a redesigned endoscope that can deliver several rubber bands after intubation of the esophagus obviates multiple insertions of the scope through an overtube, which was associated with several cases of esophageal perforation. Complications of variceal sclerotherapy are common; these include retrosternal pain, esophageal ulceration, hemorrhage, pleural effusion, and esophageal stricture and perforation. Bleeding from gastric varices is less common in patients with cirrhosis but more difficult to treat effectively, except with surgery. If variceal bleeding persists or recurs and is life-threatening, insertion of a Sengstaken-Blakemore





Positioning of a Sengstaken-Blakemore
tube in situ

or Minnesota tube will stop the bleeding, at least temporarily, in more than 90% of patients. This treatment, which is associated with significant morbidity, is fortunately seldom required.

Pharmacologic therapy

Intra-arterial vasopressin does not improve overall survival, and its administration requires specialized angiographic expertise that is not widely available. Vasopressin administered intravenously in a continuous drip is of doubtful efficacy in patients with actively bleeding esophageal varices. When vasopressin is used, adjunctive therapy with nitroglycerin should be administered to minimize side effects, particularly tissue ischemia.44 The intravenous infusion of somatostatin or its analogue, octreotide (50 μg/hr), is more effective than vasopressin and has a lower risk of side effects; it is now the standard pharmacologic therapy used for acute variceal bleeding. Octreotide is usually used with endoscopic therapy and is continued for 24 to 72 hours after the bleeding stops.

Treatment of Recurrent Variceal Bleeding

Transjugular intrahepatic portosystemic shunt The placement of a transjugular intrahepatic portosystemic shunt (TIPS) is rapidly becoming an accepted technique for the treatment of bleeding esophageal varices refractory to endoscopic therapy. This procedure creates a shunt but avoids the complications of major surgery. The initial enthusiasm surrounding the introduction of TIPS has been tempered by recognition of the complications of encephalopathy, which develops in 10% to 30% of patients and is refractory to medical therapy in approximately 5%, and shunt stenosis or occlusion, which develops in 30% to 50% of patients at 12 months. It seems reasonable to restrict this form of treatment to centers with experienced staff and to patients who are poor surgical candidates, are refractory to endoscopic therapy, or have bleeding from gastric rather than esophageal varices. A number of trials have compared TIPS with endoscopic therapy (either sclerotherapy or banding) after initial control of hemorrhage in patients with Child class A or B cirrhosis; several tentative conclusions can be drawn from these studies. Mortality associated with TIPS is not significantly different from that associated with endoscopic treatment. TIPS is superior to endoscopic therapy in the prevention of variceal rebleeding (19% versus 47%). TIPS may be particularly attractive for patients in whom compliance with follow-up endoscopy is in doubt. However, one must accept the increased risk of hepatic encephalopathy after TIPS (34%, versus 18% after endoscopic therapy). TIPS is less attractive for patients with advanced chronic liver disease and Child class C cirrhosis with poor synthetic function. The survival of patients after TIPS can be predicted by the Mayo Clinic endstage liver disease score, which includes the following four variables: serum bilirubin, serum creatinine, INR for prothrombin time, and cause of the underlying liver disease. The long-term utility of TIPS must also be evaluated in context of shunt stenosis or occlusion, which is a management problem after TIPS. Thus, for esophageal variceal bleeding, TIPS cannot be recommended as the first-choice treatment for prevention of variceal rebleeding.

Surgical portosystemic shunt Recurrent or continued bleeding may indicate a need for a surgical portosystemic shunt. This major operation carries a mortality of approximately 40% when performed on an emergency basis. If bleeding can be stopped and shunt surgery performed electively, mortality declines substantially. Although portosystemic shunting procedures do not appear to prolong survival, they do prevent subsequent bleeding. The major problem after surgery is intractable hepatic encephalopathy and hepatic failure. The preferred shunt procedure is the one with which the surgeon is most experienced. A distal splenorenal shunt with concomitant gastroesophageal devasc ularization selectively decompresses esophageal varices while maintaining mesenteric blood flow to the liver. In most but not all studies, use of the distal splenorenal shunt reduced the incidence of severe encephalopathy as a late complication after surgery, compared with conventional shunts. The procedure is technically difficult; time will reveal if it possesses any long-term advantages.

Figure 7 Endoscopy reveals large, tortuous esophageal varices that

have a characteristic bluish color.

Medical treatment.

Propranolol produces a sustained reduction in portal pressure in patients with cirrhosis and may be expected to prevent bleeding from esophageal varices. One study noted a dramatic reduction in episodes of rebleeding and improved 2-year survival when propranolol was given in a sufficient dosage to reduce the resting heart rate by 25%. However, another study found no decrease in variceal hemorrhage with a similar regimen and further reported that the beta blockade induced by propranolol complicated the resuscitation of bleeding patients. Propranolol appears to be less effective than sclerotherapy in preventing rebleeding from esophageal varices.

Prophylactic Treatment for Variceal Bleeding

Because the first episode of variceal bleeding can result in significant morbidity and mortality, there has been considerable interest in the prophylactic treatment of esophageal varices in persons who have never bled. Prophylactic portosystemic shunts decrease rebleeding but do not enhance survival. Prophylactic sclerotherapy has been studied in several centers with mixed results. In the largest study, which was restricted to alcoholic patients, this approach proved harmful. The experience with the beta-adrenergic antagonists propranolol and nadolol has been somewhat more encouraging because the drugs appear both to prevent the first episode of bleeding and to reduce mortality associated with bleeding in patients who have moderate or large esophageal varices.51 If a patient known to have large varices is well motivated and tolerates the medication, beta-adrenergic antagonists may be considered. Isosorbide-5- mononitrate, a long-acting nitrate, may also help prevent the first variceal hemorrhage.




Ascites, a common sequela of many forms of cirrhosis, is usually detected by finding shifting dullness or a fluid wave on physical examination of the abdomen.



Occasionally, ascites presents as a right-sided pleural effusion. Portal hypertension, decreased serum albumin with consequent loss of oncotic force within the vascular and interstitial spaces, and renal retention of sodium and water contribute to ascites formation. Although infectious, pancreatic, or neoplastic causes of ascites are infrequent, they should not be overlooked, because therapy and prognosis differ for each condition. To exclude such possible causes, a small amount of ascitic fluid should be removed from the abdominal cavity using a narrow-gauge needle. The gross appearance of the fluid may suggest an unusual etiology. For instance, cloudy fluid implies an infection; bloody fluid, a tumor; and milky fluid, lymphatic obstruction. Routine laboratory studies of the fluid should include white cell and differential cell counts, protein and albumin determinations, and culture. In ascites caused by cirrhosis, the serum-ascites albumin gradient is greater than 1.1, the total protein is less than 2.5 g/dl, the total white cell count is less than 300/mm3, the proportion of granulocytes is less than 30%, and cultures are negative. Approximately 5% of patients with ascites attributable to cirrhosis have ascitic fluid that has a total protein concentration greater than 2.5 g/dl.


Initial treatment The treatment of uncomplicated ascites in patients with cirrhosis is straightforward. First, any medications that inhibit prostaglandin synthesis, such as aspirin or nonsteroidal anti-inflammatory drugs, should be discontinued because they decrease the glomerular filtration rate, reduce sodium excretion, and blunt the natriuretic response to diuretics. After such agents have been withdrawn, sodium and water restriction should be instituted. Although extreme sodium and water restriction can be accomplished in the hospital, it is not usually necessary, nor will it be maintained once the patient goes home. A diet in which sodium is restricted to 2 g and water is restricted to 2,000 ml daily is often well tolerated.

Monitoring of patients with ascites

Medical treatment

If dietary restriction and bed rest do not induce diuresis, the medication of choice is spironolactone. Seventy-five percent of hospitalized patients with ascites obtain relief with spironolactone alone. Because spironolactone inhibits the action of aldosterone, it tends to prevent the renal excretion of potassium, which is desirable for patients with cirrhosis. For this reason, however, use of spironolactone is not advisable for patients with renal insufficiency. In addition, patients taking spironolactone should avoid potassium chloride salt substitutes. Long-term use of spironolactone produces gynecomastia in 20% to 30% of patients.Spironolactone is given in an initial dosage of 100 mg daily, which is increased to 200 mg daily if diuresis has not ensued after 2 to 3 days of treatment. Although spironolactone can be increased to 400 mg/day or more, the drug is less well tolerated at these higher dosages. Therefore, if diuresis has not occurred at 200 mg daily, it is preferable to add furosemide in one 40 mg dose in the morning to the 200 mg daily dose of spironolactone. The furosemide dose may then be increased each day by 40 mg increments (administered in one dose) until diuresis ensues. Most patients begin to respond before daily dosages reach 120 to 160 mg of furosemide and 200 mg of spironolactone. The aim is to use the lowest possible dosages. The maximum diuresis of ascitic fluid should not exceed 1,000 ml/day. For that reason, daily weight loss in cirrhotic patients should not exceed 1 to 2 lb. A more rapid diuresis, particularly in patients with little or no peripheral edema, leads to dangerous diminution of intravascular and intracellular fluid volumes and to azotemia. Complications of diuretic treatment include severe electrolyte abnormalities, encephalopathy, azotemia, and dehydration. Complications are most common when diuresis has been rapid or when diuretic medication has been continued after the patient has been clinically judged free of excess body fluid.


Large-volume paracentesis has become popular in the treatment of patients with ascites. In one study, paracentesis of 4 to 6 L/day was accomplished safely and resulted in shorter hospital stays and fewer complications than conventional diuretic therapy. Patients usually welcome paracentesis because it relieves considerable discomfort. It also provides the physician with the ascitic fluid necessary for diagnostic purposes. Subsequent work has shown that the administration of 6 to 8 g/L of intravenous albumin after 5 L or more prevents renal insufficiency and hyponatremia induced by paracentesis. In about 5% of patients, ascites do not respond to the usual dosages of conventional diuretic medication, or diuresis is achieved only at the expense of renal function. In these patients, insertion of the LeVeen peritoneovenous shunt has been considered. The shunt routes ascitic fluid subcutaneously from the peritoneal cavity to the internal jugular vein via a one-way valve. Compared with medical therapy alone, the peritoneovenous shunt results in speedier resolution of the ascites. However, placement of the shunt does not alter survival. Because most patients continue to require diuretics, although at lower doses, the shunt may produce benefit by increasing renal blood flow. Serious complications of the shunt include bacterial infection of the peritoneum, disseminated intravascular coagulation, and rupture of esophageal varices. Because of these complications, the peritoneovenous shunt is seldom used.

Treatment of refractory ascites

Refractory ascites can also be effectively managed by placement of a TIPS.55 The majority of patients still require diuretic therapy, albeit at reduced dosages. The value of TIPS compared with repeated large-volume paracentesis for the management of refractory ascites awaits further study. However, TIPS is effective in the treatment of hepatic hydrothorax, which often accompanies refractory ascites.


Spontaneous bacterial peritonitis (SBP) is the development of peritonitis infection in the abdominal cavity) despite the absence of an obvious source for the infection. It occurs almost exclusively in people with portal hypertension (increased pressure over the portal vein), usually as a result of cirhhosis of the liver. It can also occur in patients with nephrotic syndrome

The diagnosis of SBP requires paracentesis (aspiration of fluid with a needle) from the abdominal cavity. If the fluid contains bacteria or large numbers of neutrophil granulocytes  (>250 cells/L) (a type of white blood cells), infection is confirmed and antibiottics are required to avoid complications. In addition to antibiotics, infusions of albumin  are usually administered.

Spontaneous bacterial peritonitis (SBP) develops in 10% to 25% of cirrhotic patients followed prospectively for at least a year. The cirrhosis is usually advanced and active, as manifested by hepatic encephalopathy, esophageal varices, and jaundice. The incidence of SBP is substantially higher in patients with ascitic fluid protein levels below 1.0 g/dl and serum bilirubin levels above 2.5 mg/dl. These findings could explain the increased risk of ascitic fluid infection, because the antibacterial activity of the ascitic fluid, as measured by opsonic activity, is proportional to the level of ascitic fluid protein. The exact pathogenesis is unknown. Presumably, hematogenous seeding of the ascitic fluid, which functions as an ideal bacterial culture medium, serves as a major route of infection. Cirrhosis undoubtedly facilitates the process by allowing enteric organisms to enter the bloodstream via the portosystemic collaterals, thus bypassing the major reticuloendothelial system in the liver.


The mechanism for bacterial inoculation of ascites has been the subject of much debate since Harold Conn first recognized the disorder in the 1960s. Enteric organisms have traditionally been isolated from more than 90% of infected ascites fluid in spontaneous bacterial peritonitis, suggesting that the GI tract is the source of bacterial contamination.

The preponderance of enteric organisms, in combination with the presence of endotoxin in ascitic fluid and blood, once favored the argument that spontaneous bacterial peritonitis was due to direct transmural migration of bacteria from an intestinal or hollow organ lumen, a phenomenon called bacterial translocation. However, experimental evidence suggests that direct transmural migration of microorganisms might not be the cause.

An alternative proposed mechanism for bacterial inoculation of ascites is hematogenous transmission in combination with an impaired immune system. Nonetheless, the exact mechanism of bacterial displacement from the GI tract into ascites fluid remains controversial.

A variety of factors contributes to peritoneal inflammation and bacterial growth in ascitic fluid. A key predisposing factor may be the intestinal bacterial overgrowth found in people with cirrhosis, mainly attributed to delayed intestinal transit time. Intestinal bacterial overgrowth, along with impaired phagocytic function, low serum and ascites complement levels, and decreased activity of the reticuloendothelial system, contributes to an increased number of microorganisms and decreased capacity to clear them from the bloodstream, resulting in their migration into and eventual proliferation within ascites fluid.

Interestingly, adults with spontaneous bacterial peritonitis typically have ascites, but most children with spontaneous bacterial peritonitis do not have ascites. The reason for and mechanism behind this is the source of ongoing investigation.


Traditionally, three fourths of spontaneous bacterial peritonitis infections have been caused by aerobic gram-negative organisms (50% of these being Escherichia coli). The remainder has been due to aerobic gram-positive organisms (19% streptococcal species). E coli is displayed in the image below.


Gram-negative Escherichia coli.

Gram-negative Escherichia coli.



However, some data suggest that the percentage of gram-positive infections may be increasing. One study cites a 34.2% incidence of streptococci, ranking in second position after Enterobacteriaceae. Viridans group streptococci (VBS) accounted for 73.8% of these streptococcal isolates.

Anaerobic organisms are rare because of the high oxygen tension of ascitic fluid.

A single organism is noted in 92% of cases, and 8% of cases are polymicrobia

Risk factors

Patients with cirrhosis who are in a decompensated state are at the highest risk of developing spontaneous bacterial peritonitis. Low complement levels are associated with the development of spontaneous bacterial peritonitis. Patients at greatest risk for spontaneous bacterial peritonitis have decreased hepatic synthetic function with associated low total protein level or prolonged prothrombin time (PT).

Patients with low protein levels in ascitic fluid (< 1 g/dL) have a 10-fold higher risk of developing spontaneous bacterial peritonitis than those with a protein level greater than 1 g/dL.

In a 2012 review by Siple et al, they show several case studies and cohorts of patients with cirrhosis and chronic liver disease who were on proton pump inhibitors (PPIs) for a prolonged duration who were at significantly increased risk for the development of spontaneous bacterial peritonitis. While prospective studies are needed on this subject, there appears to be a direct correlation between a lack of an acidic environment and portal hypertension to put these patients at increased risk for spontaneous bacterial peritonitis. Thus, in patients on long-term PPI therapy, the suspicion for infection should be heightened and the benefit of long-term PPI therapy should outweigh the risk for the development of spontaneous bacterial peritonitis.


In patients with ascites, the frequency may be as high as 18%. This number has grown from 8% over the past 2 decades, most likely secondary to an increased awareness of spontaneous bacterial peritonitis and a lowered threshold to perform diagnostic paracentesis.

No race predilection is known for spontaneous bacterial peritonitis. In patients with ascites, both sexes are affected equally.

Although the etiology and incidence of hepatic failure differ between children and adults, in those individuals with ascites, the incidence of spontaneous bacterial peritonitis is roughly equal. Two peak ages for spontaneous bacterial peritonitis are characteristic in children: the first in the neonatal period and the second at age 5 years.


Clinical features The typical attack of SBP is heralded by fever, peripheral leukocytosis, abdominal pain, hypoactive or absent bowel sounds, and rebound tenderness. Most patients do not demonstrate all these symptoms, and some have none. Hence, ascitic fluid should be analyzed whenever the condition of a patient with cirrhosis suddenly deteriorates.

Laboratory tests.

The ascitic fluid is often turbid because of leukocytosis and bacterial growth. Leukocyte cell counts greater than 1,000/mm3 consisting of more than 85% granulocytes are common. Almost all patients have ascitic fluid cell counts greater than 300/mm3; more than half of these are polymorphonuclear cells. However, not all patients with ascitic fluid leukocytosis have SBP. In practice, it is wise to treat patients with antibiotics when the clinical picture is suggestive and the ascitic fluid contains more than 500 white blood cells/mm3. The ultimate criterion for infection is demonstration of organisms either by Gram stain of the fluid (one fourth of cases) or by culture. To maximize detection of the responsible infectious organisms, 5 ml of ascitic fluid should be injected at bedside into both aerobic and anaerobic blood culture bottles. Two thirds of the causative organisms are enteric; Escherichia coli and Klebsiella species are the most common agents. Pneumococcus and Streptococcus organisms are responsible for as many as 20% of cases. In nearly half of cases, blood cultures are positive for the same organism found in the ascitic fluid.


Cefotaxime administered intravenously at a dosage of 2 g every 6 hours is an appropriate initial treatment for an episode of SBP; in patients with renal insufficiency, the dosage is adjusted downward. On this regimen, 75% to 80% of treated episodes resolve. A few episodes resolve after a change in the antibiotic regimen. However, 20% to 25% of patients die before the infection resolves. Therapy is equally effective whether given for 5 days or 10 days. Patients should be monitored closely and ascitic fluid checked at least once (e.g., after 48 hours) to ensure that the infection is being effectively treated. Despite optimal therapy, 40% to 60% of patients with SBP die. Half of the deaths are a direct result of the peritonitis; the other half succumb to other complications of their severe liver disease. Long-term oral therapy with norfloxacin (400 mg/day) or ciprofloxacin (750 mg once a week) reduces the incidence of recurrent spontaneous bacterial peritonitis attributable to aerobic gram-negative bacteria and should be considered in patients at high risk for recurrence.


The hepatorenal syndrome is defined as a functional renal failure associated with well-established and usually decompensated cirrhosis. When the hepatorenal syndrome develops, the outcome is usually fatal.The pathogenesis of the hepatorenal syndrome is uncertain, but reduced renal blood flow and glomerular filtration rate may precede overt renal failure by several months. Paradoxically, these alterations occur in association with increased plasma volume. An increase in blood flow to the renal medulla at the expense of the cortex (intrarenal shunting) occurs as well. Because many patients have associated hypotension and respond poorly to pressor agents, false neurotransmitters have been implicated in the pathogenesis of the hepatorenal syndrome.

Characteristic findings associated with hepatorenal syndrome

*        Ascites (but not necessarily jaundice) is usually present

*        Hyponatraemia is usual

*        Hepatic encephalopathy is commonly present

*        Blood pressure is reduced compared with previous pressures recorded in patient

*        Pronounced oliguria

*        Low renal sodium concentration

*        Urinary protein and casts are minimal or absent


The typical patient is deeply jaundiced; is obviously moribund; and exhibits tense ascites, hypoalbuminemia and hypoprothrombinemia, and encephalopathy. As liver disease progresses, urine volume and sodium excretion fall, and serum creatinine and blood urea nitrogen (BUN) levels increase before death. In this setting, renal failure is incidental to the overwhelming liver disease. In perhaps 10% to 20% of patients, however, liver disease may be reasonably stable, and progressive renal failure represents the major threat to the patients life.


Although many diseases can affect the liver and kidney in tandem, the patient's history, oliguria, marked sodium retention, and presence of severe liver disease usually reduce the diagnostic possibilities to two: hepatorenal syndrome and prerenal azotemia. Because these two causes of renal failure are indistinguishable by common laboratory tests and physical signs, it is imperative that patients be initially treated as though they had prerenal azotemia. Diuretic medication should be discontinued, any blood loss replaced, and the plasma expanded with saline or glucose solutions. These steps should be taken carefully while the central venous pressure is being monitored, and they should be halted if diuresis does not commence when central venous pressure has been raised. Once the presence of prerenal azotemia has been excluded by these measures, treatment of the hepatorenal syndrome should be supportive and conservative. Spontaneous reversion of the syndrome, though infrequent, occurs when the liver disease begins to improve. Reversion of the hepatorenal syndrome after insertion of a peritoneovenous shunt has been reported. The shunt may be considered in the small percentage of patients with prominent renal failure. Life-threatening complications, however, would not be unusual in these patients. Emergency portacaval shunt, corticosteroids, phenoxybenzamine, metaraminol, and methyldopa have all been used without major benefit. Hepatorenal syndrome typically resolves after liver transplantation.


Hepatic encephalopathy can be roughly classified into four stages. The first stage consists of agitation without accompanying physical findings. Patients in this stage often receive sedatives that promptly deepen the encephalopathy. In the second stage, the patient is moderately obtunded but still responsive, and asterixis can be elicited. In the third stage, the patient is stuporous and barely responsive. In the fourth stage, the patient sinks into deep coma. Asterixis may be absent in the third and fourth stages.


The cause of hepatic encephalopathy is undoubtedly multifactorial. Elevated concentrations of blood ammonia, short-chain fatty acids, false neurotransmitters, and certain amino acids have all been implicated in the genesis of this syndrome. In addition, a circulating substance that has properties similar to those of benzodiazepine agonists and that can potentiate the action of ã-aminobutyric acid may be present in liver failure, contributing to the syndrome of hepatic encephalopathy. Some patients with hepatic encephalopathy appear to respond to the administration of a benzodiazepine receptor antagonist, supporting the hypothesis that a benzodiazepine-like substance may play a role in this disorder. Both the shunting of blood around the liver, as a consequence of portal hypertension, and poor function of the diseased liver contribute to the pathogenesis. In addition, the central nervous system of the patient with cirrhosis appears to be sensitive to sedative effects of endogenous products and exogenous medications. In most instances of hepatic encephalopathy, a precipitating cause can be identified. Initiating events include gastrointestinal bleeding, electrolyte abnormalities (e.g., hyponatremia and acid-base disorders), hypoxia, CO2 retention, infection, constipation, and the injudicious use of diuretics, sedatives, or other medications. In a few patients, refractory chronic encephalopathy may develop, often as a consequence of portosystemic shunting or TIPS.


The diagnosis of hepatic encephalopathy depends on documentation of mental obtundation, asterixis, and fetor hepaticus. Fetor hepaticus is an offensive, mixed feculent-fruity odor of the breath. Asterixis, the irregular flexion of the extremities, is most easily elicited by asking a patient to hold his or her arms horizontally with hands extended at the wrist. The flapping motion caused by intermittent loss of extensor tone clearly marks hepatic encephalopathy, although asterixis may also develop in patients with uremia or severe pulmonary disease. Slowing or flattening of waves on an electroencephalogram verifies encephalopathy.



*    Identify the precipitating factors

*    Stop diuretics

*    Check serum Na+, K+, and urea concentration

*    Empty bowels of nitrogen containing content

*    Control bleeding

*    Proteinfree diet

*    Lactulose

*    Neomycin (1 g four times a day by mouth for 1 week)

*    Maintain energy, fluid, and electrolyte balance

*    Increase dietary protein slowly with recovery

The most important aspect of therapy is removal or correction of precipitating causes. The medication chart should be scrupulously searched for sedatives, which should be discontinued. Once these measures have been undertaken, standard therapy for hepatic encephalopathy includes dietary protein restriction to reduce production of endogenous nitrogenous substances, such as ammonia, and administration of lactulose. The usual approach restricts dietary protein to 40 to 60 g/day. Long-term restriction to much less than 60 g/day results in protein malnutrition. The drug of choice is lactulose, a disaccharide that travels undigested to the colon, where it undergoes bacterial degradation to two- and three-carbon acids that reduce the intraluminal pH level and produce diarrhea. The usual dosage is 30 ml three or four times a day. The mechanism of action of lactulose is uncertain. Apparently, the reduced stool pH level causes ammonia to be protonated to its ionic form (NH4), which is poorly absorbed and is excreted in the stool. Lactulose has proved to be as effective as neomycin in the treatment of chronic or recurrent hepatic encephalopathy. Approximately 80% of patients respond to one of these drugs.65 In certain patients, neomycin may be effective when lactulose is not. The usual dosage of neomycin is 500 mg or 1 g given orally every 6 hours. Although neomycin is poorly absorbed from the intestine, ototoxicity and renal damage have occurred. Because lactulose is less toxic than neomycin, it should be tried first. Although it may appear theoretically that neomycin would interfere with lactulose, evidence indicates that the two drugs may act synergistically. Lactulose and neomycin are effective for patients with chronic or recurrent encephalopathy, but the benefit is less certain for those with the encephalopathy that accompanies acute overwhelming hepatic disease. Metronidazole, 250 mg three or four times a day, can be used as an alternative to neomycin, but longterm therapy may be associated with neurotoxicity.


Almost all patients with advanced liver disease have varying degrees of protein-calorie malnutrition. Severe malnutrition contributes to salt and water retention, defective immune response, and delayed recovery of liver function. A nutritional assessment should be done for all patients with advanced liver disease, and nutritional supplements should be provided when necessary. Nutritional supplementation can be accomplished by the addition of standard enteral formulas to the diet; in some critically ill patients, nutritional supplementation needs to be provided parenterally. There is little evidence that formulas enriched with branched-chain amino acids have any advantage over standard amino acid formulas, and they are considerably more expensive. These supplements are well tolerated, whether given orally or parenterally. The expected result is a more rapid return to positive nitrogen balance and improved liver function. No convincing improvement in survival has been demonstrated.

miscellaneous complications

The incidence of gallstones is increased in patients with cirrhosis, possibly because of the elevated bilirubin load generated by chronic hemolytic anemia and hypersplenism. Hence, the possibility of a common duct stone should be considered in patients with cirrhosis and jaundice. Peptic ulcer occurs more commonly in patients with cirrhosis than in the general population. The diagnosis should be considered if abdominal pain or upper gastrointestinal bleeding develops. Hypoxia is frequent in patients with advanced cirrhosis, and oxygen tension (PO2) values of 60 to 70 mm Hg are not uncommon. Ascites impairs ventilation, and pulmonary angiomas may be responsible for right-to-left shunting of blood. Because many cirrhotic patients both drink and smoke, chronic obstructive pulmonary disease often complicates the picture. Primary liver cell cancer develops in 5% to 20% of patients with cirrhosis. If left untreated, the disease follows a rapidly progressive course

Liver Transplantation

The widespread availability of liver transplantation has substantially improved the prognosis for almost all forms of end-stage liver disease. Because 1-year and 5-year survival rates after transplantation approach 90% and 80%, respectively, at several centers, this form of treatment is widely accepted. Patients who have advanced cirrhosis with the onset of complications are candidates for liver transplantation. Clinical, biochemical, psychosocial, and financial information is reviewed to determine whether global selection criteria are met. There are a number of clinical and biochemical indications for liver transplantation. Generally accepted absolute contraindications to liver transplantation include seropositivity for HIV, extrahepatic malignancy, active untreated sepsis, advanced cardiopulmonary disease, and active alcoholism or substance abuse. The major restriction of liver transplantation is the limited supply of donor organs. Approximately 4,500 people underwent liver transplantation in the United States in 1998 and 1999, though more than 15,000 were approved and on the waiting list.



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