MANAGEMENT OF PATIENT WITH HEPATOLIENAL SYNDROME

MANAGEMENT OF PATIENT WITH PORTAL HYPERTENSION

MANAGEMENT OF PATIENT WITH ASCITES

 

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.

 

10011

 

10007

 

10009

 

Post mortem specimen of cirrhotic liver and enlarged spleen

 

Post mortem specimen of banded oesophageal varix

LIVER CIRRHOSIS

 

 


CLASSIFICATION (etiological
)

*                Viral

*                Alcoholic

*                Toxic

*                Autoimmune

*                Metabolic

*                ongestive

*                Biliary

*                Cryptogenic Hepatitis

CLASSIFICATION according to

DEGREE OF PROGRESS AND PROCESS ACTIVITY

I.                              ACTIVE:

-                     Quickly progressive

-                     Slowly progressive

-                     Latent

. UNACTIVE

 

CLASSIFICATION according to
Child - Turcotte and Pugh

 

 

Parameter

Class A

Compensation

(5-6 points)

Class B

Subcompensation (7-9 points)

Class C

Decompensation (10 and >points)

 

 

 

 

Bilirubin, mcmol/l

<35

35-55

>55

Albumine, g/l

>35

30-35

<30

Prothrombin time

60-80%

40-59%

<40%

Ascites

absent

treatable

untreatable

Encephalopathy

absent

1-2 st.

3-4 st.

Points:

1

2

3

OMPLICATIONS

 

*                HEPATIC ENCEPHALOPATHY

*                VARICEAL BLEEDING

*                ASCITES

*                HEPATORENAL SYNDROME

*                PORTAL VEIN TROMBOSIS

*                BACTERIAL PERITONITIS

*                HEPATOCARCINOMA

*                 

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

 

Intra-abdominal Fluid - Sonography

 

 

Specific Forms of Cirrhosis

 

ALCOHOLIC 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.

Etiology

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

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.

 

Laboratory tests.

In patients with decompensated alcoholic cirrhosis, the serum bilirubin level is elevated, often markedly (20 to 40 mg/dl). The serum aspartate aminotransferase (AST) level is usually elevated, perhaps to as high as 200 to 300 IU/L. Characteristically, the AST level is more abnormal than the alanine aminotransferase (ALT) level. Reversal of this relation or the presence of aminotransferase levels above 300 IU/L suggests that the diagnosis may not be alcoholic liver disease. The alkaline phosphatase level is often moderately elevated. Reduction of the serum albumin level to below 3.5 g/dl and prolongation of the prothrombin time are common.

Treatment

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.4 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.

PRIMARY BILIARY CIRRHOSIS

Primary biliary cirrhosis is a chronic and progressive cholestatic disease of the liver. The etiology is unknown, although it is presumed to be autoimmune in nature. The major pathology of this disease is a destruction of the small-to-medium bile ducts, which leads to progressive cholestasis and often end-stage liver disease.

In 1851, Addison and Gull described the clinical picture of progressive obstructive jaundice in the absence of mechanical obstruction of the large bile ducts. In 1950, Ahrens and colleagues named this disease primary biliary cirrhosis. The term is controversial because cirrhosis only develops late in the course of the disease.

Primary biliary cirrhosis is most frequently a disease of women and occurs between the fourth and sixth decades of life. The symptoms may strongly affect patients' quality of life and may induce incapacitation. Various therapeutic approaches have been implemented with variable results; in selected candidates, liver transplantation is the only treatment option for the terminal stages of the disease. After the procedure, the disease has a relatively high recurrence rate despite immunosuppressive therapy.

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.

Scheme pathogenesis of primary biliary cirrhosis

 

The exact mechanism of the liver damage is unknown, although evidence indicates that it can be of autoimmune origin. The data supporting this hypothesis are as follows: (1) abnormalities of the humoral and cellular immune systems (ie, elevated serum levels of immunoglobulins, mainly immunoglobulin M [IgM]), (2) multiple circulating autoantibodies, (3) granulomas in the liver and regional lymph nodes, (4) impaired regulation of both B and T lymphocytes, and (5) the association of this disease with a variety of autoimmune-mediated diseases (eg, autoimmune thyroiditis; keratoconjunctivitis sicca; scleroderma; calcinosis cutis, Raynaud phenomenon, esophageal motility disorder, sclerodactyly, and telangiectasia [CREST] syndrome).

A continuous destruction of small and medium bile ducts occurs, which is mediated by activated CD4 and CD8 lymphocytes. As a result, chronic cholestasis is the prominent clinical and laboratory finding. Once destroyed, it is well established that regeneration of bile ducts is either not possible or inefficient.

Subsequent to the loss of the intrahepatic bile ducts, a disruption of the normal bile flow occurs with retention and deposition of toxic substances, which are normally excreted into bile. The retention of toxic substances, such as bile acids and copper, can cause a further secondary destruction of the bile ducts and the hepatocytes. In addition, increased expression of the HLA class II antigens in the liver occurs, rendering hepatocytes and bile duct epithelial cells more susceptible to activated T lymphocytes and perhaps exacerbating immunologically mediated cytotoxicity. An association has been suggested between primary biliary cirrhosis and haplotype HLA-DR8 and, for some populations, HLA-DPB1.

In a controlled, interview-based study of 1032 patients, Gershwin et al noted that in genetically susceptible persons, environmental factors, including chemicals found in cigarette smoke and infectious agents introduced through urinary tract infections, may induce primary biliary cirrhosis. The authors stated that exogenous estrogens may also contribute to the disease's development and that this may help to explain why the disease occurs more frequently in females than in males.

Diagnosis

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.

Treatment

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.

Prognosis

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.

Diagnosis

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.

http://www.drbhandari.com/GNMS_WEB_PAGES/images/biopsy_of_liver.gif

http://www.natap.org/2007/images/100507/liver-2.gif

 

 

 

 

Treatment

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

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

In half of patients with Wilson disease symptoms first appear in adolescence, only in 1% of patients the onset is after 50 years.

Classic triad of symptoms in Wilson disease is:

1.                 Liver. Are the first events that occur, but are not specific for Wilson disease. Thus, there are, hepatomegaly, splenomegaly, jaundice, vascular asterisks, ascites and other complications of cirrhosis. Acute fulminant hepatitis with hemolytic anemia is another way that disease can onset, with progressive jaundice, ascites, liver and kidney failure. The phenomenon is similar to acute copper poisoning, the prognosis is severe and death occurs within days.

2.                 Neuropsychological. Occur in young adults and are represented by coreiform movements, Parkinsons syndrome, tremors which are worse in deliberate moves. Mental changes may occur suddenly and are manifested by the mismatch in the community, deterioration of intellectual capacity. More rarely may appear: anxiety or schizophrenic events.

3.                 Eye. Is due to the deposit of copper at the periphery of the cornea and appears as a gray-brown color ring or greenish ring called Kayser-Fleischner ring.

http://www.doctortipster.com/wp-content/uploads/2011/07/Wilson-disease.gif

 

Etiology and Genetics

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.

Diagnosis

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

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

Alpha1-antitrypsin (AAT) deficiency, first described in 1963, is one of the most common inherited disorders among white persons. Its primary manifestation is early-onset panacinar emphysema. About 1-3% of patients with diagnosed (COPD) are predicted to have alpha1-antitrypsin deficiency. Slowly progressive dyspnea is the primary symptom, though many patients initially have symptoms of cough, sputum production, or wheezing.

Causes

Alpha1-antitrypsin deficiency is an uncommon but not rare disease. It is under diagnosed. The responsible genetic defect affects 1 in 3000-5000 individuals, making it 1 of the 3 most common lethal genetic diseases among whites. (The other 2 common fatal genetic defects are cystic fibrosis and Down syndrome ) Fortunately, not every individual with alpha1-antitrypsin deficiency develops clinically significant disease.

The major biochemical activity of the alpha1-antitrypsin molecule is inhibition of several neutrophil-derived proteases (eg, trypsin, elastase, proteinase 3, cathepsin G). Therefore, the protein is more accurately termed alpha1-antiprotease. However, most physicians, and virtually all patients, refer to the disease as alpha1-antitrypsin deficiency, and doctors and patients often refer to those who are affected as "alphas."

Hepatocytes synthesize alpha1-antiprotease. After its release from the liver, alpha1-antiprotease circulates unbound and diffuses into interstitial and alveolar lining fluids. Its principle function in the lung is to inactivate neutrophil elastase, an enzyme that is released during normal phagocytosis of organisms or particulates in the alveolus.

Alpha1-antiprotease constitutes about 95% of all the antiprotease activity in human alveoli, and neutrophil elastase is considered the protease largely responsible for alveolar destruction. In patients with the Z allele, the alpha1-antitrypsin produced has a lysine substituted for glutamate. This results in spontaneous polymerization within the endoplasmic reticulum of the hepatocyte, which leads to decreased serum levels of alpha1-antitrypsin and thus a deficiency of peripheral alpha1-antitrypsin.

Additionally, the accumulation of intrahepatic alpha1-antitrypsin is thought to result in apoptosis of hepatocytes. This initially can manifest as laboratory abnormalities, but also can progress to hepatitis, followed by fibrosis and cirrhosis.

In healthy persons, alpha1-antiprotease serves as a protective screen that prevents alveolar wall destruction. The lungs have a large surface area and are continuously exposed to a high burden of airborne pathogens, which results in a cellular immune response. This is characterized by local release of oxidants and proteases. The presence of alpha1-antiprotease serves to keep these proteases in check and protect the lungs from unregulated protease activity. Individuals with the alpha1-antitrypsin genetic defect do not release alpha1-antiprotease from the liver, and serum and alveolar levels of the protein are low. Consequently, alveoli lack antiprotease protection. The imbalance of proteases-antiproteases in the alveolus leads to unimpeded neutrophil elastase digestion of elastin and collagen in the alveolar walls and progressive emphysema.

Alveolar cell apoptosis may also play an important role in emphysema pathogenesis. Recent evidence suggests that alpha1-antiprotease may inhibit alveolar cell apoptosis and protect against emphysema in the absence of neutrophilic inflammation.

Cigarette smoking accelerates the onset of symptomatic disease by approximately 10 years by increasing the number of neutrophils (and neutrophil elastase) in the alveolus and inactivating the remaining small amounts of antiprotease. Other factors that can accelerate the onset or worsen symptoms of disease include infections and exposures to dust and fumes, which can also cause the recruitment of neutrophils to the alveoli.

Other than cigarette smoking, the role of environmental exposures on spirometric decline in patients with alpha1-antitrypsin deficiency has been uncertain. Banauch et al investigated the possible interaction of alpha1-antitrypsin deficiency and short-term massive pollution in New York City Fire Department (FDNY) rescue workers responding to the World Trade Center (WTC) collapse. In the first 4 years after the event, they found significant accelerated declines in spirometry and increased respiratory symptoms. Declines were related to the degree of exposure at the disaster site and to the degree of alpha1-antitrypsin deficiency. These results support the theory that environmental factors other than cigarette smoke may play a role in the progression of lung disease in alpha1-antitrypsindeficient patients. However, the size of the study was very small, and care should be taken in generalizing this theory given the unique nature of the WTC disaster. Further studies are needed.

The production of alpha1-antiprotease is controlled by a pair of genes at the protease inhibitor (Pi) locus. The SERPINA1 (formerly known as Pi) gene responsible for encoding alpha1-antitrypsin is located on chromosome 14 and is highly pleomorphic, with more than 100 allelic variants. The variants are classified based on serum levels of alpha1-antitrypsin protein. M alleles are the most common and normal variants. Most patients with clinical disease are homozygous SS or ZZ or heterozygous MS, MZ, or SZ.

Nearly 24 variants of the alpha1-antiprotease molecule have been identified, and all are inherited as codominant alleles. The most common (90%) allele is M (PiM), and homozygous individuals (MM) produce normal amounts of alpha1-antiprotease (serum levels of 20-53 mol/L or 150-350 mg/dL).

The most common form of alpha1-antitrypsin deficiency is associated with allele Z, or homozygous PiZ (ZZ). Serum levels of alpha1-antitrypsin in these patients are about 3.4-7 mol/L, 10-15% of normal serum levels. Serum levels greater than 11 mol/L appear to be protective. Emphysema develops in most (but not all) individuals with serum levels less than 9 mol/L.

Other genotypes associated with severe alpha1-antitrypsin deficiency include PiSZ, PiZ/Null, and PiNull. The S gene is more frequent among individuals of Spanish or Portuguese descent, whereas the frequency of the Z gene is highest in patients of Northern or Western European descent.

Patients with the PiSZ phenotype have a 20-50% increased likelihood of developing emphysema compared with MM homozygotes. Serum levels of patients with PiSZ alpha1-antitrypsin deficiency are 75-120 mg/dL.

Patients with the null gene for alpha1-antitrypsin will not produce any alpha1-antitrypsin and are high risk for emphysema (100% by the age of 30 y). None with the null gene develop liver disease because of a lack of production, and thus accumulation, of alpha1-antitrypsin in the hepatocytes. The null gene is the least common of the known alleles associated with alpha1-antitrypsin deficiency.

Carriers or heterozygotes (MZ, MS or M/Null) have levels approximately 35% of normal levels, but they do not develop disease.

The genetic defect in alpha1-antitrypsin (AAT) deficiency alters the configuration of the alpha1-antitrypsin molecule and prevents its release from hepatocytes. As a result, serum levels of alpha1-antitrypsin are decreased, leading to low alveolar concentrations, where the alpha1-antitrypsin molecule normally would serve as protection against antiproteases. The resulting protease excess in alveoli destroys alveolar walls and causes emphysema. The accumulation of excess alpha1-antitrypsin in hepatocytes can also lead to destruction of these cells and ultimately, clinical liver disease.

Epidemiology

Alpha1-antitrypsin (AAT) deficiency is 1 of the 3 most common lethal genetic diseases among adult white persons, affecting 1 per 3000-5000 individuals. Severe alpha1-antitrypsin deficiency affects an estimated 100,000 individuals, and approximately 25 million people carry of at least 1 deficient gene. However, less than 6% of severely deficient individuals are currently identified.

Alpha1-antitrypsin deficiency has been identified in all populations, but it is most common in individuals of Northern European and Iberian descent. Similar rates are found among white persons worldwide, with an estimated 117 million carriers and 3.4 million affected individuals.

 

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.

 

Clinical picture

Symptoms of alpha1-antitrypsin (AAT) deficiency emphysema are limited to the respiratory system.

The initial symptoms of alpha1-antitrypsin deficiency include cough, sputum production, and wheezing. Symptoms are initially intermittent, and, if wheezing is the predominant symptom, patients often are told they have asthma. If recurrent episodes of cough are most prominent, patients may be treated with multiple courses of antibiotics and evaluated for sinusitis, postnasal drip, or gastroesophageal reflux.

Dyspnea is the symptom that eventually dominates alpha1-antitrypsin deficiency.

Similar to other forms of emphysema, the dyspnea of alpha1-antitrypsin deficiency is initially evident only with strenuous exertion. Over several years, it eventually limits even mild activities.

Patients with alpha1-antitrypsin deficiency frequently develop dyspnea 20-30 years earlier (at age 30-45 y) than do smokers with emphysema and normal alpha1-antitrypsin levels.

By the time dyspnea becomes the dominant manifestation and a diagnosis is established, most patients will have seen several physicians over several years. Efforts to improve the interval between the onset of symptoms and the diagnosis of alpha1-antitrypsin deficiency have been disappointing. Between 1968 and 2003 a significant improvement has not been noted in the average interval (approximately 8 y), although improvement has been shown in the alpha1-antitrypsin deficiency detection in older individuals

No single physical sign confirms a diagnosis of alpha1-antitrypsin deficiency emphysema. Signs characteristic of increased respiratory work, airflow obstruction, and hyperinflation eventually develop but are dependent on the severity of emphysema at the time of diagnosis.

Increased respiratory work is evident as tachypnea, scalene and intercostal muscle retraction, and tripod position.

Airflow obstruction manifests as pursed-lip breathing, wheezing, and pulsus paradox.

Hyperinflation results in barrel chest, increased percussion note, decreased breath sound intensity, and distant heart sounds.

Patients with mild emphysema generally have no abnormal findings on physical examination. Even moderate disease may be evident only when a complicating acute infection occurs. Most of the signs generally considered a part of emphysema (from any cause) are signs of moderate-to-severe disease. Mild-to-moderate disease is easily missed if the physician relies solely on physical findings.

Methods of investigations

Used to identify disease and determine serum alpha1-antitrypsin (AAT) levels.

Testing is readily available in most clinical laboratories and is inexpensive and underutilized. The AAT Deficiency Task Force of the American Thoracic Society (ATS) and European Respiratory Society (ERS) has published standards aimed at improving clinical recognition of alpha1-antitrypsin deficiency and avoiding underrecognition or misdiagnosis.

Clinical features that suggest the possibility of alpha1-antitrypsin deficiency and the need for serum testing include emphysema at an early age (age of 45 y or less), emphysema in a patient with the absence of a recognized risk factor like smoking or occupational dust exposure, emphysema of the lower lungs, asthma with persistent airflow obstruction after treatment, unexplained liver disease, necrotizing panniculitis, antiproteinase 3-positive vasculitis (antineutrophil cytoplasmic antibody [C-ANCA]positive vasculitis), bronchiectasis without a clear etiology and a family history of emphysema, bronchiectasis, liver disease, or panniculitis. Serum testing is used for diagnostic testing and predispositional testing as in those patients with family histories compatible with alpha1-antitrypsin deficiency or with siblings with known alpha1-antitrypsin deficiency. However, guidelines from the ATS/ERS AAT Deficiency Task Force do not recommend predispositional fetal testing or population screening unless the prevalence of alpha1-antitrypsin deficiency is high (>1 case per 1500 population), smoking is prevalent, and adequate counseling services are available.

Most hospital laboratories report serum alpha1-antitrypsin levels in milligrams per decimeter, with a reference range of approximately 100-300 mg/dL. Levels less than 80 mg/dL suggest a significant risk for lung disease.

Reference laboratories usually report the serum levels in micromolar concentration, with a reference range of 20-60 mol/L and a threshold level for emphysema at 11 mol/L.

Test patients with low or borderline serum levels with phenotyping (serum levels < 100 mg/dL). Use an experienced reference laboratory for this test. Phenotyping with dried blood-spot samples, by using a blood drop absorbed on special paper, permits easier transport of samples and is suitable for screening purposes, but the identification of a deficient variant should be confirmed with serum or plasma samples.

Patients and healthcare providers can obtain a free Alpha-1 Test Kit (finger-stick test) from the Alpha-1 Research Registry at (877) 886-2383, which is associated with the Alpha-1 Assosiation The test sample can be submitted directly to the Registry at the Medical University of South Carolina. The test screens for the most common Z and S genotypes. If more extensive testing is needed to determine an alpha1-antitrypsin level, both patient and physician are notified. There is no charge for the Alpha-1 Screening Program.

Phenotyping is required to confirm alpha1-antitrypsin deficiency. Do not initiate alpha1-antitrypsin replacement therapy without testing.

More than 100 phenotypic variants of alpha1-antitrypsin deficiency have been identified, but 1 phenotype, PiZZ, is responsible for nearly all cases of AAT deficiency emphysema and liver disease. PiZZ phenotype serum levels range from 3.4-7 mol/L, about 10-20% of the reference range levels. Other phenotypes associated with alpha1-antitrypsin emphysema and liver disease include PiSZ and PiZ/Null. PiNull/Null is not associated with liver disease but is associated with alpha1-antitrypsin deficiency emphysema.

In rare circumstances, a third test is used to evaluate a patient with clinical features that are highly suggestive of alpha1-antitrypsin deficiency but whose serum levels are within the reference range.

Specialized laboratories can perform a functional assay of alpha1 antiprotease, which measures the ability of the patient's serum to inhibit human leukocyte elastase. Such a defect is extremely rare.

Diagnosis at a molecular level (ie, genotyping) uses DNA extracted from circulating mononuclear blood cells. Test kits capable of detecting S and Z alleles on samples from mouth swabs have made genetic testing easier. These tests will, however, miss the rare null alleles.

Evaluate hepatic function in patients with low or borderline levels of alpha1-antitrypsin. Measure serum transaminases, bilirubin, albumin, and routine clotting function (activated partial thromboplastin time and international normalized ratio

Chest ratiography

Alpha1-antitrypsin deficiency emphysema produces a hyperlucent appearance because healthy tissue has been destroyed.

The process is not uniform; certain areas are affected more than others.

Affected regions also are described as oligemic because they lack the normal rich pattern of branching blood vessels.

An unusual characteristic in alpha1-antitrypsin deficiency is found in about two thirds of PiZZ patients; the emphysema has a striking basilar distribution. In contrast, cigarette smoking is associated with more severe apical disease.

Close-up chest radiograph of the right lower zone

Close-up chest radiograph of the right lower zone of a 39-year-old woman with alpha1-antitrypsin (AAT) deficiency. Normal lung markings are absent in the costophrenic angle. Some lung markings are present in the pericardiac region, but even these are diminished.

High-resolution CT (HRCT) scanning of the chest demonstrates widespread abnormally hypoattenuating areas resulting from a lack of lung tissue. As in smoking-related emphysema, the appearance has been described as a simplification of lung architecture. As tissue is lost, pulmonary vessels appear smaller, fewer in number, and spread farther apart.

Mild forms of alpha1-antitrypsin disease can be missed on HRCT scanning. However, when the disease is moderate, discerning the panlobular nature of the process and the characteristic lower zone predominance is possible.

Severe forms may be indistinguishable from severe centrilobular emphysema.

CT scan of the right middle and right lower lobes

CT scan of the right middle and right lower lobes in a 38-year-old patient with alpha1-antitrypsin (AAT) deficiency. Entire middle lobe and much of the lower lobe are emphysematous; normal lung structures have been replaced by abnormal airspaces. Only the posterior portions of the right lower lobe maintain a normal architecture.

Complications of Cirrhosis

varices

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

10403

 

Diagnosis

 

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.

 

scites

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.

 

Treatment

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.

Paracentesis

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.

http://id3475.securedata.net/globalrph/2009/albumin.gif

 

http://jama.jamanetwork.com/data/journals/jama/4408/m_jpg0312f1.jpeg

Figure. Abdominal paracentesis

 

 

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

 

Spontaneous bacterial peritonitis (SBP) is an acute bacterial infection of ascitic fluid. Generally, no source of the infecting agent is easily identifiable, but contamination of dialysate can cause the condition among those receiving peritoneal dialysis (PD).

Spontaneous bacterial peritonitis occurs in both children and adults and is a well-known and ominous complication in patients with cirrhosis. Of patients with cirrhosis who have spontaneous bacterial peritonitis, 70% are Child-Pugh class C. In these patients, the development of spontaneous bacterial peritonitis is associated with a poor long-term prognosis.

Once thought to occur only in those individuals with alcoholic cirrhosis, spontaneous bacterial peritonitis is now known to affect patients with cirrhosis from any cause. In addition, spontaneous bacterial peritonitis can occur as a complication of any disease state that produces the clinical syndrome of ascites, such as heart failure and Budd-Chiari syndrome . Children with nephrosis or systemic lupus erythematosus who have ascites have a high risk of developing spontaneous bacterial peritonitis.

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.

http://eso-cdn.bestpractice.bmj.com/best-practice/images/bp/en-gb/793-1-hlight_default.jpg

Abdominal ultrasound showing large amount of ascites with bowel loops

 

Etiology

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.

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 polymicrobial.

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.

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.

 

 

DIAGNOSIS

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.

Treatment

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.

HEPATORENAL SYNDROME

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

Diagnosis

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.

Treatment

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

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.

Etiology

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.

Diagnosis

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.

HEPATIC ENCEPHALOPATHY (Classification)

Treatment

*                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.

malnutrition

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

 

http://transplant.surgery.ucsf.edu/media/2942315/ucsf044_liveranatomy_562x525.jpg

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.

 

http://www.discoverymedicine.com/Saleh-A-Alqahtani/files/2012/08/discovery_medicine_no_75_saleh_a_alqahtani_table_1.png

 

References.

1.       Davidson's Principles and Practice of Medicine / Edited by  Nicki R. Colledge,    Brian R. Walker ,   Stuart H. Ralston, 1st Edition. - - Philadelphia : Churchill Livingstone, 2010. 1376 p.

 

2. Harrison's Principles of Internal Medicine. Dan L.Longo M.D. New York : McGraw-Hill, 2012. 4012p.

 3. Harrisons Principles of Internal Medicine Self-Assessment and Board Review /

Charles M. WienerAnthony S. Fauci, Eugene BraunwaldDennis L. Kasper, Stephen L. HauserDan L. Longo, J.Larry Jameson, Joseph Loscalzo, Cynthia Brown, 18th Revised edition. New York : McGraw-Hill Education - Europe, 2012. 512 p

4. The Merck Manual of Diagnosis and Therapy / Edited by Robert S. Porter., 19th Revised edition. - London : Elsevier Health Sciences, 2011. 3754 p.

5. Kumar and Clark's Clinical Medicine (With STUDENTCONSULT Online Access) / Edited by Parveen Kumar, Michael L. Clark, 8th Revised edition. London : Elsevier Health Sciences, 2012. 1304 p.

 

6.      Textbook of Clinical Gastroenterology and Hepatology (2nd Revised edition) /

Edited by C. J. Hawkey, Jaime Bosch, Joel E. Richter, Guadalupe Garcia-Tsao, Francis K. L. Chan. Chicester : John Wiley and Sons Ltd, 2012. 1272 p.

 

7. Oxford Handbook of Gastroenterology and Hepatology (2nd Revised edition). Stuart Bloom, George WebsterDaniel Marks. Oxford : Oxford University Press, 2012. 648 p.

8. Harrison's Gastroenterology and Hepatology (1th edition). Dan L. LongoAnthony S. Fauci. - New York : McGraw-Hill Education - Europe, 2010. - 752 p.

9. Mayo Clinic Gastroenterology and Hepatology Board Review (4th Revised edition). Stephen Hauser. Oxford : Oxford University Press Inc., 2011. 480 p